Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese
Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese
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DOI：
10.1007/s00439-006-0231-0
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发表时间：
2006-11-01
期刊：
影响因子：
5.3
通讯作者：
Itakura, Mitsuo
中科院分区：
文献类型：
--
作者：
Tanahashi, Toshihito;Osabe, Dai;Itakura, Mitsuo
一些连锁研究预测，人类染色体20 q与2型糖尿病密切相关，但没有明确的证据表明某些变体或基因对该区域内的疾病有强烈的影响。为了检查日本人的疾病易感性变异，在19.31 Mb区域（20q11.21-13.13）中以10 kb间隔从数据库中选择次要等位基因频率大于0.15的验证SNP，该区域包含291个基因，包括肝细胞核因子4 α（HNF 4 α）。结果，使用1，818份日本样本，使用TaqMan测定法对总计1，147个SNP进行基因分型。通过寻找HNF 4 α作为代表性的疾病易感基因，没有HNF 4 α的变体与疾病密切相关。为了确定与疾病相关的其他遗传变异，我们设计了一个广泛的两阶段关联研究（725个第一和1，093个第二测试样本）。尽管SNP 1146（rs 220076）被选为19.31 Mb区域内的标志，但标称P值（P = 0.0023）的幅度相当弱。随后，基于单倍型的关联研究表明，两种常见的单倍型与疾病弱相关。所有这些测试在调整Bonferroni校正和错误发现率以控制多次测试的影响后均无显著性。与最初的预期相反，我们不能得出结论，某些SNP对这个有希望的基因座在这里提出的框架内有重大影响。作为扩展我们观察的一种方式，我们强调随后的关联研究的重要性，包括在多个人群中的重复和/或荟萃分析。
Several linkage studies have predicted that human chromosome 20q is closely related to type 2 diabetes, but there is no clear evidence that certain variant(s) or gene(s) have strong effects on the disease within this region. To examine disease susceptibility variant in Japanese, verified SNPs from the databases, with a minor allele frequency larger than 0.15, were selected at 10-kb intervals across a 19.31-Mb region (20q11.21-13.13), which contained 291 genes, including hepatocyte nuclear factor 4 alpha (HNF4 alpha). As a result, a total of 1,147 SNPs were genotyped with TaqMan assay using 1,818 Japanese samples. By searching for HNF4 alpha as a representative disease-susceptible gene, no variants of HNF4 alpha were strongly associated with disease. To identify other genetic variant related with disease, we designed an extensive two-stage association study (725 first and 1,093 second test samples). Although SNP1146 (rs220076) was selected as a landmark within the 19.31 Mb region, the magnitude of the nominal P value (P = 0.0023) was rather weak. Subsequently, a haplotype-based association study showed that two common haplotypes were weakly associated with disease. All of these tests resulted in non-significance after adjusting for Bonferroni's correction and the false discovery rate to control for the impact of multiple testing. Contrary to the initial expectations, we could not conclude that certain SNPs had a major effect on this promising locus within the framework presented here. As a way to extend our observations, we emphasize the importance of a subsequent association study including replication and/or meta-analysis in multiple populations.