Weyrich Peter, Staiger Harald, Stancáková 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
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
BMC Med Genet. 2009 Aug 14;10:77. doi: 10.1186/1471-2350-10-77.
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 beta-cell dysfunction.
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 >or= 0.05) covering 100% of genetic variation within the NR4A3 locus (with D' = 1.0, r2 >or= 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.
All five SNPs were in Hardy-Weinberg equilibrium (p >or= 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), AUCC C-peptide-to-AUC Gluc ratio and the AUC Ins30-to-AUC Gluc30 ratio with rs12686676 reaching the level of significance (p <or= 0.03, all; additive model). The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort (p <or= 0.03, additive model). There was no consistent association with glucose tolerance or insulin resistance in both study cohorts.
We conclude that common genetic variation within the NR4A3 locus determines insulin secretion. Thus, NR4A3 represents a novel candidate gene for beta-cell function which was not covered by the SNP arrays of recent genome-wide association studies for type 2 diabetes mellitus.
神经元衍生的孤儿受体（Nor）1、核受体（Nur）77和核受体相关蛋白（Nurr）1构成了孤儿核受体的NR4A家族，最近发现它们可调节肝脏葡萄糖生成、脂肪细胞中的胰岛素信号传导以及骨骼肌中的氧化代谢。在本研究中，我们评估了编码Nor-1的NR4A3基因座内的常见基因变异是否有助于糖尿病前期表型的发展，如葡萄糖耐量异常、胰岛素抵抗或β细胞功能障碍。
我们对来自德国南部的1495名非糖尿病受试者进行了基因分型，检测了5个标签单核苷酸多态性（SNP），即rs7047636、rs1526267、rs2416879、rs12686676和rs10819699（次要等位基因频率≥0.05），这些SNP覆盖了NR4A3基因座内100%的遗传变异（D' = 1.0，r2≥0.9），并评估了它们与空腹状态、口服葡萄糖耐量试验（OGTT）和高胰岛素-正常血糖钳夹试验（亚组，N = 506）得出的代谢数据之间的关联。随后，在第二个队列（METSIM研究；芬兰；N = 5265）中对显示与糖尿病前期表型有一致关联的SNP进行基因分型以进行重复验证。
所有5个SNP均处于哈迪-温伯格平衡（p≥0.7，全部）。三个SNP的次要等位基因，即rs1526267、rs12686676和rs10819699，始终倾向于与较高的胰岛素释放相关，如OGTT中30分钟时的血浆胰岛素、AUC C肽与AUC葡萄糖比值以及AUC Ins30与AUC Gluc30比值所示，其中rs12686676达到显著水平（p≤0.03，全部；加性模型）。SNP rs12686676与胰岛素分泌的关联在METSIM队列中得到了重复验证（p≤0.03，加性模型）。在两个研究队列中，均未发现与葡萄糖耐量或胰岛素抵抗有一致的关联。
我们得出结论，NR4A3基因座内的常见基因变异决定胰岛素分泌。因此，NR4A3代表了一个新的β细胞功能候选基因，而2型糖尿病的近期全基因组关联研究的SNP阵列未涵盖该基因。
