Whole genome association study on type 2 diabetes susceptibility genes using microsatellite markers and DNA pool

为了预防2型糖尿病的发生，需要鉴定其易感基因。我们最初计划在整个基因组和每个病例或对照的DNA池中使用微卫星标记进行全基因组关联研究，并建立了一个可重复的系统。原来我们所在的千年计划的糖尿病团队也在用SNP和微卫星标记进行全基因组关联研究。由于这一进展比预期的要快，我们决定在该项目确定候选位点后开始精细定位。与此同时，我们分析了2型糖尿病患者胰岛素抵抗的候选基因，如FOXC 2、磷酸二酯酶3 B（PDE 3 B）和PDE3。我们对FOXC 2基因5'端侧翼区和编码区的100kb序列进行了分析，发现了3个常见的SNPs和4种常见的单倍型。2型糖尿病的发生率为100%。我们还分析了PDE3B基因5'侧翼区沿着的101kb的多态性位点+1389 G>A，但与2型糖尿病没有明显的关联。我们还发现，即使与对脂质代谢至关重要的基因的频繁SNP组合，BDN的频繁SNP+299 G>A与2型糖尿病也不相关。因此，在FOXC 2，PDE3B和rsistin中分析的频繁SNP不太可能对2型糖尿病的易感性产生重大影响。

To prevent the onset of type 2 diabetes, it is required to identify its susceptibility genes. We initially planned to employ microsatellite markers throughout the whole genome and each DNA pool of cases or controls for the whole genome association study, and established a reproducible system. It has been turned out that the diabetes team in the millennium project we belong to are also doing the whole genome association study using SNPs and microsatellite markers. Since this progress is faster than expected, we have decided to start fine mapping after the candidate loci have been identified by this project. In parallel, we analyzed candidate gene for insulin resistance seen with type 2 diabetes such as FOXC2, phosphodiesterase 3 B(PDE3B), and resistin. We analyzed〜1kb of the 5' flanking region and the coding region of the FOXC2 gene, and identified three frequent SNPs and four frequent haplotypes defined by them. Neither of them was associated with type 2 diabetes. We also analyzed the 〜1kb of the 5' flanking region of the PDE3B gene along with a frequent SNP+1389G>A, but no association with type 2 diabetes was evident. We also found that the frequent SNP+299G>A of the resistin was not associated with type 2 diabetes even in combination with frequent SNPs of genes critical for lipid metabolism. Therefore, frequent SNPs analyzed in FOXC2, PDE3B, and rsistin are unlikely to have major effects on susceptibility to type 2 diabetes.