Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant.
Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant.
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作者：
Palmer ND;Hester JM;An SS;Adeyemo A;Rotimi C;Langefeld CD;Freedman BI;Ng MC;Bowden DW
转录因子7-样2 （TCF7L2）位点的变异与多种族2型糖尿病有关。本研究的目的是阐明TCF7L2的哪个变异使非裔美国人易患糖尿病。通过标记单核苷酸多态性（snp）评估，2型糖尿病易感性限制在4.3 kb区间，该区间包含含有rs7903146的YRI （African）连锁不平衡（LD）区。为了更好地确定2型糖尿病风险与遗传变异之间的关系，我们对96个非裔美国人dna中的4.3 kb区域进行了重新测序。共鉴定出33个新snp和13个已知snp，其中20个为次要等位基因频率(MAF) >.05, 12个为MAF >0.10。这些多态性和先前鉴定的DG10S478微卫星在非裔美国2型糖尿病患者（n = 1033）和对照组（n = 1106）中进行了评估。从直接测序和数据库中鉴定的变异进行基因分型或估算。15个snp与2型糖尿病相关（P < 0.05），其中rs7903146最为显著（P = 6.32 × 10−6）。SNP的归算、单倍型和条件分析结果与rs7903146为性状定义SNP一致。DG10S478微卫星位于4.3 kb LD区之外，分析结果显示，在欧洲人群中，风险等位基因8与2型糖尿病存在一致的关联（优势比[OR] = 1.33; P = 0.022）；然而，与先前的研究相比，等位基因16 （MAF = 0.016，对照组为0.032）与风险降低密切相关（OR = 0.39; P = 5.02 × 10−5）。在非裔美国人中，这些观察结果表明rs7903146是与2型糖尿病风险相关的性状定义多态性。总的来说，这些结果支持2型糖尿病相关的种族差异。
Variation in the transcription factor 7-like 2 (TCF7L2) locus is associated with type 2 diabetes across multiple ethnicities. The aim of this study was to elucidate which variant in TCF7L2 confers diabetes susceptibility in African Americans. Through the evaluation of tagging single nucleotide polymorphisms (SNPs), type 2 diabetes susceptibility was limited to a 4.3-kb interval, which contains the YRI (African) linkage disequilibrium (LD) block containing rs7903146. To better define the relationship between type 2 diabetes risk and genetic variation we resequenced this 4.3-kb region in 96 African American DNAs. Thirty-three novel and 13 known SNPs were identified: 20 with minor allele frequencies (MAF) >0.05 and 12 with MAF >0.10. These polymorphisms and the previously identified DG10S478 microsatellite were evaluated in African American type 2 diabetic cases (n = 1,033) and controls (n = 1,106). Variants identified from direct sequencing and databases were genotyped or imputed. Fifteen SNPs showed association with type 2 diabetes (P < 0.05) with rs7903146 being the most significant (P = 6.32 × 10−6). Results of imputation, haplotype, and conditional analysis of SNPs were consistent with rs7903146 being the trait-defining SNP. Analysis of the DG10S478 microsatellite, which is outside the 4.3-kb LD block, revealed consistent association of risk allele 8 with type 2 diabetes (odds ratio [OR] = 1.33; P = 0.022) as reported in European populations; however, allele 16 (MAF = 0.016 cases and 0.032 controls) was strongly associated with reduced risk (OR = 0.39; P = 5.02 × 10−5) in contrast with previous studies. In African Americans, these observations suggest that rs7903146 is the trait-defining polymorphism associated with type 2 diabetes risk. Collectively, these results support ethnic differences in type 2 diabetes associations.
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