全基因組關聯研究所發現之第2型糖尿病基因的再驗證研究

Abstract

背景 基因遺傳與第2型糖尿病（Type 2 Diabetes）有顯著關聯性，近期的全基因組和候選基因關聯研究中更成功確定了高加索人種的潛在第2型糖尿病相關基因。為了降低第2型糖尿病相關基因研究中假陽性結果及了解不同族群間基因變異情形，我們針對20個與第2型糖尿病相關的基因在台灣的族群做再驗證實驗，並評估在第2型糖尿病相關基因的單獨變異及相互影響之間的關係以確定台灣族群中這些基因的作用點位與第2型糖尿病的相關性。 方法 本研究對象針對居住在台灣的漢人，包含1520個第2型糖尿病患實驗組及1520個正常對照組。進行ADAM30、NOTCH2、THADA、BCL11A、IGF2BP2、PPARG、ADAMTS9、WFS1、CDKAL1、VEGFA、JAZF1、SLC30A8、CDKN2A/B、HHEX、TCF7L2、EXT2、DCD、TSPAN8/LGR5、FTO、LOC387761 20個基因之基因定型，並分析對偶基因(Allele) 以及基因型(genotype)與其交互作用，對第2型糖尿病之相關性。 結果 研究20個與第2型糖尿病相關的基因，經過年齡，性別，身體質量指數調整後之統計分析，發現SLC30A8-rs13266643，風險值1.311（95%的信賴區間為1.176-1.461; p<0.0045）；HHEX-rs1111875，風險值1.238（95%的信賴區間為1.103-1.389; p=0.0132）為台灣漢人第2型糖尿病的危險對偶基因。除此之外以基因計量分析檢測累積效應，結果顯示出累積>42個危險基因型比起<35的風險值為1.75（95%的信賴區間為1.39 to 2.20; P<0.001）。基因與基因的交互作用分析結果看出SLC30A8 及 CDKN2A之間的交互作用，在罹患第2型糖尿病上，高風險群基因型組合明顯比低風險高，其風險值為1.584（95%的信賴區間為1.372-1.828）。另外共8個基因多型性（SNP）在統合分析亞洲人與歐洲人（白人）的研究中被發現與第2型糖尿病具有意義之相關；此外本研究也發現10個SNP位點，在亞洲人與歐洲人（白人）有很強的異質性。 結論 我們的研究發現在從歐洲人（白人）的全基因研究所找出的20個基因中，在單一核苷酸多型性分析中，只有兩個被確定在台灣族群中與第2型糖尿病有顯著相關性，且在20個基因的危險對偶基因有很強的劑量效應。SLC30A8、CDKN2A的基因基因間交互作用或許可以做為將來第2型糖尿病臨床之參考。

Background There is a strong inheritable genetic connection in type 2 diabetes (T2D). Recently, a set of potential T2D genes in the Caucasian race have been successfully identified in several genome-wide and candidate gene association studies. In order to reduce the false-positive results of candidate genes studies and to understand the genetic variants of different races in T2D, we performed a replication study by genotyping 20 genetic variants which are in the most promising loci of Han Chinese of Taiwan to evaluate the individual and interacting effects of these variants in T2D. Based on the results, we could understand more about the roles of these candidate genes in T2D. Methods The study was comprised of 1520 type 2 diabetic cases and 1520 normoglycemic controls from Han Chinese of Taiwan. Then we performed a replication study by genotyping 20 genetic variants in the most promising loci, including ADAM30,NOTCH2,THADA,BCL11A,IGF2BP2,PPARG,ADAMTS9,WFS1,CDKAL1,VEGFA,JAZF1,SLC30A8,CDKN2A/B,HHEX,TCF7L2,EXT2,DCD,TSPAN8/LGR5,FTO and LOC387761. Allele and genotype of each SNP and their interactions were analyzed to assess the association with T2D. Results In single SNP association analysis, we replicated and confirmed 2 among the 20 genetic loci in association with T2D, with risk allele-specific odds ratios (ORs) of 1.311 (95% CI, 1.176-1.461; p<0.0045) for SLC30A8-rs13266643 and 1.238 (95% CI, 1.103-1.389; p=0.0132) for HHEX-rs1111875 after adjustment for age, gender, and body mass index, indicating that SLC30A8-rs13266643 and HHEX-rs1111875 are risk alleles of type 2 diabetes in Han Chinese in Taiwan. Besides, the result of gene-dose analysis to test cumulative effects, indicating that OR was 1.75 (95% confidence interval, 1.39 to 2.20; P<0.001) in subjects with risk alleles >42 compared with those with risk alleles <35.Gene-gene interaction analysis was carried out by means of the multifactor dimensionality reduction (MDR). This indicates that the high risk group had increased risk of T2D with OR1.584 (95%CI, 1.372-1.828), compared with the low risk group between SLC30A8 and CDKN2A . In meta-analyses, we found 8 SNPs were significantly associated with T2D in Asian and Caucasian population, and 10 SNPs showed marked heterogeneity between Asian and Caucasian populations. Conclusions We found that only two of the 20 T2D susceptibility genes identified by GWAS in Caucasian populations were confirmed to be T2D genes in our population. There is a cumulative effect of the risk alleles of these SNPs in association with T2D in Han Chinese in Taiwan. The SNP of the gene and gene-gene interaction between SLC30A8 and CDKN2A may be useful in clinical diagnosis of T2D in Taiwan.