Genetic variation near the hepatocyte nuclear factor-4α gene predicts susceptibility to type 2 diabetes
Genetic variation near the hepatocyte nuclear factor-4α gene predicts susceptibility to type 2 diabetes
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DOI：
10.2337/diabetes.53.4.1141
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发表时间：
2004-04-01
期刊：
影响因子：
7.7
通讯作者：
Collins, FS
中科院分区：
文献类型：
--
作者：
Silander, K;Mohlke, KL;Collins, FS
芬兰-美国NIDDM遗传学调查（FUSION）研究旨在通过研究芬兰受影响的兄弟姐妹家庭，确定易患2型糖尿病的遗传变异。第20号染色体显示了最有力的初始证据。目前，在一组495个家庭中，70厘米处的最大赔率对数（LOD）分数为2.48。在本研究中，我们通过对病例和对照DNA池中的单核苷酸多态性（SNP）标记进行基因分型，在2013年q13寻找糖尿病易感变异。在7.5 mb的间隔内成功分型的291个SNP中，个体基因分型证实的最强关联是SNP rs2144908，位于肝细胞核因子- 4α (HNF4A)初级β细胞启动子P2下游1.3 kb处。该SNP显示与糖尿病疾病状态相关（优势比[OR] 1.33, 95% CI 1.06-1.65, P = 0.011），并与几种糖尿病相关性状相关。2013年q2的大部分关联证据可以归因于携带风险等位基因的家庭。随后，我们发现了跨越64kb区域的9个额外的相关snp，包括P2和P1启动子以及外显子1-3。我们的研究结果以及在德系犹太血统的单独研究人群中P2启动子附近的snp与糖尿病的独立观察表明，位于HNF4A附近或内部的变异增加了对2型糖尿病的易感性。
The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary beta-cell promoter P2 of hepatocyte nuclear factor-4alpha (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes.