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

Diabetic nephropathy in type 2 diabetes mellitus: risk factors and prevention

A nefropatia diabética (ND) é responsável pelo aumento do número de pacientes em diálise em países em desenvolvimento, e já é a principal causa de terapia de substituição renal nos países desenvolvidos. Neste manuscrito, revisamos os fatores de risco e apontamos estratégias para prevenir esta complicação microvascular nos pacientes com diabete melito tipo 2 (DM2). Alguns fatores de risco genéticos e não-genéticos estão relacionados ao desenvolvimento e à progressão da ND em pacientes DM2. Genes candidatos têm sido analisados, mas ainda há controvérsias sobre os marcadores genéticos da doença. Os fatores de risco não-genéticos reconhecidos são o mau controle glicêmico, pressórico e lipídico. Além disso, tem sido sugerido que a presença de retinopatia diabética e de neuropatia autonômica, do hábito de fumar, da alta ingestão protéica, e de níveis mais altos de albuminúria (mesmo dentro dos níveis normais) estão associados com um risco aumentado de desenvolvimento de ND. Algumas estratégias têm sido investigadas e comprovadas para prevenir ou, no mínimo, postergar o desenvolvimento da ND, tais como o controle da pressão arterial, da glicemia e da dislipidemia. Adicionalmente, os inibidores da ECA e os bloqueadores da angiotensina II apresentam efeitos independentes, não apenas explicado pelo controle da pressão arterial. Outras medidas terapêuticas são a baixa ingestão de proteínas na dieta e a suspensão do fumo.Diabetic nephropathy (DN) is responsible for the increasing number of patients on dialysis in developing countries, and is already the most common cause of renal replacement therapy in the developed ones. In this manuscript, we review the risk factors and point out strategies to prevent this microvascular complication in type 2 diabetic patients (DM2). There are some known genetic and non-genetic risk factors related to the development and progression of DN in DM2 patients. Candidate genes have been analysed, but there are still controversy about the genetic markers of the disease. Recognized non-genetic risk factors are poor glycemic, pressoric and lipidic control. Additionally, it has been suggested that the presence of diabetic retinopathy, autonomic neuropathy, smoking habit, higher protein ingestion, and higher normal levels of albuminuria (even within the normal range) are associated with an increased risk of developing DN. Some strategies have been investigated and proved to prevent or at least to postpone DN, such as to control blood pressure, glycemic levels and dyslipidemia. Furthermore, angiotensinconverting enzyme inhibitors and angiotensin-II blockers have independent effects, not explained by blood pressure control alone. Other therapeutic items are to consume a low protein diet and to quit smoking