Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjectsReportar como inadecuado




Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Medical Genetics

, 10:77

First Online: 14 August 2009Received: 13 March 2009Accepted: 14 August 2009

Abstract

BackgroundNeuron-derived orphan receptor Nor 1, nuclear receptor Nur 77, and nuclear receptor-related protein Nurr 1 constitute the NR4A family of orphan nuclear receptors which were recently found to modulate hepatic glucose production, insulin signalling in adipocytes, and oxidative metabolism in skeletal muscle. In this study, we assessed whether common genetic variation within the NR4A3 locus, encoding Nor-1, contributes to the development of prediabetic phenotypes, such as glucose intolerance, insulin resistance, or β-cell dysfunction.

MethodsWe genotyped 1495 non-diabetic subjects from Southern Germany for the five tagging single nucleotide polymorphisms SNPs rs7047636, rs1526267, rs2416879, rs12686676, and rs10819699 minor allele frequencies ≥ 0.05 covering 100% of genetic variation within the NR4A3 locus with D- = 1.0, r ≥ 0.9 and assessed their association with metabolic data derived from the fasting state, an oral glucose tolerance test OGTT, and a hyperinsulinemic-euglycemic clamp subgroup, N = 506. SNPs that revealed consistent associations with prediabetic phenotypes were subsequently genotyped in a second cohort METSIM Study; Finland; N = 5265 for replication.

ResultsAll five SNPs were in Hardy-Weinberg equilibrium p ≥ 0.7, all. The minor alleles of three SNPs, i.e., rs1526267, rs12686676, and rs10819699, consistently tended to associate with higher insulin release as derived from plasma insulin at 30 minOGTT, AUCC-peptide-to-AUCGluc ratio and the AUCIns30-to-AUCGluc30 ratio with rs12686676 reaching the level of significance p ≤ 0.03, all; additive model. The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort p ≤ 0.03, additive model. There was no consistent association with glucose tolerance or insulin resistance in both study cohorts.

ConclusionWe conclude that common genetic variation within the NR4A3 locus determines insulin secretion. Thus, NR4A3 represents a novel candidate gene for β-cell function which was not covered by the SNP arrays of recent genome-wide association studies for type 2 diabetes mellitus.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2350-10-77 contains supplementary material, which is available to authorized users.

Peter Weyrich, Harald Staiger contributed equally to this work.

Download fulltext PDF



Autor: Peter Weyrich - Harald Staiger - Alena Stančáková - Silke A Schäfer - Kerstin Kirchhoff - Susanne Ullrich - Felicia Ra

Fuente: https://link.springer.com/







Documentos relacionados