December 28th, 2010 
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Variation in the Transcription Factor 7-like 2 (TCF7L2) locus is associated with type 2 diabetes (T2D) 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 polymorphism (SNPs), T2D-susceptibility was limited to a 4.3kb interval which contains the YRI (African) linkage disequilibrium (LD) block containing rs7903146. To better define the relationship between T2D risk and genetic variation we resequenced this 4.3kb 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 T2D cases (n=1033) and controls (n=1106).
Variants identified from direct sequencing and databases were genotyped or imputed. Fifteen SNPs showed association with T2D (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 4.3kb LD block, revealed consistent association of “risk” allele 8 with T2D (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 T2D risk. Collectively, these results support ethnic differences in T2D associations.
Diabetes Journal publish ahead of print articles
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