Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.Please refer to the manuscript or visit the publisher's website for funding infomation

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

Ligand modulated antagonism of PPARγ by genomic and non-genomic actions of PPARδ

Abstract Top Background Members of the Peroxisome Proliferator Activated Receptor, PPAR, subfamily of nuclear receptors display complex opposing and overlapping functions and a wide range of pharmacological and molecular genetic tools have been used to dissect their specific functions. Non-agonist bound PPARδ has been shown to repress PPAR Response Element, PPRE, signalling and several lines of evidence point to the importance of PPARδ repressive actions in both cardiovascular and cancer biology. Methodology/Principal Findings In this report we have employed transient transfections and luciferase reporter gene technology to study the repressing effects of PPARδ and two derivatives thereof. We demonstrate for the first time that the classical dominant negative deletion of the Activation Function 2, AF2, domain of PPARδ show enhanced repression of PPRE signalling in the presence of a PPARδ agonist. We propose that the mechanism for the phenomenon is increased RXR heterodimerisation and DNA binding upon ligand binding concomitant with transcriptional co-repressor binding. We also demonstrated ligand-dependent dominant negative action of a DNA non-binding derivative of PPARδ on PPARγ1 signalling. This activity was abolished upon over-expression of RXRα suggesting a role for PPAR/cofactor competition in the absence of DNA binding. Conclusions/Significance These findings are important in understanding the wide spectrum of molecular interactions in which PPARδ and PPARγ have opposing biological roles and suggest novel paradigms for the design of different functional classes of nuclear receptor antagonist drugs

PPARδΔAF2 represses (A) PPARδ and (B) PPARγ1 signalling. (C) PPARδΔAF2 represses TK-promoter activity in a ligand-enhanced fashion.

<p>COS-1 cells were transiently transfected with (per well in six-well plates) (A) 50 ng pCLDN-hPPARδ or (B) pCDLN-hPPARγ1 and 250 ng pCLDN or pCLDN-hPPARδΔAF2. (C) and (D) T47D cells were transfected with (per well in a six-well plate) 500 ng pCLDN, pCLDN-hPPARδΔAF2 or pCLDN-hPPARδ. (D) is identical to (C) except for the two additional bars representing over-expression of PPARδ with and without CF.</p

(A) The PPARδ LBD is functional with respect to transcriptional transactivation and RXR heterodimerisation and (B), (C) and (D) possess ligand-dependent dominant negative behaviour.

<p>(A) COS-1 cells were transfected with 500 ng pCMVgRXR and 500 ng pCLDN or pCLDN-δLBD. (B), (C) and (D) COS-1 cells were transiently transfected with: (B) 500 ng pJ3Nuc (hPPARδ expression plasmid) and 0 to 500 ng pCLDN or pCLDN-δLBD; (C) 50 ng pCLDN-hPPARγ1 and 0 to 500 ng pCLDN or pCLDN-δLBD; (D) 50 ng pCLDN-hPPARγ1 and 500 ng pCLDN-δLBD.</p

The effect of (A) non-liganded PPARγ1 on PPARδ signalling and of (B) non-liganded PPARδ on PPARγ1 signalling.

<p>COS-1 cells were transiently transfected with (per well in six-well plates) 50 ng (A) pCLDN-hPPARδ or (B) pCDLN-hPPARγ1 and 250 ng (A) pCLDN or pCLDN-hPPARγ1 and (B) pCLDN or pCLDN-hPPARδ, respectively.</p