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Lawler, Patrick R., Akintunde O. Akinkuolie, Paulette D. Chandler, et al. "Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk." Circulation Research 118, no. 7 (2016): 1106–15. http://dx.doi.org/10.1161/circresaha.115.308078.
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Kasher, Melody, Maxim B. Freidin, Frances M. K. Williams, Stacey S. Cherny, Shai Ashkenazi, and Gregory Livshits. "Glycoprotein Acetyls Is a Novel Biomarker Predicting Cardiovascular Complications in Rheumatoid Arthritis." International Journal of Molecular Sciences 25, no. 11 (2024): 5981. http://dx.doi.org/10.3390/ijms25115981.
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The relationship between rheumatoid arthritis (RA) and early onset atherosclerosis is well depicted, each with an important inflammatory component. Glycoprotein acetyls (GlycA), a novel biomarker of inflammation, may play a role in the manifestation of these two inflammatory conditions. The present study examined a potential mediating role of GlycA within the RA–atherosclerosis relationship to determine whether it accounts for the excess risk of cardiovascular disease over that posed by lipid risk factors. The UK Biobank dataset was acquired to establish associations among RA, atherosclerosis, GlycA, and major lipid factors: total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TGs). Genome-wide association study summary statistics were collected from various resources to perform genetic analyses. Causality among variables was tested using Mendelian Randomization (MR) analysis. Genes of interest were identified using colocalization analysis and gene enrichment analysis. MR results appeared to indicate that the genetic relationship between GlycA and RA and also between RA and atherosclerosis was explained by horizontal pleiotropy (p-value = 0.001 and <0.001, respectively), while GlycA may causally predict atherosclerosis (p-value = 0.017). Colocalization analysis revealed several functionally relevant genes shared between GlycA and all the variables assessed. Two loci were apparent in all relationships tested and included the HLA region as well as SLC22A1. GlycA appears to mediate the RA–atherosclerosis relationship through several possible pathways. GlycA, although pleiotropically related to RA, appears to causally predict atherosclerosis. Thus, GlycA is suggested as a significant factor in the etiology of atherosclerosis development in RA.
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Saner, Christoph C. S., Brooke B. H. Harcourt, Melissa M. W. Wake, et al. "Glycoprotein acetyls (GlycA) associate with BMI and co-morbidities in childhood obesity." Obesity Research & Clinical Practice 13, no. 3 (2019): 292–93. http://dx.doi.org/10.1016/j.orcp.2018.11.164.
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Chandler, Paulette D., Akintunde O. Akinkuolie, Deirdre K. Tobias, et al. "Association of N-Linked Glycoprotein Acetyls and Colorectal Cancer Incidence and Mortality." PLOS ONE 11, no. 11 (2016): e0165615. http://dx.doi.org/10.1371/journal.pone.0165615.
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Lahti-Pulkkinen, Marius, Polina Girchenko, Rachel Robinson, et al. "Maternal depression and inflammation during pregnancy." Psychological Medicine 50, no. 11 (2019): 1839–51. http://dx.doi.org/10.1017/s0033291719001909.
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BackgroundMaternal depression during pregnancy increases the risk for adverse developmental outcomes in children. However, the underpinning biological mechanisms remain unknown. We tested whether depression was associated with levels of and change in the inflammatory state during pregnancy, if early pregnancy overweight/obesity or diabetes/hypertensive pregnancy disorders accounted for/mediated these effects, and if depression added to the inflammation that typically accompanies these conditions.MethodsWe analyzed plasma high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls at three consecutive stages during pregnancy, derived history of depression diagnoses before pregnancy from Care Register for Healthcare (HILMO) (N = 375) and self-reports (N = 347) and depressive symptoms during pregnancy using the Center for Epidemiological Studies Depression Scale completed concurrently to blood samplings (N = 295). Data on early pregnancy body mass index (BMI) and diabetes/hypertensive pregnancy disorders came from medical records.ResultsHigher overall hsCRP levels, but not change, during pregnancy were predicted by history of depression diagnosis before pregnancy [HILMO: mean difference (MD) = 0.69 standard deviation (s.d.) units; 95% confidence interval (CI) 0.26–1.11, self-report: MD = 0.56 s.d.; 95% CI 0.17–0.94] and higher depressive symptoms during pregnancy (0.06 s.d. per s.d. increase; 95% CI 0.00–0.13). History of depression diagnosis before pregnancy also predicted higher overall glycoprotein acetyls (HILMO: MD = 0.52 s.d.; 95% CI 0.12–0.93). These associations were not explained by diabetes/hypertensive disorders, but were accounted for and mediated by early pregnancy BMI. Furthermore, in obese women, overall hsCRP levels increased as depressive symptoms during pregnancy increased (p = 0.006 for interaction).ConclusionsDepression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity.
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Prokić, Ivana, Lies Lahousse, Vries Maaike de, et al. "A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease." BMC Pulmonary Medicine 20, no. 1 (2020): 193. https://doi.org/10.1186/s12890-020-01222-7.
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<strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.<strong>Methods: </strong>We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.<strong>Results: </strong>There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, <i>P</i> = 5.6 × 10<sup>− 4</sup> in the discovery and OR = 1.30, <i>P</i> = 1.8 × 10<sup>− 6</sup> in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20).<strong>Conclusions: </strong>Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.
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Bizzarri, Daniele, Martijn E. T. Dollé, Bette Loef, Erik B. van den Akker, and Linda W. M. van Kerkhof. "GlycA, a Biomarker of Low-Grade Inflammation, Is Increased in Male Night Shift Workers." Metabolites 12, no. 12 (2022): 1172. http://dx.doi.org/10.3390/metabo12121172.
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Sustained night shift work is associated with various adverse health risks, including an increased risk of cardiovascular disease, type II diabetes, and susceptibility to infectious respiratory diseases. The extent of these adverse health effects, however, seems to greatly vary between night shift workers, yet the underlying reasons and the mechanisms underlying these interindividual differences remain poorly understood. Metabolomics assays in the blood have recently gained much attention as a minimally invasive biomarker platform capturing information predictive of metabolic and cardiovascular diseases. In this cross-sectional study, we explored and compared the metabolic profiles of 1010 night shift workers and 1010 age- and sex-matched day workers (non-shift workers) from the Lifelines Cohort Study. The metabolic profiles were determined using the 1H-NMR Nightingale platform for the quantification of 250 parameters of metabolism, including routine lipids, extensive lipoprotein subclasses, fatty acid composition, and various low-molecular metabolites, including amino acids, ketone bodies, and gluconeogenesis-related metabolites. Night shift workers had an increased BMI (26.6 vs. 25.9 kg/m2) compared with day workers (non-shift workers) in both sexes, were slightly more likely to be ever smokers (only in males) (54% vs. 46%), worked on average 5.9 ± 3.7 night shifts per month, and had been working in night shifts for 18.3 ± 10.5 years on average. We observed changes in several metabolic markers in male night shift workers compared with non-shift workers, but no changes were observed in women. In men, we observed higher levels of glycoprotein acetyls (GlycA), triglycerides, and fatty acids compared with non-shift workers. The changes were seen in the ratio of triglycerides and cholesterol(esters) to total lipids in different sizes of VLDL particles. Glycoprotein acetyls (GlycAs) are of particular interest as markers since they are known as biomarkers for low-grade chronic inflammation. When the analyses were adjusted for BMI, no significant associations were observed. Further studies are needed to better understand the relationship between night shift work and metabolic profiles, particularly with respect to the role of sex and BMI in this relationship.
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Jaurila, Henna, Vesa Koivukangas, Marjo Koskela, et al. "1H NMR Based Metabolomics in Human Sepsis and Healthy Serum." Metabolites 10, no. 2 (2020): 70. http://dx.doi.org/10.3390/metabo10020070.
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Early diagnosis is essential but challenging in severe sepsis. Quantifying and comparing metabolite concentrations in serum has been suggested as a new diagnostic tool. Here we used proton nuclear magnetic resonance spectroscopy (1H NMR) based metabolomics to analyze the possible differences in metabolite concentrations between sera taken from septic patients and healthy controls, as well as between sera of surviving and non-surviving sepsis patients. We took serum samples from 44 sepsis patients when the first sepsis induced organ dysfunction was found. Serum samples were also collected from 14 age and gender matched healthy controls. The samples were analyzed by quantitative 1H NMR spectroscopy for non-lipid metabolites. We found that the serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls (mostly alpha-1-acid glycoprotein, AGP) were significantly (p < 0.05) higher in sepsis compared to healthy sera, whereas citrate and histidine were significantly (p < 0.05) lower in sepsis patients compared to healthy controls. We found statistically significantly higher serum lactate and citrate concentrations in non-survivors compared to 30-day survivors. According to our study, 3-hydroxybutyrate, citrate, glycine, histidine, and AGP are candidates for further studies to enable identification of phenotype association in the early stages of sepsis.
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Collier, Fiona, Susan Ellul, Markus Juonala, et al. "Glycoprotein acetyls (GlycA) at 12 months are associated with high-sensitivity C-reactive protein and early life inflammatory immune measures." Pediatric Research 85, no. 5 (2019): 584–85. http://dx.doi.org/10.1038/s41390-019-0307-x.
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Kononoff, A., L. Arstila, H. Kautiainen, et al. "FRI0032 Patient Reported Outcomes Correlated with the Concentrations of Glycoprotein Acetyls in Patients with Early Untreated Rheumatoid Arthritis: Table 1." Annals of the Rheumatic Diseases 74, Suppl 2 (2015): 430.1–430. http://dx.doi.org/10.1136/annrheumdis-2015-eular.5579.
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Määttä, Anne-Mari, Aino Salminen, Milla Pietiäinen, et al. "Endotoxemia is associated with an adverse metabolic profile." Innate Immunity 27, no. 1 (2020): 3–14. http://dx.doi.org/10.1177/1753425920971702.
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Our aim was to analyze whether endotoxemia, i.e. translocation of LPS to circulation, is reflected in the serum metabolic profile in a general population and in participants with cardiometabolic disorders. We investigated three Finnish cohorts separately and in a meta-analysis ( n = 7178), namely population-based FINRISK97, FinnTwin16 consisting of young adult twins, and Parogene, a random cohort of cardiac patients. Endotoxemia was determined as serum LPS activity and metabolome by an NMR platform. Potential effects of body mass index (BMI), smoking, metabolic syndrome (MetS), and coronary heart disease (CHD) status were considered. Endotoxemia was directly associated with concentrations of VLDL, IDL, LDL, and small HDL lipoproteins, VLDL particle diameter, total fatty acids (FA), glycoprotein acetyls (GlycA), aromatic and branched-chain amino acids, and Glc, and inversely associated with concentration of large HDL, diameters of LDL and HDL, as well as unsaturation degree of FAs. Some of these disadvantageous associations were significantly stronger in smokers and subjects with high BMI, but did not differ between participants with different CHD status. In participants with MetS, however, the associations of endotoxemia with FA parameters and GlycA were particularly strong. The metabolic profile in endotoxemia appears highly adverse, involving several inflammatory characters and risk factors for cardiometabolic disorders.
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Fan, Bohan, and Jie V. Zhao. "Sex-Specific Associations of Red Meat and Processed Meat Consumption with Serum Metabolites in the UK Biobank." Nutrients 14, no. 24 (2022): 5306. http://dx.doi.org/10.3390/nu14245306.
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Red meat consumption has been found to closely related to cardiometabolic health, with sex disparity. However, the specific metabolic factors corresponding to red meat consumption in men and women have not been examined previously. We analyzed the sex-specific associations of meat consumption, with 167 metabolites using multivariable regression, controlling for age, ethnicity, Townsend deprivation index, education, physical activity, smoking, and drinking status among ~79,644 UK Biobank participants. We also compared the sex differences using an established formula. After accounting for multiple testing with false discovery rate < 5% and controlling for confounders, the positive associations of unprocessed red meat consumption with branched-chain amino acids and several lipoproteins, and the inverse association with glycine were stronger in women, while the positive associations with apolipoprotein A1, creatinine, and monounsaturated fatty acids were more obvious in men. For processed meat, the positive associations with branched-chain amino acids, several lipoproteins, tyrosine, lactate, glycoprotein acetyls and inverse associations with glutamine, and glycine were stronger in women than in men. The study suggests that meat consumption has sex-specific associations with several metabolites. This has important implication to provide dietary suggestions for individuals with or at high risk of cardiometabolic disease, with consideration of sex difference.
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Hartley, April, Diana L. Santos Ferreira, Emma L. Anderson, and Debbie A. Lawlor. "Metabolic profiling of adolescent non-alcoholic fatty liver disease." Wellcome Open Research 3 (December 28, 2018): 166. http://dx.doi.org/10.12688/wellcomeopenres.14974.1.
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Background:Adolescent non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic risk factors. The association between adolescent NAFLD and a wide range of metabolic biomarkers is unclear. We have attempted to determine the differences in metabolic profile of adolescents with and without markers of NAFLD.Methods:We performed cross-sectional analyses in a sample of 3,048 participants from the Avon Longitudinal Study of Parents and Children at age 17. We used three indicators of NAFLD: ALT >40 U/l; AST >40 U/l and ultrasound scan-assessed steatosis. Associations between each measure of NAFLD and 154 metabolic traits, assessed by Nuclear Magnetic Resonance, were analyzed by multivariable linear regression, adjusting for age, sex and BMI.Results:All three indicators of NAFLD were associated with ~0.5 standard deviation (SD) greater concentrations of all extremely large to small very low-density lipoproteins (VLDL) measures. ALT >40U/l was associated with ~0.5SD greater concentrations of very small VLDLs, intermediate-density lipoproteins and low-density lipoproteins. Concentrations of most cholesterols, including remnant cholesterol, all triglycerides and monounsaturated fatty acids, in addition to glycoprotein acetyls (inflammatory marker), were also higher in participants with NAFLD.Conclusions:We have identified differing metabolic profiles between adolescents with and without indicators of NAFLD. These results provide the foundations for future research to determine whether these differences persist and result in adverse future cardiometabolic health.
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Hartley, April, Diana L. Santos Ferreira, Emma L. Anderson, and Debbie A. Lawlor. "Metabolic profiling of adolescent non-alcoholic fatty liver disease." Wellcome Open Research 3 (September 19, 2019): 166. http://dx.doi.org/10.12688/wellcomeopenres.14974.2.
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Background: Adolescent non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic risk factors. The association between adolescent NAFLD and a wide range of metabolic biomarkers is unclear. We have attempted to determine the differences in metabolic profile of adolescents with and without markers of NAFLD. Methods: We performed cross-sectional analyses in a sample of 3,048 participants from the Avon Longitudinal Study of Parents and Children at age 17. We used three indicators of NAFLD: ALT >40 U/l; AST >40 U/l and ultrasound scan-assessed steatosis. Associations between each measure of NAFLD and 154 metabolic traits, assessed by Nuclear Magnetic Resonance, were analyzed by multivariable linear regression, adjusting for age, sex and BMI. Results: All three indicators of NAFLD were associated with ~0.5 standard deviation (SD) greater concentrations of all extremely large to small very low-density lipoproteins (VLDL) measures. ALT >40U/l was associated with ~0.5SD greater concentrations of very small VLDLs, intermediate-density lipoproteins and low-density lipoproteins. Concentrations of most cholesterols, including remnant cholesterol, all triglycerides and monounsaturated fatty acids, in addition to glycoprotein acetyls (inflammatory marker), were also higher in participants with NAFLD. Conclusions: We have identified differing metabolic profiles between adolescents with and without indicators of NAFLD. These results provide the foundations for future research to determine whether these differences persist and result in adverse future cardiometabolic health.
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Vilcins, Dwan, Wen Ray Lee, Cindy Pham, et al. "Association of Maternal Air Pollution Exposure and Infant Lung Function Is Modified by Genetic Propensity to Oxidative Stress." Children 11, no. 8 (2024): 937. http://dx.doi.org/10.3390/children11080937.
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Background and objective: The association between air pollution and poor respiratory health outcomes is well established. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. This study investigated maternal exposure to air pollution during pregnancy and oxidative stress (OS), inflammation, and infant lung function at 4 weeks of age. Methods: Data from the Barwon Infant Study were available for 314 infants. The exposure to NO2 and PM2.5 were estimated. Infant lung function (4 weeks) was measured by multiple-breath washout. Glycoprotein acetyls (GlycA) (36 weeks prenatal), cord blood, and OS biomarkers were measured in maternal urine (28 weeks). A genetic pathway score for OS (gPFSox) was calculated. Linear regression was used and potential modification by the OS genotype was tested. Results: There was no relationship between maternal exposure to air pollution and infant lung function, or with GlycA or OS during pregnancy. We found an association in children with a genetic propensity to OS between NO2 and a lower functional residual capacity (FRC) (β = −5.3 mls, 95% CI (−9.3, −1.3), p = 0.01) and lung clearance index (LCI) score (β = 0.46 turnovers, (95% CI 0.10, 0.82), p = 0.01). Conclusion: High prenatal exposure to ambient NO2 is associated with a lower FRC and a higher LCI score in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.
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Fan, Bohan, Xin Huang, and Jie V. Zhao. "Exploration of Metabolic Biomarkers Linking Red Meat Consumption to Ischemic Heart Disease Mortality in the UK Biobank." Nutrients 15, no. 8 (2023): 1865. http://dx.doi.org/10.3390/nu15081865.
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Growing evidence suggests that red meat consumption is a risk factor for cardiovascular health, with potential sex disparity. The metabolic mechanisms have not been fully understood. Using the UK Biobank, first we examined the associations of unprocessed red meat and processed meat with ischemic heart disease (IHD) mortality overall and by sex using logistic regression. Then, we examined the overall and sex-specific associations of red meat consumption with metabolites using multivariable regression, as well as the associations of selected metabolites with IHD mortality using logistic regression. We further selected metabolic biomarkers that are linked to both red meat consumption and IHD, with concordant directions. Unprocessed red meat and processed meat consumption was associated with higher IHD mortality overall and in men. Thirteen metabolites were associated with both unprocessed red meat and IHD mortality overall and showed a consistent direction, including triglycerides in different lipoproteins, phospholipids in very small very-low-density lipoprotein (VLDL), docosahexaenoic acid, tyrosine, creatinine, glucose, and glycoprotein acetyls. Ten metabolites related to triglycerides and VLDL were positively associated with both unprocessed red meat consumption and IHD mortality in men, but not in women. Processed meat consumption showed similar results with unprocessed red meat. Triglycerides in lipoproteins, fatty acids, and some nonlipid metabolites may play a role linking meat consumption to IHD. Triglycerides and VLDL-related lipid metabolism may contribute to the sex-specific associations. Sex differences should be considered in dietary recommendations.
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Crick, Daisy C. P., Sarah L. Halligan, Laura D. Howe, et al. "Associations between Adverse Childhood Experiences and the novel inflammatory marker glycoprotein acetyls in two generations of the Avon Longitudinal Study of Parents and Children birth cohort." Brain, Behavior, and Immunity 100 (February 2022): 112–20. http://dx.doi.org/10.1016/j.bbi.2021.11.001.
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Lord, Jodie, Bradley Jermy, Rebecca Green, et al. "Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer’s disease." Proceedings of the National Academy of Sciences 118, no. 16 (2021): e2009808118. http://dx.doi.org/10.1073/pnas.2009808118.
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There are currently no disease-modifying treatments for Alzheimer’s disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition—a preclinical predictor of AD—translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR–BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs—particularly XL.HDL.FC—as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies.
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Tofte, Nete, Nicole Vogelzangs, Dennis Mook-Kanamori, et al. "Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes." Journal of Clinical Endocrinology & Metabolism 105, no. 7 (2020): 2275–87. http://dx.doi.org/10.1210/clinem/dgaa173.
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Abstract Context There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. Objective To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). Design 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. Main outcome measures Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. Results In total, 125 metabolites were significantly associated (PFDR = 1.5×10–32 − 0.046; β = −11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR &lt; 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR &lt; 0.05). Albeit some metabolites were associated with UACR levels (P &lt; 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated &lt; 0.05), but not after. Conclusions This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.
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Richardson, Tom G., Genevieve M. Leyden, Qin Wang, et al. "Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation." PLOS Biology 20, no. 2 (2022): e3001547. http://dx.doi.org/10.1371/journal.pbio.3001547.
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Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome. We firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9, and NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4, and LPL). Conducting mendelian randomisation (MR) provided strong evidence of an effect of drug-based genetic scores on coronary artery disease (CAD) risk with the exception of ANGPTL3. We then systematically estimated the effects of each score on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants. Genetically predicted effects were generally consistent among drug targets, which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r2 = 0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (for instance, HMGCR versus each of the 4 triglyceride targets all had r2 < 0.02). Furthermore, we highlight this discrepancy for specific metabolic traits, for example, finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation, whereas triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, despite largely consistent effects on risk of CAD, with potential implications for biomarkers in clinical development and measuring treatment response.
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Fizelova, Maria, Raimo Jauhiainen, Antti J. Kangas, et al. "Differential Associations of Inflammatory Markers With Insulin Sensitivity and Secretion: The Prospective METSIM Study." Journal of Clinical Endocrinology & Metabolism 102, no. 9 (2017): 3600–3609. http://dx.doi.org/10.1210/jc.2017-01057.
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Abstract Context Low-grade inflammation is involved in the development of type 2 diabetes and cardiovascular disease (CVD); however, prospective studies evaluating inflammatory markers as predictors of changes in insulin secretion and insulin sensitivity are lacking. Objective We investigated the associations of glycoprotein acetyls (GlycA), interleukin-1 receptor antagonist (IL-1RA), and high-sensitivity C-reactive protein (hs-CRP) with insulin secretion, insulin sensitivity, incident type 2 diabetes, hypertension, CVD events, and total mortality in the prospective Metabolic Syndrome in Men (METSIM) study. Design A prospective study. Participants The cross-sectional METSIM study included 8749 nondiabetic Finnish men aged 45 to 73 years, who had been randomly selected from the population register of Kuopio, Finland. A total of 5401 men participated in the 6.8-year follow-up study. Main Outcome Measures Changes in insulin secretion, insulin sensitivity, and cardiometabolic traits during the follow-up period and the incidence of type 2 diabetes, hypertension, CVD events, and total mortality. Results During the follow-up period, GlycA was associated with impaired insulin secretion, hyperglycemia, incident type 2 diabetes (hazard ratio, 1.37; 95% confidence interval, 1.29 to 1.46) and CVD (hazard ratio, 1.21; 95% confidence interval, 1.12 to 1.32). IL-1RA and hs-CRP were associated with adverse changes in insulin sensitivity and obesity-related traits and with total mortality (hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.20; and hazard ratio, 1.08; 95% confidence interval, 1.04 to 1.11, respectively). Conclusions Inflammatory markers differentially predicted changes in insulin secretion and insulin sensitivity. GlycA predicted impaired insulin secretion, and IL-1RA and hs-CRP predicted changes in insulin sensitivity. Combining the three markers improved the prediction of disease outcomes, suggesting that they capture different aspects of low-grade inflammation.
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Hu, Wenyi, Tiancheng Chu, Huan Liao, et al. "Distinct and Overlapping Metabolites Associated with Visual Impairment and Cognitive Impairment." Journal of Alzheimer's Disease Reports 8, no. 1 (2024): 1093–104. http://dx.doi.org/10.3233/adr-230154.
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Background: Previous studies found that visual impairment (VI) is associated with higher risk of cognitive impairment, but the molecular basis of these conditions is unknown. Objective: We aim to compare the metabolite associations of VI and cognitive impairment. Methods: The study population with comprehensive measurements was derived from the UK Biobank study. Visual acuity worse than 0.3 logMAR units were defined as VI. Failure in one or more of the four cognitive tests was defined as cognitive impairment. A panel of 249 metabolites was measured using a nuclear magnetic resonance metabolites profiling platform. Logistic regression models were applied to compare metabolite associations with VI and cognitive impairment. Results: 23,775 participants with complete data on visual acuity, cognitive tests and metabolomics, and without a history of neurological disorders at baseline were included. After adjusting for confounding factors, VI was significantly associated with cognitive impairment (odds ratio[OR] = 1.49, 95% confidence interval [CI]: 1.27–1.74, p < 0.001). After multiple testing correction (p < 9×10–4), five metabolites including the ratio of omega-6 to omega-3 fatty acids (FAs) (OR = 1.18[1.10–1.27]), ratio of omega-3 to total FAs (OR = 0.84[0.77–0.91]), ratio of docosahexaenoic acid (DHA) to total FAs (OR = 0.86[0.80–0.94]), DHA (OR = 0.85[0.78–0.92]), and omega-3 FAs (OR = 0.84[0.77–0.91]) were uniquely associated with VI. Glycoprotein acetyls (OR = 1.06[1.03–1.10]) and alanine (OR = 0.95[0.92–0.98]) were exclusively associated with cognitive impairment. Albumin was identified as the common metabolite shared by the two phenotypes (OR = 0.90[0.85–0.95] for VI, and 0.95[0.92–0.98]) for cognitive impairment). Conclusions: We identified distinct and overlapping metabolites associated with VI and cognitive impairment, unveiling their distinct metabolic profiles and potential common pathophysiology.
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Lange, Katherine, Kate Lycett, Susan Ellul, et al. "Cross-sectional metabolic profiles of mental health in population-based cohorts of 11- to 12-year-olds and mid-life adults: The Longitudinal Study of Australian Children." Australian & New Zealand Journal of Psychiatry 54, no. 9 (2020): 928–37. http://dx.doi.org/10.1177/0004867420924092.
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Objective: Poorer mental health in adulthood is associated with increased risk of cardiovascular disease and reduced life expectancy. However, little is known of the molecular pathways underpinning this relationship and how early in life adverse metabolite profiles relate to self-reported variation in mental health. We examined cross-sectional associations between mental health and serum metabolites indicative of cardiovascular health, in large Australian population-based cohorts at two stages of the life-course. Methods: We characterised cross-sectional serum nuclear magnetic resonance metabolite profiles of positively and negatively framed mental health in a large population-based sample of Australian 11- to 12-year-olds ( n = 1172; 51% girls) and mid-life adults (n = 1322; mean age 45 years; 87% women). We examined multiple standard self-report mental health scales, spanning psychosocial health, general well-being, life satisfaction, and health-related quality of life. Linear regression was used to investigate the cross-sectional association between mental health and each metabolite (n = 73) in children and adults separately, unadjusted and adjusted for age, sex, socioeconomic position and body mass index. Results: Better child and adult mental health were associated with lower levels of the inflammatory marker glycoprotein acetyls, and a favourable, less atherogenic lipid/lipoprotein profile. Patterns of association in children were generally weaker than in adults. Associations were generally modest and partially attenuated when adjusted for body mass index. Conclusions: In general, metabolite profiles associated with better child and adult mental health closely aligned with those predictive of better cardiovascular health in adults. Our findings support previous evidence for the likely bidirectional relationship between mental health and cardiovascular disease risk, by extending this evidence base to the molecular level and in children.
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Kettunen, Johannes, Anni Joensuu, Maria Hagnäs, et al. "Associations of increased physical performance and change in body composition with molecular pathways of heart disease and diabetes risk." American Journal of Physiology-Endocrinology and Metabolism 316, no. 2 (2019): E221—E229. http://dx.doi.org/10.1152/ajpendo.00260.2018.
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Higher physical activity is associated with a reduced hazard for a plethora of diseases. It has remained unknown how the two primary physical activity-associated health effects, improved physical performance and change in body composition, independently modulate metabolic profiles toward a reduced risk for adverse outcomes. Here, we utilized a prospective cohort of 664 young men undergoing military service. We studied the metabolic associations of changes in muscle performance and body composition during military service (range 6–12 mo). We subsequently replicated our results for body composition change in 234 population-based samples with a 7-yr follow-up. We found that increased physical performance was associated with reduced very-low-density lipoprotein (VLDL)-related measures [change in VLDL cholesterol: beta = −0.135; 95% confidence interval (CI) = −0.217, −0.054, P = 1.2 × 10−3] and lower inflammation (change in glycoprotein acetyls: beta = −0.138, 95% CI = −0.217, −0.059, P = 6.5 × 10−4), independent of change in body composition. Lower body fat percentage, independent of change in muscle performance, was associated with metabolic changes including lower low-density lipoprotein (LDL) cholesterol measures (change in LDL cholesterol: beta = −0.193, 95% CI = −0.295, −0.090; P = 2.5 × 10−4), increased high-density lipoprotein (HDL) cholesterol measures (change in large HDL cholesterol: beta = 0.316, 95% CI = 0.205, 0.427; P = 3.7 × 10−8), and decreased concentrations of amino acids (change in leucine concentration: beta = −0.236, 95% CI = −0.341, −0.132; P = 1.0 × 10−5) that are type 2 diabetes biomarkers. Importantly, all body fat percentage associations were replicated in a general population-based cohort. Our findings indicate that improved muscle performance showed weaker associations on the metabolic profiles than change in body composition and reduction in body fat percentage reduces cardiometabolic risk mediated by atherogenic lipoprotein particles and branched-chain and aromatic amino acid concentrations.
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Rome, L. H., and D. F. Hill. "Lysosomal degradation of glycoproteins and glycosaminoglycans. Efflux and recycling of sulphate and N-acetylhexosamines." Biochemical Journal 235, no. 3 (1986): 707–13. http://dx.doi.org/10.1042/bj2350707.
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Lysosomal degradation of the carbohydrate portion of glycoproteins and glycosaminoglycans produces monosaccharides and sulphate, which must efflux from the lysosomes before re-entering biosynthetic pathways. We examined the degradation of glycoproteins and glycosaminoglycans by lysosomes isolated from cultured human diploid fibroblasts. Cells were grown for 24 h in medium containing [3H]glucosamine and [35S]sulphate. When lysosomes are isolated from these cells, they contain label primarily in macromolecules (glycoproteins and glycosaminoglycans). Glycoprotein degradation by isolated lysosomes was followed by measuring the release of tritiated sugars from macromolecules and efflux of these sugars from the organelles. Glycosaminoglycan degradation was monitored by the release of both tritiated sugars and [35S]sulphate. During macromolecule degradation, the total amounts of free [35S]sulphate, N-acetyl[3H]glucosamine and N-acetyl[3H]galactosamine found outside the lysosome parallels the amounts of these products released by degradation. The total degradation of glycoproteins and glycosaminoglycans by intact cultured cells was also examined. The lysosomal contribution to degradation was assessed by measuring inhibition by the lysosomotropic amine NH4Cl. After 48 h incubation, inhibition by NH4Cl exceeded 55% of glycoprotein and 72% of glycosaminoglycan degradation. Recycling of [3H]hexosamines and [35S]sulphate by intact cells was estimated by measuring the appearance of ‘newly synthesized’ radioactively labelled macromolecules in the medium. Sulphate does not appear to be appreciably recycled. N-Acetylglucosamine and N-acetylgalactosamine, on the other hand, are reutilized to a significant extent.
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Piskarev, V. E., J. Navrátil, H. Karásková, K. Bezouska, and J. Kocourek. "Interaction of egg-white glycoproteins and their oligosaccharides with the monomer and the hexamer of chicken liver lectin. A multivalent oligosaccharide-combining site exists within the carbohydrate-recognition domain." Biochemical Journal 270, no. 3 (1990): 755–60. http://dx.doi.org/10.1042/bj2700755.
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Binding of egg-white glycoproteins and their oligosaccharides to hexameric solubilized form of the chicken hepatic lectin and the monomeric soluble fragment containing the carbohydrate-recognition domain has been investigated by several techniques. Ligand blotting revealed significant differences in binding to two forms of the lectin only for glycoproteins bearing multiple N-linked oligosaccharide moieties in their molecule (riboflavin-binding glycoprotein, avidin or ovomucoid). Inhibition studies indicated that inhibitory potency in a series of linear and branched N-acetyl-D-glucosamine-terminated oligosaccharides is critically dependent on the number and spatial arrangement of the terminal monosaccharide residues for both forms of the lectin. Direct binding of 4-hydroxyphenyl-derivatized radioiodinated oligosaccharides measured by equilibrium dialysis and frontal affinity chromatography points to the existence of two N-acetyl-D-glucosamine-combining sites per one subunit of the lectin, as has been recently reported for the rabbit and rat liver lectin [Lee & Lee (1988) Biochem. Biophys. Res. Commun. 155, 1444-1452]. Highly branch (penta-antennary) oligosaccharides interact with more than one subunit of the hexameric form of the lectin and thus resemble the more complex interaction of the whole glycoprotein.
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Linenberg, Inbar, Kate Bermingham, Mohsen Mazidi, et al. "Postprandial and Fasting Metabolic Signatures: Insights From the ZOE PREDICT 1 Study." Current Developments in Nutrition 6, Supplement_1 (2022): 448. http://dx.doi.org/10.1093/cdn/nzac057.014.
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Abstract Objectives Postprandial metabolomic signatures, although not well characterized, may provide greater insight into individuals’ responses to food and subsequent cardiometabolic disease risk compared to fasting and routine clinical measures. Using the PREDICT 1 cohort, we assessed postprandial changes and inter-individual variability in metabolites sequenced by NMR. Methods The ZOE PREDICT 1 study (n = 1,002 healthy UK adults; NCT03479866) measured 250 metabolite parameters (Nightingale Health NMR panel, related to lipids, amino acids, glycolysis, ketones, and glycoprotein acetyls (GlycA)) by venous cannulation at fasting and postprandially after a mixed nutrient sequential test meal (4 and 6 h after meal 1, 3.7 MJ; meal 2 given at 4 h, 2.2 MJ). Postprandial changes in metabolites and their inter-individual variability (median absolute difference from the median (MADM)/median (%)) were evaluated. Associations (Spearman's correlations) and differences in variances (Fligner-Killeen test) were assessed between fasting and postprandial (6 h) measures. Results A significant 6 h postprandial change from fasting was seen in 85% of metabolites; of which, 47% increased, and 53% decreased (Kruskal-Wallis p &lt; 0.05 for all). Ketone bodies and very-large lipoprotein particles showed the greatest changes. Fasting and postprandial measures had large, yet similar, inter-individual variability (MADM/median; 15% at 0, 4 and 6 h (mean for all)) and were strongly correlated (r &gt; 0.8; 71% of measures), although ketone bodies, glucose, branched chain amino acids and LDL diameter were only weakly correlated (r &lt; 0.5). Inter-individual patterns of response differed postprandially compared to fasting (Fligner-Killeen test of variance, p &lt; 0.05). Conclusions In this large and generally healthy cohort, we demonstrate significant changes in circulating metabolites between the fasting and postprandial phase, as expected, within lipoprotein size and composition remodelling, glycolysis, essential amino acid and ketone body pathways. The large inter-individual variability in postprandial metabolite levels, suggests dietary challenges offer an opportunity for stratifying metabolic responses. Funding Sources ZOE Ltd.
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Arlt, Sebastian P., Claudia Ottka, Hannes Lohi, et al. "Metabolomics during canine pregnancy and lactation." PLOS ONE 18, no. 5 (2023): e0284570. http://dx.doi.org/10.1371/journal.pone.0284570.
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During pregnancy and parturition, female dogs have to cope with various challenges such as providing nutrients for the growth of the fetuses, hormonal changes, whelping, nursing, milk production, and uterine involution. Metabolomic research has been used to characterize the influence of several factors on metabolism such as inter- and intra-individual factors, feeding, aging, inter-breed differences, drug action, behavior, exercise, genetic factors, neuter status, and pathologic processes. Aim of this study was to identify metabolites showing specific changes in blood serum at the different phases of pregnancy and lactation. In total, 27 privately owned female dogs of 21 different breeds were sampled at six time points: during heat, in early, mid and late pregnancy, at the suspected peak of lactation and after weaning. A validated and highly automated canine-specific NMR metabolomics technology was utilized to quantitate 123 measurands. It was evaluated which metabolite concentrations showed significant changes between the different time points. Metabolites were then grouped into five clusters based on concentration patterns and biochemical relationships between the metabolites: high in mid-pregnancy, low in mid-pregnancy, high in late pregnancy, high in lactation, and low in lactation. Several metabolites such as albumin, glycoprotein acetyls, fatty acids, lipoproteins, glucose, and some amino acids show similar patterns during pregnancy and lactation as shown in humans. The patterns of some other parameters such as branched-chain amino acids, alanine and histidine seem to differ between these species. For most metabolites, it is yet unstudied whether the observed changes arise from modified resorption from the intestines, modified production, or metabolism in the maternal or fetal tissues. Hence, further species-specific metabolomic research may support a broader understanding of the physiological changes caused by pregnancy that are likely to be key for the normal fetal growth and development. Our findings provide a baseline of normal metabolic changes during healthy canine pregnancy and parturition. Combined with future metabolomics findings, they may help monitor vital functions of pre-, intra-, and post-partum bitches and may allow early detection of illness.
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Koutaki, Diamanto, Garyfallia Stefanou, Sofia-Maria Genitsaridi, et al. "Exploring Metabolic Signatures: Unraveling the Association with Obesity in Children and Adolescents." Nutrients 17, no. 11 (2025): 1833. https://doi.org/10.3390/nu17111833.
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Background: Childhood obesity is a growing global health concern. Metabolomics, the comprehensive study of metabolites within biological systems, offers a powerful approach to better define the phenotype and understand the complex biochemical alterations associated with obesity. The aim of this systematic review was to summarize current knowledge in the field of metabolomics in childhood obesity and to identify metabolic signatures or biomarkers associated with overweight/obesity (Ov/Ob) and Metabolically Unhealthy Obesity (MUO) in children and adolescents. Methods: We performed a systematic search of Medline and Scopus databases according to PRISMA guidelines. We included only longitudinal prospective studies or randomized controlled trials with ≥12 months of follow-up, as well as meta-analyses of the above that assessed the relation between metabolic signatures related to obesity and Body Mass Index (BMI) or other measures of adiposity in children and adolescents aged 2–19 years with overweight or obesity. Initially, 595 records were identified from PubMed and 1565 from Scopus. After removing duplicates and screening for relevance, 157 reports were assessed for eligibility. From the additional search, 75 new records were retrieved, of which none were eligible for our study. Finally, 7 reports were included in the present systematic review (4 reporting on Ov/Ob and 4 on MUO). Results: The presented studies suggest that the metabolism of amino acids and lipids is primarily affected by childhood obesity. Metabolites like glycoprotein acetyls, the Apolipoprotein B/Apolipoprotein A-1 ratio, and lactate have emerged as potential biomarkers for insulin resistance and metabolic syndrome, highlighting their potential value in clinical applications. Conclusions: There is a need for future longitudinal studies to assess metabolic changes over time, interventional studies to evaluate the efficacy of therapeutic strategies, and large-scale population studies to explore metabolic diversity across different demographics. Our findings reveal specific biomarkers in the amino acid and lipid pathway that may serve as early indicators of childhood obesity and its associated cardiometabolic complications.
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Um, Caroline, Rebecca Hodge, Andrew Gewirtz, Victoria Stevens, Eric Jacobs, and Marjorie McCullough. "Emulsifier and Highly Processed Food Intake and Biomarkers of Intestinal Permeability and inflammation in the Cancer Prevention Study-3 Diet Assessment Sub-Study." Current Developments in Nutrition 4, Supplement_2 (2020): 1498. http://dx.doi.org/10.1093/cdn/nzaa061_126.
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Abstract Objectives Emulsifiers may increase intestinal permeability, inflammation, and colorectal carcinogenesis in animals. Highly processed foods are associated with obesity and may increase risk of chronic diseases, including cancer. We estimated intake of emulsifiers and highly processed foods in participants from the Cancer Prevention Study-3 Diet Assessment Sub-study and examined their association with biomarkers of gut permeability and inflammation. Methods This study included 657 men and women who completed six 24-hr dietary recalls and two fasting blood samples over one year. Antibodies (IgG and IgA) to flagellin and lipopolysaccharide (LPS) and glycoprotein acetyls (GlycA) were measured using enzyme-linked immunosorbent assay and nuclear magnetic resonance, respectively. Total flagellin and LPS were each calculated as the sum of IgG and IgA; total antibody comprised the sum of total flagellin and LPS. Foods containing ≥1 emulsifier were identified from ingredient lists; foods typically containing emulsifiers were coded as such if an ingredient list was not available. We estimated emulsifier intake as 0.5% of total food weight, per FDA guidance. Highly processed foods were defined using the NOVA and Poti et al. classification systems and calculated as % grams of total foods and % kcal of total energy. Multivariable-adjusted generalized linear models were used to estimate associations of emulsifier and processed food quartiles with continuous antibody or inflammatory biomarkers. Results Higher emulsifier intake (g/d) was not associated with total flagellin (P-trend = 0.48), total LPS (P-trend = 0.61), total antibody (P-trend = 0.49), or GlycA (P-trend = 0.16). Higher processed food intake (% kcal/d) was associated with higher total LPS (P-trend = 0.001) and total antibody (P-trend = 0.01) but not with other biomarkers, whereas processed food intake estimated as % g/d was only associated with higher GlycA (P-trend = 0.02). Conclusions Our results suggest highly processed food, but not emulsifier, intake may be associated with gut permeability biomarkers. Additional studies are needed to further understand the relationship between emulsifier and highly processed food intake and intestinal permeability and inflammation. Funding Sources The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-3 cohort.
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Berry, Sarah, Mohsen Mazidi, Paul Franks, et al. "Impact of Postprandial Lipemia and Glycemia on Inflammatory Factors in over 1000 Individuals in the US and UK: Insights from the PREDICT 1 and InterCardio Studies." Current Developments in Nutrition 4, Supplement_2 (2020): 1518. http://dx.doi.org/10.1093/cdn/nzaa068_003.
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Abstract Objectives Postprandial glycemia (PPG) and lipemia (PPL) initiate an acute inflammatory response, which may be relevant to future CVD. We characterised the impact of PPL and PPG on inflammatory responses using traditional (IL-6) and emerging (glycoprotein acetyls; GlycA) biomarkers of inflammation in a large scale, tightly controlled study (PREDICT 1; NCT03479866) and an independent validation study (InterCardio; NCT03438084). Methods The PREDICT 1 dietary intervention study of 1102 healthy individuals from the US and UK, assessed the postprandial (0–6 h) metabolic responses to sequential mixed-nutrient meals (50 g fat and 85 g carb at 0 h; 22 g fat and 71 g carb at 4 h). Baseline microbial diversity (16S Shannon diversity) and visceral fat mass (VFM; based on DXA) were also measured. Results were validated in an independent randomised crossover trial (n = 50). For both studies, glucose, triacylglycerol (TG), IL-6 and GlycA were measured at multiple intervals. Results In PREDICT 1, GlycA and IL-6 concentrations increased significantly after meals (by 4.5 and 169%; peak 6 h, respectively) but were not correlated. Peak postprandial TG and glucose concentrations were strongly associated with GlycA (r = 0.832 and r = 0.239, respectively) but not IL-6. Machine learning with cross-validation, revealed that PPL was the strongest predictor of postprandial GlycA. There was evidence of an interaction; individuals with higher microbial diversity and lower VFM had an attenuated inflammatory response. Individuals eliciting an enhanced response (30% rise at 6 h) had higher predicted CVD risk compared to the rest of the cohort. In the InterCardio study, the postprandial inflammatory increase in GlycA was also significantly correlated with PPL and varied within the four different types of fat tested. Conclusions In the first study to investigate postprandial inflammation at scale, we observed that PPL was a stronger determinant of systemic inflammation compared with PPG. The clinically significant and variable postprandial inflammatory response, and its association with lipemia and glycemia, highlights the potential for personalized dietary strategies to lower postprandial metabolic responses to reduce low grade inflammatory related diseases. Funding Sources NIHR, Wellcome Trust, Zoe Global Ltd, BBSRC DRINC.
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Goso, Y., and K. Hotta. "Types of oligosaccharide sulphation, depending on mucus glycoprotein source, corpus or antral, in rat stomach." Biochemical Journal 264, no. 3 (1989): 805–12. http://dx.doi.org/10.1042/bj2640805.
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Radiolabelled mucus glycoprotein was obtained from tissue and a culture medium each of the corpus and antrum of rat stomach incubated with [35S]sulphate in vitro. Gel-filtration analysis of oligosaccharides liberated by alkaline-borohydride treatment from glycoproteins indicated that 35S-labelled oligosaccharides from the corpus vary considerably with respect to chain length whereas those from antral mucus glycoprotein are composed of small oligosaccharides. Examination of the reduced radiolabelled products obtained by HNO2 cleavage of the hydrazine-treated oligosaccharides indicated sulphate esters of N-acetylglucosamine to be present at three locations on a carbohydrate unit: [35S]sulphated monosaccharide (2,5-anhydromannitol 6-sulphate), [35S]sulphated disaccharide [galactosyl(beta 1-4)-2,5-anhydromannitol 6-sulphate] and [35S]sulphated trisaccharide [fucosyl(alpha 1-2)-galactosyl(beta 1-4)-2,5-anhydromannitol 6-sulphate]. Sulphated disaccharide and trisaccharide, possibly originating from the N-acetyl-lactosamine and fucosyl-N-acetyl-lactosamine sequences respectively, were detected in the corpus, especially as large oligosaccharides, but were present in the antrum in only very small amounts. The sulphated monosaccharide, however, most probably originating from 6-sulphated N-acetylglucosamine residues at non-reducing termini, was present in all oligosaccharide fractions in both the corpus and antrum.
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Colaco, K., K. A. Lee, S. Akhtari, et al. "OP0221 TARGETED METABOLOMIC PROFILING AND PREDICTION OF CARDIOVASCULAR EVENTS: A PROSPECTIVE STUDY OF PATIENTS WITH PSORIATIC ARTHRITIS AND PSORIASIS." Annals of the Rheumatic Diseases 80, Suppl 1 (2021): 132–33. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1154.
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Background:Psoriatic arthritis and psoriasis, collectively termed psoriatic disease (PsD), are associated with increased cardiovascular (CV) risk. Metabolites comprise biomarkers that may add predictive value over traditional CV risk factors.Objectives:We aimed to identify metabolites associated with CV events (CVEs) and to determine whether they could improve CV risk prediction beyond traditional CV risk factors.Methods:Patients from a longitudinal PsD cohort without a prior history of CVEs were included. In the first available serum sample, a targeted nuclear magnetic resonance (NMR) metabolomics platform was used to quantify 64 metabolite measures comprised of lipoprotein subclasses, fatty acids, glycolysis precursors, ketone bodies and amino acids. The study outcome included any of the following CVEs occurring within the first 10 years of biomarker assessment: angina, myocardial infarction, congestive heart failure, transient ischemic attack, cerebrovascular accident, revascularization procedures and CV death. The association of each metabolite with incident CVEs were analyzed separately using Cox proportional hazards regression models first adjusted for age and sex, and subsequently for traditional CV risk factors. Variable selection was performed using penalization with boosting after adjusting for age and sex. The added predictive value of the selected metabolites to improve risk prediction beyond traditional CV risk factors was assessed using the area under the receiver operator characteristic curve (AUC).Results:A total of 977 patients with PsD, followed between 2002 and 2019, were analyzed (mean age 49.1 ± 12.6 years, 45.1% female). During a mean follow-up of 7.1 years, 70 (7.2%) patients developed incident CVEs. In Cox regression models adjusted for CV risk factors, alanine, tyrosine, total high-density lipoprotein (HDL) cholesterol, medium and large HDL particles, and the degree of unsaturation of fatty acids were significantly associated with decreased CV risk. Glycoprotein acetyls, apolipoprotein B, remnant cholesterol, very low-density lipoprotein (VLDL) cholesterol, and very small VLDL particles were associated with an increased CV risk. In proportional sub-distribution hazards regression models adjusted for age and sex, 13 metabolites were selected (Table 1). The age- and sex-adjusted expanded model (base model + 13 metabolites) significantly improved prediction of CVEs beyond the base model (only age and sex) with an AUC of 79.9 vs. 72.6, respectively (p=0.019) (Figure 1).Table 1.Regression coefficients of the selected metabolites in a model adjusted for age and sex.CategoryMetaboliteModel adjusted for Age and SexAmino AcidsAlanine-0.1179Glycine-0.0339Tyrosine-0.1010Fatty acid ratios, relative to total fatty acidsDocosahexaenoic acid-0.0862Unsaturation degree, double bonds per fatty acid-0.1265Fluid BalanceAlbumin+0.0685GlyceridesTriglycerides in IDL cholesterol+0.1546Glycolysis precursorsGlucose+0.1391InflammationGlycoprotein acetyls+0.1478Ketone bodiesAcetoacetate+0.0464Lipoprotein subclassesHDL3 Cholesterol-0.0211Medium HDL-0.0296Large HDL-0.0309Figure 1.Predictive performance of a model with age and sex alone is compared to a model with age and sex plus selected metabolites.Conclusion:Using NMR metabolomics profiling, we identified a variety of metabolites associated with a lower and higher risk of developing CVEs in patients with PsD. Further study of their underlying association with CVEs is needed to clarify the clinical utility of these biomarkers to guide CV risk assessment in this population.References:[1]Eder L, Wu Y, Chandran V, et al. Incidence and predictors for cardiovascular events in patients with psoriatic arthritis. Ann Rheum Dis 2016;75(9):1680-6.[2]Soininen P, Kangas AJ, Wurtz P, et al. Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics. Circ Cardiovasc Genet 2015;8(1):192-206.Acknowledgements:Keith Colaco is supported by the Enid Walker Estate, Women’s College Research Institute, Arthritis Society (TGP-19-0446), National Psoriasis Foundation (Early Career Grant) and the Edward Dunlop Foundation. Lihi Eder is supported by a Young Investigator Award from the Arthritis Society and an Early Researcher Award from the Ontario Ministry of Science and Innovation. The study was supported in part by a discovery grant from the National Psoriasis Foundation and an operating grant from the Arthritis Society (YIO-16-394).Disclosure of Interests:None declared
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Amigó, Núria, Rocío Fuertes-Martín, Ana Irene Malo, et al. "Glycoprotein Profile Measured by a 1H-Nuclear Magnetic Resonance Based on Approach in Patients with Diabetes: A New Robust Method to Assess Inflammation." Life 11, no. 12 (2021): 1407. http://dx.doi.org/10.3390/life11121407.
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Patients with type 2 diabetes mellitus (T2DM) and atherogenic dyslipidemia (AD) are at higher risk of developing cardiovascular diseases (CVDs), so an interest in discovering inflammation biomarkers as indicators of processes related to CVD progression is increasing. This study aims (a) to characterize the plasma glycoprotein profile of a cohort of 504 participants, including patients with and without T2DM and/or AD and controls, and (b) to study the associations between the glycoprotein profile and other lipid and clinical variables in these populations. We characterized the plasma glycoprotein profiles by using 1H-NMR. We quantified the two peaks associated with the concentration of plasma glycoproteins (GlycA and GlycB) and their height/width ratios (H/W GlycA and H/W GlycB), as higher and narrower signals have been related to inflammation. We also quantified GlycF, the signal of which is proportional to the concentration of the acetyl groups of free N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic in the samples. The lipoprotein profile was also determined (Liposcale®). Standard clinical and anthropometric measurements were taken. Multivariate classification models were developed to study the differences between the study groups. Reduced HDL-C levels, increased small dense LDL and HDL particles, and elevated TG levels were significantly associated with glycoprotein variables. Glycoprotein values in the diagnostic groups were significantly different from those in the CT groups. AD and DM conditions together contribute to a positive and significant synergetic effect on the GlycA area (<0.05) and the H/W ratios of GlycA (<0.01) and GlycB (<0.05). By adding the new glycoprotein variables to the traditionally used marker of inflammation C-reactive protein (CRP), the AUC increased sharply for classification models between the CT group and the rest (0.68 to 0.84), patients with and without dyslipidemia (0.54 to 0.86), and between patients with and without diabetes (0.55 to 0.75). 1H-NMR-derived glycoproteins can be used as possible markers of the degree of inflammation associated with T2DM and AD.
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Villers, C., R. Cacan, A. M. Mir, O. Labiau, and A. Verbert. "Release of oligomannoside-type glycans as a marker of the degradation of newly synthesized glycoproteins." Biochemical Journal 298, no. 1 (1994): 135–42. http://dx.doi.org/10.1042/bj2980135.
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The N-glycosylation of proteins is accompanied by the release of soluble oligosaccharide material. Besides oligosaccharide phosphates originating from the cleavage of lipid intermediates, neutral free oligosaccharides represent the major part of this material and are heterogeneous depending on whether the reducing end has one or two N-acetylglucosamine residues. The present study focuses on the intracellular origin of neutral free oligosaccharides in a CHO cell line. Kinetic and pulse-chase experiments clearly indicate that oligosaccharides possessing a chitobiosyl unit are derived from oligosaccharide pyrophosphodolichol, whereas oligosaccharides possessing one N-acetyl-glucosamine residue are derived from newly synthesized glycoprotein. This relationship is confirmed by comparing the glycosylation pattern of lipid donors and glycoproteins with those of neutral free oligosaccharides under various incubation conditions (inhibition of protein synthesis, presence of processing inhibitors, presence or absence of glucose). Degradation of newly synthesized glycoprotein and formation of neutral oligosaccharides with one N-acetylglucosamine residue are inhibited at 16 degrees C but not affected by lysosomotropic agents such as leupeptin or NH4Cl. Together with the fact that the degradation of newly synthesized glycoproteins and the subsequent release of the glycan are recovered in permeabilized cells, these results suggest that this phenomenon occurs in the rough endoplasmic reticulum or in a closely related compartment.
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Ottka, Claudia, Katariina Vapalahti, Sebastian P. Arlt, Alexander Bartel, and Hannes Lohi. "The metabolic differences of anestrus, heat, pregnancy, pseudopregnancy, and lactation in 800 female dogs." Frontiers in Veterinary Science 10 (February 2, 2023). http://dx.doi.org/10.3389/fvets.2023.1105113.
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IntroductionReproduction causes major hormonal and physiological changes to the female body. However, the metabolic changes occurring during canine reproduction are scarcely studied.MethodsIn this cross-sectional study, we assessed the metabolic effects of canine reproductive status using a 1H NMR metabolomics platform optimized and validated for canine use. The study population consisted of a total of 837 healthy, intact female dogs in breeding age, of which 663 dogs were in anestrus, 78 in heat, 43 were pseudopregnant, 15 were pregnant, and 38 were lactating. The differences in metabolite profiles between these states were studied by the Kruskal-Wallis test with post-hoc tests performed using the Dunn's test, and visualized by box plots and a heatmap. The ability of the metabolite profile to differentiate pregnant dogs from non-pregnant ones was assessed by creating a multivariate Firth logistic regression model using forward stepwise selection.ResultsLactation, pregnancy and heat all were associated with distinct metabolic changes; pregnancy caused major changes in the concentrations of glycoprotein acetyls, albumin and creatinine, and smaller changes in several lipids, citrate, glutamine, and alanine. Pseudopregnancy, on the other hand, metabolically largely resembled anestrus. Lactation caused major changes in amino acid concentrations and smaller changes in several lipids, albumin, citrate, creatinine, and glycoprotein acetyls. Heat, referring to proestrus and estrus, affected cholesterol and LDL metabolism, and increased HDL particle size. Albumin and glycoprotein acetyls were the metabolites included in the final multivariate model for pregnancy detection, and could differentiate pregnant dogs from non-pregnant ones with excellent sensitivity and specificity.DiscussionThese results increase our understanding of the metabolic consequences of canine reproduction, with the possibility of improving maternal health and ensuring reproductive success. The identified metabolites could be used for confirming canine pregnancy.
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McNestry, Catherine, Rachel K. Crowley, Sharleen L. O'Reilly, et al. "Breastfeeding duration is associated with favorable body composition and lower glycoprotein acetyls in later life." International Journal of Gynecology & Obstetrics, April 8, 2024. http://dx.doi.org/10.1002/ijgo.15484.
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AbstractObjectiveThe aim of the present study was to investigate associations between lifetime breastfeeding behaviors and cardiovascular risk in later reproductive years.MethodThis was a prospective 10‐year longitudinal cohort study of 168 parous women. Health, lifestyle and infant feeding questionnaires, blood samples, anthropometry and body composition were collected. Cardiovascular risk was estimated using QRISK®3 and hierarchical multiple linear regression analysis performed.ResultsMean age was 42.4 years (SD 3.8; range 31–50) and 98.7% (n = 156/158) were premenopausal. Ever breastfeeding rates were 72.6% (n = 122/168) and 37.5% (n = 63/168) lifetime ≥12 months breastfeeding duration. Median durations were 5.5 weeks for exclusive breastfeeding (IQR 35.8; range 0–190) and 30.5 weeks for any breastfeeding (IQR 84.0; range 0–488). Breastfeeding duration was not associated with QRISK®3 scores in adjusted models. Lower glycoprotein acetyls were associated with ever breastfeeding (P = 0.03), and lifetime breastfeeding ≥12 months (P = 0.001). Lifetime breastfeeding ≥12 months and longer exclusive breastfeeding were associated with lower fat mass index (P = 0.03, P = 0.01), tissue percentage fat (P = 0.02, P = 0.009) and visceral adipose tissue volume (P = 0.04, P = 0.025) after correcting for confounders including body mass index.ConclusionLonger breastfeeding is associated with favorable body composition and lower glycoprotein acetyls, a novel inflammatory biomarker associated with cardiometabolic risk. Breastfeeding is a low‐cost, health promoting behavior for women and infants. Pregnant women, especially those at higher risk of cardiovascular disease, should be counseled about the potential benefits of exclusive and longer breastfeeding duration.
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Chiesa, Scott T., Marietta Charakida, Georgios Georgiopoulos, et al. "Glycoprotein Acetyls: A Novel Inflammatory Biomarker of Early Cardiovascular Risk in the Young." Journal of the American Heart Association 11, no. 4 (2022). http://dx.doi.org/10.1161/jaha.121.024380.
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Background Low‐grade inflammation in the young may contribute to the early development of cardiovascular disease. We assessed whether circulating levels of glycoprotein acetyls (GlycA) were better able to predict the development of adverse cardiovascular disease risk profiles compared with the more commonly used biomarker high‐sensitivity CRP (C‐reactive protein). Methods and Results A total of 3306 adolescents and young adults from the Avon Longitudinal Study of Parents and Children (mean age, 15.4±0.3; n=1750) and Cardiovascular Risk in Young Finns Study (mean age, 32.1±5.0; n=1556) were included. Baseline associations between inflammatory biomarkers, body composition, cardiovascular risk factors, and subclinical measures of vascular dysfunction were assessed cross‐sectionally in both cohorts. Prospective risk of developing hypertension and metabolic syndrome during 9‐to‐10‐year follow‐up were also assessed as surrogate markers for future cardiovascular risk. GlycA showed greater within‐subject correlation over 9‐to‐10‐year follow‐up in both cohorts compared with CRP, particularly in the younger adolescent group (r=0.36 versus 0.07). In multivariable analyses, GlycA was found to associate with multiple lifestyle‐related cardiovascular disease risk factors, cardiometabolic risk factor burden, and vascular dysfunction (eg, mean difference in flow‐mediated dilation=−1.2 [−1.8, −0.7]% per z‐score increase). In contrast, CRP levels appeared predominantly driven by body mass index and showed little relationship to any measured cardiovascular risk factors or phenotypes. In both cohorts, only GlycA predicted future risk of both hypertension (risk ratio [RR], ≈1.1 per z‐score increase for both cohorts) and metabolic syndrome (RR, ≈1.2–1.3 per z‐score increase for both cohorts) in 9‐to‐10‐year follow‐up. Conclusions Low‐grade inflammation captured by the novel biomarker GlycA is associated with adverse cardiovascular risk profiles from as early as adolescence and predicts future risk of hypertension and metabolic syndrome in up to 10‐year follow‐up. GlycA is a stable inflammatory biomarker which may capture distinct sources of inflammation in the young and may provide a more sensitive measure than CRP for detecting early cardiovascular risk.
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Ottka, Claudia, Corinna Weber, Elisabeth Müller, and Hannes Lohi. "Serum NMR metabolomics uncovers multiple metabolic changes in phenobarbital-treated dogs." Metabolomics 17, no. 6 (2021). http://dx.doi.org/10.1007/s11306-021-01803-5.
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Abstract Introduction Phenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized. Objectives To identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels. Methods Leftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 µg/mL to 50.8 µg/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific 1H NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression. Results Increasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value < .0033, and area under the curve (AUC) > .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed. Conclusion The identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.
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Goulding, Neil, Maxime Bos, Diana van Heemst, Raymond Noordam, and Deborah Lawlor. "454Relationships between sleep traits and metabolic profiles: evidence from multivariable regression and Mendelian randomization analyses." International Journal of Epidemiology 50, Supplement_1 (2021). http://dx.doi.org/10.1093/ije/dyab168.236.
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Abstract Background Sleep traits are associated with cardiometabolic disease. The aim of this study was to explore the causal effect of sleep traits (duration and insomnia) on multiple metabolic traits. Methods We used age, sex and BMI adjusted multivariable regression (N = 17,370) and two-sample summary statistic Mendelian randomization (MR) to examine effects of sleep duration and insomnia symptoms on ∼150 NMR metabolites. Multivariable analyses were conducted on data from nine European cohorts and meta-analysed. MR analyses utilised summary statistics from published genome-wide association studies (GWAS) of self-reported sleep traits (sample 1; N = 446,118 to 1,331,010) and from GWAS on NMR serum metabolites (sample 2; N = 38,618). We used inverse-variance weighted (IVW) for the main MR analyses and weighed median (WM) and MR-Egger to explore bias due to pleiotropy. Results MR IVW and multivariable analyses both suggest a positive effect of insomnia symptoms on glycoprotein acetyls (MR: 0.06 s.d. increase in mean concentration comparing any symptoms to none; p = 5.9e-4) and between total sleep duration and creatinine (MR: 0.16 s.d. increase per additional hour; p = 0.03). WM and MR-Egger analyses show consistent results. There was evidence for thirteen and eight effects of insomnia and duration in multivariable only and three and one, respectively, in MR only. Conclusions Insomnia symptoms lead to higher levels of an inflammatory marker (glycoprotein acetyls) and longer sleep duration leads to higher creatinine levels. Key messages We found no evidence of widespread metabolic disruption by sleep traits.
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Sanghvi, M. M., W. J. Young, S. Chadalavada, S. E. Petersen, N. Aung, and P. B. Munroe. "Non-lipid metabolomic biomarkers are associated with adverse cardiac remodelling and cardiovascular outcomes." European Heart Journal 45, Supplement_1 (2024). http://dx.doi.org/10.1093/eurheartj/ehae666.2754.
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Abstract Background Metabolomics is the detailed profiling of circulating metabolites including carbohydrates, lipids, amino and fatty acids, and ketones, all of which are substrates used in energy metabolism by cardiomyocytes. Purpose The role of cholesterol fractions with cardiovascular risk is well-established. This novel study examines the association between non-lipid circulating metabolites and markers of cardiac remodelling as assessed by cardiovascular magnetic resonance (CMR) imaging. Metabolites associated with adverse remodelling were taken forward to examine their impact on incident cardiovascular disease (CVD); ischaemic heart disease (IHD) and heart failure (HF). Methods This study used data from the UK Biobank. After exclusions (prevalent IHD, HF; outliers), there were a maximum of 34,727 individuals for CMR analyses and 262,536 individuals for incident CVD analysis. For CMR analyses, outcome variables were LV end-diastolic volume (EDV), LV mass, LV mass:volume ratio (MVR), LV global longitudinal strain (GLS) and native T1. Separate regression models were built for each of the 40 scaled metabolite biomarkers. Each model incorporated one metabolite at a time with additional covariates: age, sex, ethnicity, systolic blood pressure, cholesterol medication use, type 2 diabetes, dietary intake, smoking status, fasting time, and time between recruitment and CMR examination. A Bonferroni-corrected significance threshold of 2.4x10-4 was used. To account for correlation between metabolites, Lasso regression with 10 fold cross-validation to identify the most important predictors was performed for LV MVR, LV GLS and native T1 whereby all metabolites and above covariates were included in the model. Metabolite predictors of adverse remodelling were included in an adjusted logistic regression model with incident CVD as an outcome. Results Metabolites demonstrating significant (p &lt; 2.4x10-4) associations with CMR parameters are presented in Fig 1. For higher LV MVR and more positive LV GLS, the metabolites with the largest effect were monounsaturated fatty acids and glycoprotein acetyls. Higher omega-6:omega-3 ratio was associated with higher T1 values. The Lasso model identified 8 important predictors for adverse cardiac remodelling. Of these, two were routine biomarkers (creatinine, glucose). Of the remainder, monounsaturated fatty acids, glycoprotein acetyls and apolipoprotein B:apolipoprotein A1 ratio were significantly associated with increased risk of incident CVD (Fig 2). Current evidence regarding monounsaturated fatty acids in CVD is mixed. Glycoprotein acetyls are implicated in vascular inflammation. Apolipoproteins are thought to be a potential therapeutic target for CVD risk reduction. Conclusion This study demonstrates a role of non-lipid metabolites on subclinical CVD as assessed by adverse remodelling with CMR as well as associations with incident CVD. We highlight potential novel biomarkers for identification of CVD.Metabolite association with LV MVR/GLSMetabolite association with incident CVD
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Ottka, Claudia, Jenni Puurunen, Elisabeth Müller, Corinna Weber, Ruth Klein, and Hannes Lohi. "Metabolic changes associated with two endocrine abnormalities in dogs: elevated fructosamine and low thyroxine." Metabolomics 18, no. 8 (2022). http://dx.doi.org/10.1007/s11306-022-01917-4.
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Abstract Introduction Metabolomics studies in canine endocrine abnormalities are sparse and basic information on these abnormalities must be generated. Objectives To characterize the metabolic changes associated with elevated fructosamine, reflecting poor glycemic control, and low thyroxine, a thyroid hormone controlling metabolism. Methods Leftovers of clinical serum samples; 25 controls, 79 high fructosamine, and 47 low thyroxine, were analyzed using 1H NMR and differences were evaluated using Firth logistic regression. Results Both high fructosamine and low thyroxine were associated with changes in concentrations of multiple metabolites, including glycoprotein acetyls and lipids. Conclusion These findings suggest promising makers for further research and clinical validation.
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Huang, Shu-Yi, Yu-Xiang Yang, Ya-Ru Zhang, et al. "Investigating Causal Relations Between Circulating Metabolites and Alzheimer’s Disease: A Mendelian Randomization Study." Journal of Alzheimer's Disease, March 11, 2022, 1–15. http://dx.doi.org/10.3233/jad-220050.
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Background: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer’s disease (AD). However, the causal relationships between metabolism and AD are poorly understood. Objective: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. Methods: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. Results: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52–6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05–1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41–5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53–3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71–0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. Conclusion: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.
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XUE, QIAOCHU, XIANG LI, XUAN WANG, HAO MA, YORIKO HEIANZA, and LU QI. "183-OR: Metabolic Signatures of Type 2 Diabetes Subtypes in UK Biobank." Diabetes 72, Supplement_1 (2023). http://dx.doi.org/10.2337/db23-183-or.
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Type 2 diabetes (T2D) is a complex disease with heterogeneous pathophysiology. Five distinct subtypes of T2D were previously identified in the UK Biobank and validated in the All of Us cohort through a novel clustering algorithm: Cluster 1-5, characterized by early-onset of T2D, late-onset of T2D, severe obesity, poor glycemic control, and poor renal function, respectively. We aim to establish the subtype-specific signatures of metabolites. Nuclear magnetic resonance spectroscopy-derived metabolomic profiling was undertaken on baseline plasma samples in 12,271 UK Biobank participants with T2D. Among a subset of 2828 participants with metabolomic data available, elastic net regularized regressions with 10-fold cross-validation were applied to identify subtype-specific metabolic signatures. Of the 168 named metabolites used in the analyses, we selected a combination of 39 metabolites most significantly associated with subtypes of T2D (P&lt;0.0001, FDR&lt;0.05). We observed subtype-specific highest levels of creatinine in the impaired renal function characterized Cluster 5 and the lowest level in Cluster 1, featured by early-onset of T2D (mean difference= 2.46 [SD=0.09], P&lt;0.0001). Cluster 4 characterized by poor glycemic control had increased levels of glucose and decreased levels of glutamine, indicating a greater level of hyperglycemia. Individuals in Cluster 3 characterized by severe obesity exhibited elevated levels of inflammation metabolites biomarker (glycoprotein acetyls) and obesity-related amino acids (tyrosine and valine). The plasma unsaturation degree of fatty acid was also lower in Cluster 3 compared to other clusters. Cluster 2 patients had lower levels of glucose and glycoprotein acetyls and higher levels of glutamine, omega-3 fatty acids, and docosahexaenoic acids. Overall, Cluster 1 and 2 had the least metabolic dysregulation among the T2D subtypes. We have identified metabolic signatures for T2D subtypes, revealing subtype-specific metabolic mechanisms for precision interventions. Disclosure Q.Xue: None. X.Li: None. X.Wang: None. H.Ma: None. Y.Heianza: None. L.Qi: None.
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Salminen, A., A. M. Määttä, P. Mäntylä, et al. "Systemic Metabolic Signatures of Oral Diseases." Journal of Dental Research, November 15, 2023. http://dx.doi.org/10.1177/00220345231203562.
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Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 ( n = 6,229) and Parogene ( n = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants ( n = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B–containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.
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McNestry, C., R. K. Crowley, S. L. O'Reilly, and F. M. McAuliffe. "Response: Breastfeeding duration is associated with favorable body composition and lower glycoprotein acetyls in later life." International Journal of Gynecology & Obstetrics, February 20, 2025. https://doi.org/10.1002/ijgo.16168.
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Crick, Daisy C. P., Eleanor Sanderson, Hannah Jones, et al. "Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses." Journal of Affective Disorders, May 2023. http://dx.doi.org/10.1016/j.jad.2023.05.033.
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Bos, Maxime M., Neil J. Goulding, Matthew A. Lee, et al. "Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses." BMC Medicine 19, no. 1 (2021). http://dx.doi.org/10.1186/s12916-021-01939-0.
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Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
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Bell, Joshua A., Diana L. Santos Ferreira, Abigail Fraser, et al. "Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics." BMC Medicine 19, no. 1 (2021). http://dx.doi.org/10.1186/s12916-021-01929-2.
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Abstract Background Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood. Methods Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (1H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations). Results At 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides—males had 0.19 standard deviations (SD) (95% CI = 0.12, 0.26) higher at 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion. Conclusions Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.
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Bålsrud, Pia, Stine M. Ulven, Jacob J. Christensen, Inger Ottestad, and Kirsten B. Holven. "Inflammatory markers and frailty in home-dwelling elderly, a cross-sectional study." BMC Geriatrics 24, no. 1 (2024). http://dx.doi.org/10.1186/s12877-024-04690-2.
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Abstract Background Low-grade, chronic inflammation during ageing, (“inflammageing”), is suggested to be involved in the development of frailty in older age. However, studies on the association between frailty, using the frailty index definition, and inflammatory markers are limited. The aim of this study was to investigate the relationship between inflammatory markers and frailty index (FI) in older, home-dwelling adults. Method Home-dwelling men and women aged ≥ 70 years old, living in South-East Norway were recruited and included in a cross-sectional study. The FI used in the current study was developed according to Rockwood’s frailty index and included 38 variables, resulting in an FI score between 0 and 1 for each participant. Circulating inflammatory markers (IL-6, CRP, IGF-1, cystatin C, cathepsin S, and glycoprotein Acetyls) were analyzed from non-fasting blood samples using ELISA. Whole-genome PBMC transcriptomics was used to study the association between FI score and inflammation. Results The study population comprised 403 elderly (52% women), with a median age of 74 years and a mean BMI of 26.2 kg/m2. The mean FI score for the total group was 0.15 (range 0.005–0.56). The group was divided into a frail group (FI score ≥ 0.25) and non-frail group. After adjusting for BMI, age, sex, and smoking in the whole group, IL-6, cathepsin S, cystatin C, and Gp-acetyls remained significant associated to FI score (IL-6: 0.002, 95% CI: 0.001, 0.002, cathepsin S: 6.7e-06, 95% CI 2.44e-06, 0.00001, cystatin C: 0.004, 95% CI: 0.002, 0.006, Gp- Acetyls: 0.09, 95% CI: 0.05, 0.13, p < 0.01 for all), while CRP and IGF-1 were not (0.0003, 95% CI: -00001, 0.0007, p = 0.13, (-1.27e-06), 95% CI: (-0.0003), 0.0003, p = 0.99). There was a significant association between FI score and inflammatory markers, and FI score and monocyte-specific gene expression. Conclusions We found an association between FI score and inflammatory markers, and between FI score and monocyte-specific gene expression among elderly subjects above 70 years of age. Whether inflammation is a cause or consequence of frailty and whether the progression of frailty can be attenuated by reducing inflammation remains to be clarified.