To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of... Show moreTo date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases. Show less
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here... Show moreGlycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets. Show less
Background Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other... Show moreBackground Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods This study includes baseline data from 634 adults with overweight or obesity (BMI >= 27 kg/m(2)) (<= 65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI >= 27 kg/m(2); 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages. Show less
Merino, J.; Dashti, H.S.; Li, S.X.; Sarnowski, C.; Justice, A.E.; Graff, M.; ... ; Tanaka, T. 2019
The prevalence of type 2 diabetes (T2D) has increased rapidly. Adopting a heathy diet is suggested as one of the effective behaviors to prevent or delay onset of T2D. Dairy consumption has been... Show moreThe prevalence of type 2 diabetes (T2D) has increased rapidly. Adopting a heathy diet is suggested as one of the effective behaviors to prevent or delay onset of T2D. Dairy consumption has been recommended as part of a healthy diet, but there remains uncertainty in both the scientific community and the public about the effect of different dairy products on T2D risk. In a recent workshop, the evidence on dairy products and T2D risk was presented and discussed by a group of experts. The main conclusions from the workshop are presented in this position paper and are as follows. 1) Available evidence from large prospective cohort studies and limited randomized controlled trials (RCTs) suggests that total dairy consumption has a neutral or moderately beneficial effect on T2D risk. 2) Increasing evidence from prospective cohort studies indicates that yogurt is most strongly associated with a lower T2D risk, but evidence from RCTs is scarce. 3) Fatty acids from dairy (medium-chain, odd, and very long-chain SFAs as well as trans-palmitoleic acid) are associated with lower T2D risk and improved metabolic health, but more research is needed on studies that explore cause and effect relations to exclude the possibility that the dairy fatty acids simply serve as markers of overall dairy consumption. 4) The food matrix can be a stronger determinant of health effects than SFA content. This review further identifies research gaps in the existing knowledge and highlights key research questions that need to be addressed to better understand the impact of dairy consumption on future T2D risk. Show less
Teumer, A.; Chaker, L.; Groeneweg, S.; Li, Y.; Munno, C. di; Barbieri, C.; ... ; Lifelines Cohort Study 2018
Obesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid... Show moreObesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid profiles in overweight/obese individuals who show muscle-IR and/or liver-IR.). Muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI) were derived from a 5-point oral glucose tolerance test. The 140 plasma lipids were quantified by liquid chromatography-mass spectrometry. Linear mixed models were used to evaluate associations between MISI, HIRI and plasma lipids.MISI was comparable between sexes while HIRI and triacylglycerol (TAG) levels were lower in women than in men. MISI was associated with higher lysophosphatidylcholine (LPC) levels (standardized (std)β = 0.126; FDR-p = 0.032). Sex interactions were observed for associations between HIRI, TAG and diacylglycerol (DAG) lipid classes. In women, but not in men, HIRI was associated with higher levels of TAG (44 out of 55 species) and both DAG species (stdβ: 0.139-0.313; FDR-p < 0.05), a lower odd-chain/even-chain TAG ratio (stdβ = -0.182; FDR-p = 0.005) and a lower very-long-chain/long-chain TAG ratio (stdβ = -0.156; FDR-p = 0.037).In overweight/obese individuals, muscle insulin sensitivity is associated with higher plasma LPC concentrations. Women have less hepatic IR and lower TAG than men. Nevertheless, hepatic IR is associated with higher plasma TAG and DAG concentrations and a lower abundance of odd-chain and very-long-chain TAG in women, but not in men. This suggests a more pronounced worsening of plasma lipid profile in women with the progression of hepatic IR.BACKGROUND/OBJECTIVESSUBJECTS/METHODSRESULTSCONCLUSIONS Show less
Merino, J.; Dashti, H.S.; Li, S.X.; Sarnowski, C.; Justice, A.E.; Graff, M.; ... ; Tanaka, T. 2018
