Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population
Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population
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DOI：
10.1007/s00125-007-0631-2
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发表时间：
2007-06-01
期刊：
影响因子：
8.2
通讯作者：
Itakura, M.
中科院分区：
文献类型：
--
作者：
Moritani, M.;Nomura, K.;Itakura, M.
目的/假说为了确定日本人群中的2型糖尿病易感基因(S)，我们对染色体3p24.3-22.1上D3S1293和D3S2319之间的20.4Mb区域进行了区域病例对照关联检验，并与日本人和多个人群中的2型糖尿病及其相关性状相关联。材料与方法我们对1,762名日本人进行了两阶段关联检验，这些标记以485个基因为中心，分布均匀，具有微小等位基因频率的普通单核苷酸多态性标记>；0.1。结果从BKS.Cg-+Lepr(Db)/+Lepr(Db)和对照小鼠，以及MIN6、NIH3T3和C2C12细胞系中检测到一个标志性的SNP375(A/G)(rs2051211，p=0.000046，优势比=1.33，95%可信区间1.16~1.53)。系统致密SNPs方法在EndoGL1中通过垂直条带D‘垂直条带、一个Ld单位图和一个2.1kb的临界区r(2)确定了一个116.5 kb的易感连锁不平衡(LD)区块。基于单倍型的关联检验表明，高危单倍型与疾病状态相关(p=0.00001)。ENDOGL1的表达相当普遍，在脑组织和胰岛β细胞系中也有较丰富的表达。高血糖BKS Cg-+Lepr(Db)/+Lepr(Db)小鼠胰岛中Endogl1表达增加。结论基于群体遗传学、LD区精细定位和单倍型分析，EndoGL1是日本人群中2型糖尿病的候选易感基因。需要在更大的样本量中进行进一步的分析才能证实这一结论。
Aims/hypothesis In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case-control association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations.Materials and methods We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single nucleotide polymorphism (SNP) markers with minor allele frequency > 0.1. For mouse studies, total RNA was extracted from various organs of BKS.Cg-+Lepr(db)/+Lepr(db) and control mice, and from MIN6, NIH3T3 and C2C12 cell lines.Results We detected a landmark SNP375 (A/G) (rs2051211, p=0.000046, odds ratio=1.33, 95% CI 1.16-1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by vertical bar D'vertical bar, an LD units map and a critical region of 2.1 kb by r(2) in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p=0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and also in a pancreatic islet beta cell line. Mouse Endogl1 expression increased in pancreatic islets of hyperglycaemic BKS.Cg-+Lepr(db)/+Lepr(db) mice compared with that in control mice.Conclusions/interpretation Based on the population genetics, fine mapping of LD block and haplotype analysis, we conclude that ENDOGL1 is a candidate disease-susceptibility gene for type 2 diabetes in a Japanese population. Further analysis in a larger sample size is required to substantiate this conclusion.