Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes.
Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes.
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作者：
Gaulton KJ;Willer CJ;Li Y;Scott LJ;Conneely KN;Jackson AU;Duren WL;Chines PS;Narisu N;Bonnycastle LL;Luo J;Tong M;Sprau AG;Pugh EW;Doheny KF;Valle TT;Abecasis GR;Tuomilehto J;Bergman RN;Collins FS;Boehnke M;Mohlke KL
2型糖尿病是一种常见的复杂疾病，有环境和遗传因素。我们使用了一种基于候选基因的方法来鉴定222个影响2型糖尿病易感性的候选基因中的单核苷酸多态性（SNP）变异。研究设计和方法-在一项病例对照研究中，1,161名2型糖尿病受试者和1,174名正常葡萄糖耐量的对照芬兰人，我们对3,531个tagSNPs和基于注释的SNPs进行了基因分型，并估算了另外7,498个SNPs，在222个候选基因中提供了99.9%的常见HapMap变体覆盖率。在另外1，211例2型糖尿病病例受试者和1，259例葡萄糖耐受正常的对照受试者中对选定的SNP进行基因分型，这些受试者也来自芬兰。利用SNP和基因为基础的分析方法，我们重复了先前报道的PPARG、KCNJ 11和SLC 2A 2中SNP与2型糖尿病的相关性;在先前报道的相关基因中鉴定了显著的SNP（ENPP 1 [rs2021966，P = 0.00026]和NRF 1 [rs1882095，P = 0.00096]）; RAPGEF 1（rs 4740283，P = 0.00013）和TP 53（rs 1042522，Arg 72 Pro，P = 0.00086）等新基因与2型糖尿病易感性有关。结论-我们的研究提供了一个有效的基于基因的关联研究设计和分析的方法。一个或多个新发现的相关基因可能与2型糖尿病的发病机制有关。需要分析额外的样本，以确定其对敏感性的影响。
OBJECTIVE—Type 2 diabetes is a common complex disorder with environmental and genetic components. We used a candidate gene–based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to type 2 diabetes. RESEARCH DESIGN AND METHODS—In a case-control study of 1,161 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also from Finland. RESULTS—Using SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in PPARG, KCNJ11, and SLC2A2; identified significant SNPs in genes with previously reported associations (ENPP1 [rs2021966, P = 0.00026] and NRF1 [rs1882095, P = 0.00096]); and implicated novel genes, including RAPGEF1 (rs4740283, P = 0.00013) and TP53 (rs1042522, Arg72Pro, P = 0.00086), in type 2 diabetes susceptibility. CONCLUSIONS—Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility.