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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

ABSTRACT: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

SUBMITTER: Lagou V

PROVIDER: S-EPMC7785747 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Additive effects of genetic variation in GCK and G6PC2 on insulin secretion and fasting glucose.

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| S-EPMC2780888 | biostudies-literature

Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program.

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| S-EPMC3439414 | biostudies-literature

Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans.

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| S-EPMC3459464 | biostudies-literature

Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.

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| S-EPMC2857908 | biostudies-literature

Genetic variation at glucose and insulin trait loci and response to glucose-insulin-potassium (GIK) therapy: the IMMEDIATE trial.

Project description:The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10(-6)). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS).

| S-EPMC6512969 | biostudies-literature

Racial/ethnic differences in association of fasting glucose-associated genomic loci with fasting glucose, HOMA-B, and impaired fasting glucose in the U.S. adult population.

Project description:ObjectiveTo estimate allele frequencies and the marginal and combined effects of novel fasting glucose (FG)-associated single nucleotide polymorphisms (SNPs) on FG levels and on risk of impaired FG (IFG) among non-Hispanic white, non-Hispanic black, and Mexican Americans.Research design and methodsDNA samples from 3,024 adult fasting participants in the National Health and Nutrition Examination Survey (NHANES) III (1991-1994) were genotyped for 16 novel FG-associated SNPs in multiple genes. We determined the allele frequencies and influence of these SNPs alone and in a weighted genetic risk score on FG, homeostasis model assessment of β-cell function (HOMA-B), and IFG by race/ethnicity, while adjusting for age and sex.ResultsAll allele frequencies varied significantly by race/ethnicity. A weighted genetic risk score, based on 16 SNPs, was associated with a 0.022 mmol/l (95% CI 0.009-0.035), 0.036 mmol/l (0.019-0.052), and 0.033 mmol/l (0.020-0.046) increase in FG levels per risk allele among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. Adjusted odds ratios for IFG were 1.78 for non-Hispanic whites (95% CI 1.00-3.17), 2.40 for non-Hispanic blacks (1.07-5.37), and 2.39 for Mexican Americans (1.37-4.14) when we compared the highest with the lowest quintiles of genetic risk score (P=0.365 for testing heterogeneity of effect across race/ethnicity).ConclusionsWe conclude that allele frequencies of 16 novel FG-associated SNPs vary significantly by race/ethnicity, but the influence of these SNPs on FG levels, HOMA-B, and IFG were generally consistent across all racial/ethnic groups.

| S-EPMC2963497 | biostudies-literature

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Project description:Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

| S-EPMC3018764 | biostudies-literature

Age- and sex-specific profiles of temporal fasting plasma glucose variability in a population undergoing routine health screening.

Project description:BackgroundFasting plasma glucose (FPG) variability is a significant predictor of mortality, especially in patients with poor glycemic control. This study aimed to explore the temporal age- and sex-specific profiles of temporal FPG variability in a Chinese population undergoing routine health screening and to guide the development of targeted public health interventions for the prevention and control of diabetes.MethodsIn this cross-sectional study, we used a general linear model to compare differences in temporal FPG values between sexes and across age groups in 101,886 Nanjing residents who underwent a routine physical health examination at the Health Management Center, the First Affiliated Hospital of Nanjing Medical University, in 2018. The variability of FPG as a function of time, age, and sex, independently and in combination, was analyzed.ResultsThe participants included 57,455 (56.4%) males and 44,431 (43.6%) females, with a mean ± SD age of 42.8 ± 15.0 years. The average ± SD FPG level was 5.5 ± 1.1 mmol/L. The monthly variation contributed to 22% of the overall FPG variability. A significant main effect for the age group was observed (F = 7.39, P < 0.05), with an excellent fitting effect (Eta-squared =0.15). The variability of FPG showed sex differences in the percentage difference of the coefficient of variation, which was 34.1% higher in males than females. There were significant interaction effects for month*age*sex and day*age*sex.ConclusionsTemporal variability in FPG is evident in the general Chinese population and is affected by both age and sex. To avoid complications associated with FPG variability, interventions should be directed at females and males at specific ages for optimal control of FPG variability and to reduce the risk of diabetes and cardiovascular events.

| S-EPMC7871645 | biostudies-literature

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.

Project description:ObjectiveWhole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.Research design and methodsVia meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.ResultsGreater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.ConclusionsOur results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

| S-EPMC2992213 | biostudies-literature

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

Project description:Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

| S-EPMC5005440 | biostudies-literature

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