TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population

<p>Abstract</p> <p>Background</p> <p>In adults, the <it>TCF7L2 </it>rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance.</p> <p>Methods</p> <p>The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10^thpercentile; n = 764), and AGA (25^th< birth weight < 75^thpercentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees.</p> <p>Results</p> <p>The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78–1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele.</p> <p>Conclusion</p> <p>The <it>TCF7L2 </it>rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA.</p

Glucose-Dependent Regulation of NR2F2 Promoter and Influence of SNP-rs3743462 on Whole Body Insulin Sensitivity

Background: The Nuclear Receptor 2F2 (NR2F2/COUP-TFII) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses NR2F2 gene expression in pancreatic β-cells. The cis-regulatory region of the NR2F2 promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control NR2F2 gene transcription and to evaluate the effect of NR2F2 promoter variation on glucose homeostasis in humans. Methodology/Principal Findings: Regulation of the NR2F2 promoter was assessed using gene reporter assays, ChIP and gel shift experiments. The effects of variation at SNP rs3743462 in NR2F2 on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4α activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried the rs3743462 T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levels and lower HOMA-IR index. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased NR2F2 gene expression. Conclusions/Significance: The rs3743462 polymorphism affects glucose-responsive NR2F2 promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans. © 2012 Boutant et al

Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity

<p>Abstract</p> <p>Background</p> <p>7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, <it>SGNE1 </it>is located. The aim of this study is to analyze associations of <it>SGNE1 </it>genetic variation with obesity and metabolism related quantitative traits.</p> <p>Methods</p> <p>We screened <it>SGNE1 </it>for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort.</p> <p>Results</p> <p>We did not find any association between <it>SGNE1 </it>SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55–1.01]; p = 0.06) in the prospective cohort.</p> <p>Conclusion</p> <p><it>SGNE1 </it>genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.</p

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

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

A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far

No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Peer reviewe

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Analysis of common <it>PTPN1 </it>gene variants in type 2 diabetes, obesity and associated phenotypes in the French population

<p>Abstract</p> <p>Background</p> <p>The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the <it>PTPN1 </it>gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D) in several populations. <it>PTPN1 </it>gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of <it>PTPN1 </it>genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population.</p> <p>Methods</p> <p>Fourteen single nucleotide polymorphisms (SNPs) spanning the <it>PTPN1 </it>locus were selected from previous association reports and from HapMap linkage disequilibrium data. SNPs were evaluated for association with T2D in two case-control groups with 1227 cases and 1047 controls. Association with moderate and severe obesity was also tested in a case-control study design. Association with metabolic traits was evaluated in 736 normoglycaemic, non-obese subjects from a general population. Five SNPs showing a trend towards association with T2D, obesity or metabolic parameters were investigated for familial association.</p> <p>Results</p> <p>From 14 SNPs investigated, only SNP rs914458, located 10 kb downstream of the <it>PTPN1 </it>gene significantly associated with T2D (p = 0.02 under a dominant model; OR = 1.43 [1.06–1.94]) in the combined sample set. SNP rs914458 also showed association with moderate obesity (allelic p = 0.04; OR = 1.2 [1.01–1.43]). When testing for association with metabolic traits, two strongly correlated SNPs, rs941798 and rs2426159, present multiple consistent associations. SNP rs2426159 exhibited evidence of association under a dominant model with glucose homeostasis related traits (p = 0.04 for fasting insulin and HOMA-B) and with lipid markers (0.02 = p = 0.04). Moreover, risk allele homozygotes for this SNP had an increased systolic blood pressure (p = 0.03). No preferential transmission of alleles was observed for the SNPs tested in the family sample.</p> <p>Conclusion</p> <p>In our study, <it>PTPN1 </it>variants showed moderate association with T2D and obesity. However, consistent associations with metabolic variables reflecting insulin resistance and dyslipidemia are found for two intronic SNPs as previously reported. Thus, our data indicate that <it>PTPN1 </it>variants may modulate the lipid profile, thereby influencing susceptibility to metabolic disease.</p