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

New susceptibility loci associated with kidney disease in type 1 diabetes

WOS:000309817900008Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.Peer reviewe

O OR RI IG GI IN NA Investigation of P213S SELL gene polymorphism in type 2 diabetes mellitus and related end stage renal disease. A case-control study

Abstract SELL (L-selectin) is a candidate gene for several complex diseases including diabetes mellitus and renal failure. Our aim was to investigate the involvement of P213S SELL gene polymorphism (rs2229569) in type 2 diabetes mellitus (T2DM) and related end stage renal disease (ESRD). Type 2 diabetes mellitus patients without ESRD (n=250) or with ESRD (n=90), ESRD patients without diabetes (n=119) and sex and age matched healthy subjects (n=459) were analyzed in this study. DNA samples from all these subjects were genotyped for the P213S polymorphism by PCR-RFLP technique. Statistical analysis indicated that SELL P213S genotypes and alleles were similar distributed in the patients and control groups (ORSS=0.37, CI 95%: 0.131&gt;0.372&gt;1.06, p=0.05, Yate&apos;s correction p=0.09, for T2DM patients without ESRD, ORSS=2.04, CI 95%: 0.365&gt;2.047&gt;1.465, p=0.4, Yate&apos;s correction p=0.67, for T2DM patients with ESRD and ORSS=1, CI95%: 0.198&gt;1&gt;5.057, p=1, Yate&apos;s correction p=0.67, for non-diabetic with ESRD patients). Also, no significant differences were noticed when we compared the ESRD subjects with diabetes vs. non-diabetic ones (OR=1.798, CI 95%: 0.392&gt;1.798&gt;8.245, p=0.44, Yate&apos;s correction p=0.7). No statistically significant results were found in order to sustain the hypothesis of association between SELL gene P213S polymorphism, type 2 diabetes mellitus and end stage renal disease

Characteristics of samples successfully analyzed in each discovery collection and the meta-analyses.

<p>n = total number of patients; Micro = patients with microalbuminuria; M/F = number of males/females; HbA_1C blood glycosylated hemoglobin; BMI = body mass index. Case = macroalbuminuria or ESRD, Control = normoalbuminuric, see text for full details.</p

Flow chart summarizing study design.

<p>We applied a two stage study design, where the top signals from the meta-analysis of three GENIE studies (UK-ROI, FinnDiane and GoKinD US) were followed up in phase two analysis, consisting of nine T1D cohorts. After combined meta-analysis, two signals reached genome-wide significance in the analysis of ESRD (<i>P</i><5×10⁻⁸). For DN phenotype no loci reached this threshold, but the strongest association was observed for <i>ERBB4</i>. These signals were followed up with eQTL studies and functional analysis. The number of patients (N) refers to the number of samples after genotype quality control; either the total number of samples or divided into cases/controls.</p