Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant.

Abstract

OBJECTIVE:

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.

RESEARCH DESIGN AND METHODS:

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).

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Nicholette D Palmer, Jessica M Hester, S Sandy An, Adebowale Adeyemo, Charles Rotimi, Carl D Langefeld, Barry I Freedman, Maggie C Y Ng, Donald W Bowden
• Journal: Diabetes (Diabetes) Vol. 60 Issue 2 Pg. 662-8 (Feb 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 20980453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• TCF7L2 protein, human
• Transcription Factor 7-Like 2 Protein

Topics

• Adult
• Black or African American (genetics)
• Aged
• Alleles
• Diabetes Mellitus, Type 2 (ethnology, genetics)
• Female
• Gene Frequency
• Genetic Linkage
• Genetic Predisposition to Disease
• Genetic Variation
• Genotype
• Haplotypes
• Humans
• Linkage Disequilibrium
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Transcription Factor 7-Like 2 Protein (genetics)