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Background: Juvenile idiopathic arthritis (JIA) is challenging to classify and effectively monitor due to the lack of disease- and subtype-specific biomarkers. A robust molecular signature that tracks with specific JIA features over time is urgently required, and targeted plasma metabolomics may reveal such a signature. The primary aim of this study was to characterise the differences in the plasma metabolome between JIA patients and non-JIA controls and identify specific markers of JIA subtype. We also assessed the extent to which these signatures are due to underlying inflammation as assessed by glycoprotein acetyls (GlycA) and high-sensitivity C-Reactive Protein (hsCRP) levels. Methods: Targeted nuclear magnetic resonance (NMR) metabolomic profiles of plasma of 72 children with JIA and 18 controls were assessed cross-sectionally. Associations between 71 metabolomic biomarkers and JIA, JIA subtype, disease activity status, and inflammation markers (GlycA and hsCRP) were assessed using multivariable linear regression models. Results: JIA was associated with higher GlycA (mean difference = 0.93 standard deviations, 95% confidence interval = [0.370, 1.494], Padj = 0.039) and docosahexaenoic acid (1.06, [0.51, 1.60], Padj = 0.021), and lower acetate (-0.92, [-1.43, -0.41], Padj = 0.024) relative to controls. This variation was largely driven by systemic JIA (sJIA), with 24 of 71 total biomarkers significantly different (Padj <0.05) relative to controls. There were no specific differences identified in oligoarticular (oJIA) or polyarticular (rheumatoid factor positive or negative) JIA relative to controls. Despite being generally highly correlated with hsCRP (r > 0.70), GlycA, but not hsCRP, was positively associated with active disease in sJIA (0.22, [-0.40, -0.04], Padj = 0.018), and 6 of 24 sJIA-associated markers were associated with GlycA levels. Only 1 sJIA-associated biomarker, histidine, was associated with hsCRP levels. Conclusion: Differences in the plasma NMR metabolomic profiles are apparent in children with sJIA, but not other JIA subtypes, relative to non-JIA controls. These findings suggest a potential utility for classifying and monitoring JIA through metabolomic profiling, with chronic inflammation, measured by GlycA, potentially playing a role in at least some of these metabolomic differences.Key messages: • Children with JIA showed limited metabolomic differences in plasma compared to non-JIA controls. • Subtype-associated analysis identified exclusive metabolomic variation in sJIA. • Some metabolomic differences in sJIA may be driven by chronic inflammation. • GlycA may better reflect disease activity and metabolomic differences in sJIA than other inflammatory markers such as hsCRP. [ABSTRACT FROM AUTHOR]

It is generally known that although a connection between abdominal obesity and chronic kidney disease (CKD) is well-established, there is a lack of systematic research investigating the specific roles of serum metabolites, including lipid metabolites, amino acid metabolites, carbohydrate metabolites and inflammatory substances in explaining this associations. We included 118,020 general patients with data of serum metabolites from UK Biobank. We defined abdominal obesity and CKD based on waist circumference and ICD-10 criteria. The serum metabolites were assessed by a high-throughput nuclear magnetic resonance (NMR) based metabolic biomarker profiling platform. We conducted mediation analysis by R software and used the proportion of mediation to quantify the mediation effect. This study demonstrated that lipid metabolites played a more important role in mediating the relationship between abdominal obesity and CKD than amino acid metabolites and carbohydrate metabolites. And Glycoprotein Acetyls (GlycA) was the strongest mediator for the correlation between abdominal obesity and CKD, accounting for 26.4 %. And In the mediation analysis stratified by sex, we found that the mediating effects of lipid metabolites were mostly higher in men than in women, while GlycA accounted for the largest proportion of the mediation association in both two groups (31.0 % for women and 19.8 % for men). Among lipid metabolites, amino acid metabolites, carbohydrate metabolites and inflammatory substances, our study showed that infammation marker GlycA was the novel and key mediator for the correlation between abdominal obesity and CKD. [ABSTRACT FROM AUTHOR]

Inflammageing is a condition of perpetual low-grade inflammation induced by ageing. Inflammageing may be predicted by the C-reactive protein (CRP) or by a recently described biomarker which measures N-glycosylated side chains of the carbohydrate component of several acute-phase proteins known as GlycA. The objective of this study was to examine in depth the genetic relationships between CRP and GlycA as well as between each of them and other selected cytokines, which may shed light on the mechanisms of inflammageing. Using the Olink 96 Inflammation panel, data on inflammatory mediators for 1518 twins from the TwinsUK dataset were acquired. Summary statistics for genome-wide association studies for several cytokines as well as CRP and GlycA were collected from public sources. Extensive genetic correlation analyses, colocalization and genetic enrichment analyses were carried out to detect the shared genetic architecture between GlycA and CRP. Mendelian randomization was carried out to assess potential causal relationships. GlycA predicted examined cytokines with a magnitude twice as great as that of CRP. GlycA and CRP were significantly genetically correlated (Rg = 0.4397 ± 0.0854, p-value = 2.60 × 10−7). No evidence of a causal relationship between GlycA and CRP, or between these two biomarkers and the cytokines assessed was obtained. However, the aforementioned relationships were explained well by horizontal pleiotropy. Five exonic genetic variants annotated to five genes explain the shared genetic architecture observed between GlycA and CRP: IL6R, GCKR, MLXIPL, SERPINA1, and MAP1A. GlycA and CRP possess a shared genetic architecture, but the relationship between them appears to be modest, which may imply the promotion of differing inflammatory pathways. GlycA appears to be a more robust predictor of cytokines compared to CRP. [ABSTRACT FROM AUTHOR]

It has been suggested that glycoprotein acetyls (GlycA) better reflects chronic inflammation than high sensitivity C‐reactive protein (hsCRP), but paediatric/life‐course data are sparse. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we compared short‐ (over weeks) and long‐term (over years) correlations of GlycA and hsCRP, cross‐sectional correlations between GlycA and hsCRP, and associations of pro‐inflammatory risk factors with GlycA and hsCRP across the life‐course. GlycA showed high short‐term (weeks) stability at 15 years (r = 0.75; 95% CI = 0.56, 0.94), 18 years (r = 0.74; 0.64, 0.85), 24 years (r = 0.74; 0.51, 0.98) and 48 years (r = 0.82 0.76, 0.86) and this was comparable to the short‐term stability of hsCRP at 24 years. GlycA stability was moderate over the long‐term, for example between 15 and 18 years r = 0.52; 0.47, 0.56 and between 15 and 24 years r = 0.37; 0.31, 0.44. These were larger than equivalent correlations of hsCRP. GlycA and concurrently measured hsCRP were moderately correlated at all ages, for example at 15 years (r = 0.44; 0.40, 0.48) and at 18 years (r = 0.55; 0.51, 0.59). We found similar associations of known proinflammatory factors and inflammatory diseases with GlycA and hsCRP. For example, BMI was positively associated with GlycA (mean difference in GlycA per standard deviation change in BMI = 0.08; 95% CI = 0.07, 0.10) and hsCRP (0.10; 0.08, 0.11). This study showed that GlycA has greater long‐term stability than hsCRP, however associations of proinflammatory factors with GlycA and hsCRP were broadly similar. [ABSTRACT FROM AUTHOR]

• Pre-pregnancy obesity increases the risk of depression and stress during pregnancy. • Overweight and obesity increase systemic inflammation during pregnancy. • Obesity-induced inflammation is associated with antenatal depression and stress. Pre-pregnancy obesity is an emerging risk factor for perinatal depression. However, the underlying mechanisms remain unclear. We investigated the association between pre-pregnancy body mass index (BMI) and perinatal depressive symptoms in a large population-based pre-birth cohort, the Barwon Infant Study. We also assessed whether the levels of circulating inflammatory markers during pregnancy mediated this relationship. Depressive symptoms were assessed in 883 women using the Edinburgh Postnatal Depression Scale (EPDS) and psychological stress using the Perceived Stress Scale (PSS) at 28 weeks gestation and 4 weeks postpartum. Glycoprotein acetyls (GlycA), high-sensitivity C-reactive protein (hsCRP) and cytokines were assessed at 28 weeks gestation. We performed regression analyses, adjusted for potential confounders, and investigated mediation using nested counterfactual models. The estimated effect of pre-pregnancy obesity (BMI ≥ 30 kg/m2) on antenatal EPDS scores was 1.05 points per kg/m2 increase in BMI (95% CI: 0.20, 1.90; p = 0.02). GlycA, hsCRP, interleukin (IL) −1ra and IL-6 were higher in women with obesity, compared to healthy weight women, while eotaxin and IL-4 were lower. Higher GlycA was associated with higher EPDS and PSS scores and partially mediated the association between pre-pregnancy obesity and EPDS/PSS scores in unadjusted models, but this association attenuated upon adjustment for socioeconomic adversity. IL-6 and eotaxin were negatively associated with EPDS/PSS scores, however there was no evidence for mediation. Pre-pregnancy obesity increases the risk of antenatal depressive symptoms and is also associated with systemic inflammation during pregnancy. While discrete inflammatory markers are associated with antenatal depressive symptoms and perceived stress, their role in mediating the effects of pre-pregnancy obesity on antenatal depression requires further investigation. [ABSTRACT FROM AUTHOR]

Inflammation is associated with depression, but causality remains unclear. We investigated potential causality and direction of effect between inflammation and depression. Using data from the ALSPAC birth cohort (n = 4021; 42.18 % male), we used multivariable regression to investigate bidirectional longitudinal associations of GlycA and depression and depression symptoms, assessed at ages 18y and 24y. We used two-sample Mendelian randomization (MR) to investigate potential causality and directionality. Genetic variants for GlycA were obtained from UK Biobank (UKB) (N = 115,078); for depression from the Psychiatric Genomics Consortium and UKB (N = 500,199); and for depressive symptoms (N = 161,460) from the Social Science Genetic Association Consortium. In addition to the Inverse Variance Weighted method, we used sensitivity analyses to strengthen causal inference. We conducted multivariable MR adjusting for body mass index (BMI) due to known genetic correlation between inflammation, depression and BMI. In the cohort analysis, after adjusting for potential confounders we found no evidence of associations between GlycA and depression symptoms score or vice versa. We observed an association between GlycA and depression (OR = 1∙18, 95 % CI: 1∙03–1∙36). MR suggested no causal effect of GlycA on depression, but there was a causal effect of depression on GlycA (mean difference in GlycA = 0∙09; 95 % CI: 0∙03–0∙16), which was maintained in some, but not all, sensitivity analyses. The GWAS sample overlap could incur bias. We found no consistent evidence for an effect of GlycA on depression. There was evidence that depression increases GlycA in the MR analysis, but this may be confounded/mediated by BMI. • The direction of effect/causality between inflammation and depression is unclear. • GlycA may be a superior marker of chronic inflammation compared to CRP or IL-6. • We find no consistent evidence for an effect of GlycA on depression. • We find depression increases levels of GlycA. • The effect of depression on GlycA levels may be confounded/mediated by BMI. [ABSTRACT FROM AUTHOR]

Abstract Background Metabolic profiles differ between healthy humans and those with inflammatory bowel disease. Few studies have examined metabolic profiles in dogs with chronic enteropathy (CE). Hypothesis Serum metabolic profiles of dogs with CE are significantly different from those of healthy dogs. Animals Fifty‐five dogs with CE and 204 healthy controls. Methods A cross‐sectional study. The serum concentrations of 99 metabolites measured using a canine‐specific proton nuclear magnetic resonance spectroscopy platform were studied. A 2‐sample unpaired t‐test was used to compare the 2 study samples. The threshold for significance was set at P

Background: Metabolic profiles differ between healthy humans and those with inflammatory bowel disease. Few studies have examined metabolic profiles in dogs with chronic enteropathy (CE). Hypothesis: Serum metabolic profiles of dogs with CE are significantly different from those of healthy dogs. Animals: Fifty‐five dogs with CE and 204 healthy controls. Methods: A cross‐sectional study. The serum concentrations of 99 metabolites measured using a canine‐specific proton nuclear magnetic resonance spectroscopy platform were studied. A 2‐sample unpaired t‐test was used to compare the 2 study samples. The threshold for significance was set at P <.05 with a Bonferroni correction for each metabolite group. Results: Nineteen metabolites and 18 indices of lipoprotein composition were significantly different between the CE and healthy dogs. Four metabolites were significantly higher in dogs with CE, including phenylalanine (mean and SD) (healthy: 0.0417 mmol/L; [SD] 0.0100; CE: 0.0480 mmol/L; SD: 0.0125; P value: <.001) and lactate (healthy: 1.8751 mmol/L; SD: 0.7808; CE: 2.4827 mmol/L; SD CE: 1.4166; P value:.003). Fifteen metabolites were significantly lower in dogs with CE, including total fatty acids, and glycine (healthy: 0.2273 mmol/L; SD: 0.0794; CE: 0.1828 mmol/L; SD CE: 0.0517; P value: <.001). Conclusions and Clinical Importance: The metabolic profile of dogs with CE is significantly different from that of healthy dogs, this opens novel research avenues to develop better diagnostic and prognostic approaches as well as therapeutic trials. [ABSTRACT FROM AUTHOR]

• Glycoprotein acetyls levels at birth (GlycA birth) were positively associated with emotional and behavioral problems (EBP) at two years. • Inflammation at birth has a stronger association with EBP than 12-month measures. • Socioeconomic disadvantage was associated with increased EBP. • Some risk factors for EBP are partially mediated by higher inflammation at birth. Emotional and behavioral problems (EBP) are common in children. Environmental factors like socioeconomic disadvantage influence EBP pathogenesis and can trigger inflammation. However, the link between early inflammation-EBP in children is unclear. We investigated the associations between i) infant inflammatory biomarkers and subsequent EBP and ii) early life environmental factors and EBP and assessed whether infant inflammation mediated these associations. Inflammatory biomarkers glycoprotein acetyls (GlycA) and high-sensitivity C-reactive protein (hsCRP) were quantified at birth and 12 months in a population – derived birth cohort, the Barwon Infant Study. Early life factors including demographic, prenatal, and perinatal factors were collected from antenatal to the two-year period. Internalizing and externalizing problems at age two were measured by the Child Behavior Checklist. Prospective associations were examined by multivariable regression analyses adjusted for potential confounders. Indirect effects of early life factors on EBP through inflammation were identified using mediation analyses. Elevated GlycA levels at birth (GlycA birth) were associated with greater internalizing problems at age two (β = 1.32 per SD increase in GlycA; P = 0.001). Inflammation at birth had a stronger magnitude of effect with later EBP than at 12 months. GlycA birth partially mediated the associations between lower household income (6%), multiparity (12%) and greater number of older siblings (13%) and EBP. Patterns were less evident for hsCRP or externalizing problems. GlycA birth was positively associated with EBP at age two and partially mediated the association between several indicators of socioeconomic disadvantage and EBP. Prenatal and perinatal inflammation may be relevant to early neurodevelopment and emotional health. [ABSTRACT FROM AUTHOR]

Context: While Asians have a higher risk of type 2 diabetes (T2D) than Europeans for a given body mass index (BMI), it remains unclear whether the same markers of metabolic pathways are associated with diabetes. Objective: We evaluated associations between metabolic biomarkers and incidence of T2D in 3 major Asian ethnic groups (Chinese, Malay, and Indian) and a European population. Methods: We analyzed data from adult males and females of 2 cohorts from Singapore (n = 6393) consisting of Chinese, Malays, and Indians and 3 cohorts of European-origin participants from Finland (n = 14 558). We used nuclear magnetic resonance to quantify 154 circulating metabolic biomarkers at baseline and performed logistic regression to assess associations with T2D risk adjusted for age, sex, BMI and glycemic markers. Results: Of the 154 metabolic biomarkers, 59 were associated with higher risk of T2D in both Asians and Europeans (P < 0.0003, Bonferroni-corrected). These included branched chain and aromatic amino acids, the inflammatory marker glycoprotein acetyls, total fatty acids, monounsaturated fatty acids, apolipoprotein B, larger very low-density lipoprotein particle sizes, and triglycerides. In addition, 13 metabolites were associated with a lower T2D risk in both populations, including omega-6 polyunsaturated fatty acids and larger high-density lipoprotein particle sizes. Associations were consistent within the Asian ethnic groups (all Phet ≥ 0.05) and largely consistent for the Asian and European populations (Phet ≥ 0.05 for 128 of 154 metabolic biomarkers). Conclusion: Metabolic biomarkers across several biological pathways were consistently associated with T2D risk in Asians and Europeans. [ABSTRACT FROM AUTHOR]

• Adverse Childhood Experiences positively associate with non-communicable diseases. • Chronic inflammation may mediate these associations, but evidence is inconsistent. • Glycoprotein Acetyls is a proposed marker of chronic and cumulative inflammation. • Total Adverse Childhood Experiences were not associated with GlycA in childhood. • Total Adverse Childhood Experiences were associated with GlycA in mid-adulthood. Adverse childhood experiences (ACEs) are associated with increased risk of non-communicable diseases in adulthood, potentially mediated by chronic low-grade inflammation. Glycoprotein acetyls (GlycA) is a marker of chronic and cumulative inflammation. We investigated associations between ACEs and GlycA at different ages, in two generations of the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. ALSPAC offspring's total ACE scores were generated for two age periods using prospectively collected data: 0-7y and 0-17y. GlycA was measured using high-resolution proton nuclear magnetic resonance at mean ages 8y, 18y, and 24y. Sample sizes ranged from: n = 5116 (8y) to n = 3085 (24y). ALSPAC mothers (n = 4634) retrospectively reported ACEs experienced before age 18y and GlycA was assessed at mean age 49y. We used multivariable linear regression to estimate associations between ACEs (total ACE score and individual ACEs) and subsequent GlycA in both samples, adjusting for key confounders. Mean GlycA levels were similar in offspring and mothers and over time. In offspring, there was no evidence that ACEs (total score or individual ACE) were associated with GlycA at age 8y or 18y, or 24y after adjustment for maternal age at birth and parity, maternal marital status, household occupational social class, maternal education, maternal smoking, own ethnicity, sex, and age in months. In mothers, there was evidence of a positive association between the total ACE score and GlycA at age 49y (adjusted mean difference 0.007 mmol/L; 95%CI: 0.003, 0.01). Emotional neglect was the only individual ACE associated with higher GlycA after adjusting for confounders and other ACEs. Results suggest the association between ACEs and GlycA may emerge in middle age. Future research should explore the extent to which inflammation in adulthood mediates well-documented associations between ACEs and adverse health outcomes in later life. [ABSTRACT FROM AUTHOR]

Abstract Background 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. Methods 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. Results 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, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 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). Conclusions Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.

Aims  Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement. Methods and results  Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function. Conclusions  Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 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).Conclusions: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology. [ABSTRACT FROM AUTHOR]

Context: While Asians have a higher risk of type 2 diabetes (T2D) than Europeans for a given body mass index (BMI), it remains unclear whether the same markers of metabolic pathways are associated with diabetes., Objective: We evaluated associations between metabolic biomarkers and incidence of T2D in 3 major Asian ethnic groups (Chinese, Malay, and Indian) and a European population., Methods: We analyzed data from adult males and females of 2 cohorts from Singapore (n = 6393) consisting of Chinese, Malays, and Indians and 3 cohorts of European-origin participants from Finland (n = 14 558). We used nuclear magnetic resonance to quantify 154 circulating metabolic biomarkers at baseline and performed logistic regression to assess associations with T2D risk adjusted for age, sex, BMI and glycemic markers., Results: Of the 154 metabolic biomarkers, 59 were associated with higher risk of T2D in both Asians and Europeans (P < 0.0003, Bonferroni-corrected). These included branched chain and aromatic amino acids, the inflammatory marker glycoprotein acetyls, total fatty acids, monounsaturated fatty acids, apolipoprotein B, larger very low-density lipoprotein particle sizes, and triglycerides. In addition, 13 metabolites were associated with a lower T2D risk in both populations, including omega-6 polyunsaturated fatty acids and larger high-density lipoprotein particle sizes. Associations were consistent within the Asian ethnic groups (all Phet ≥ 0.05) and largely consistent for the Asian and European populations (Phet ≥ 0.05 for 128 of 154 metabolic biomarkers)., Conclusion: Metabolic biomarkers across several biological pathways were consistently associated with T2D risk in Asians and Europeans., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)