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Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects
BACKGROUND: Neuron-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 metabo...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741445/ https://www.ncbi.nlm.nih.gov/pubmed/19682370 http://dx.doi.org/10.1186/1471-2350-10-77 |
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author | Weyrich, Peter Staiger, Harald Stančáková, Alena Schäfer, Silke A Kirchhoff, Kerstin Ullrich, Susanne Ranta, Felicia Gallwitz, Baptist Stefan, Norbert Machicao, Fausto Kuusisto, Johanna Laakso, Markku Fritsche, Andreas Häring, Hans-Ulrich |
author_facet | Weyrich, Peter Staiger, Harald Stančáková, Alena Schäfer, Silke A Kirchhoff, Kerstin Ullrich, Susanne Ranta, Felicia Gallwitz, Baptist Stefan, Norbert Machicao, Fausto Kuusisto, Johanna Laakso, Markku Fritsche, Andreas Häring, Hans-Ulrich |
author_sort | Weyrich, Peter |
collection | PubMed |
description | BACKGROUND: Neuron-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. METHODS: We 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(2 )≥ 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. RESULTS: All 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 min(OGTT), AUC(C-peptide)-to-AUC(Gluc )ratio and the AUC(Ins30)-to-AUC(Gluc30 )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. CONCLUSION: We 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. |
format | Text |
id | pubmed-2741445 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-27414452009-09-11 Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects Weyrich, Peter Staiger, Harald Stančáková, Alena Schäfer, Silke A Kirchhoff, Kerstin Ullrich, Susanne Ranta, Felicia Gallwitz, Baptist Stefan, Norbert Machicao, Fausto Kuusisto, Johanna Laakso, Markku Fritsche, Andreas Häring, Hans-Ulrich BMC Med Genet Research Article BACKGROUND: Neuron-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. METHODS: We 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(2 )≥ 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. RESULTS: All 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 min(OGTT), AUC(C-peptide)-to-AUC(Gluc )ratio and the AUC(Ins30)-to-AUC(Gluc30 )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. CONCLUSION: We 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. BioMed Central 2009-08-14 /pmc/articles/PMC2741445/ /pubmed/19682370 http://dx.doi.org/10.1186/1471-2350-10-77 Text en Copyright © 2009 Weyrich et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Weyrich, Peter Staiger, Harald Stančáková, Alena Schäfer, Silke A Kirchhoff, Kerstin Ullrich, Susanne Ranta, Felicia Gallwitz, Baptist Stefan, Norbert Machicao, Fausto Kuusisto, Johanna Laakso, Markku Fritsche, Andreas Häring, Hans-Ulrich Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
title | Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
title_full | Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
title_fullStr | Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
title_full_unstemmed | Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
title_short | Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
title_sort | common polymorphisms within the nr4a3 locus, encoding the orphan nuclear receptor nor-1, are associated with enhanced β-cell function in non-diabetic subjects |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741445/ https://www.ncbi.nlm.nih.gov/pubmed/19682370 http://dx.doi.org/10.1186/1471-2350-10-77 |
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