Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population

• Published in: Diabetologia 2007-01, Vol.50 (1), p.63-67
• Main Authors: CHANDAK, G. R, JANIPALLI, C. S, BHASKAR, S, KULKARNI, S. R, MOHANKRISHNA, P, HATTERSLEY, A. T, FRAYLING, T. M, YAJNIK, C. S
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Biological and medical sciences; Body mass index; Case-Control Studies; Diabetes; Diabetes Mellitus, Type 2 - ethnology; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Ethnicity; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic Predisposition to Disease; Genotype; Glucose; Homeostasis; Humans; India; Insulin resistance; Linkage Disequilibrium - genetics; Male; Medical sciences; Middle Aged; Odds Ratio; Plasma; Polymorphism; Polymorphism, Single Nucleotide - genetics; Research centers; Risk Factors; TCF Transcription Factors - genetics; TCF Transcription Factors - physiology; Transcription Factor 7-Like 2 Protein; Transcription factors
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0502-2

India has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood. Common non-coding variants in the transcription factor 7-like 2 gene (TCF7L2) have recently been strongly associated with increased risk of type 2 diabetes in European populations. We investigated whether TCF7L2 variants are also associated with type 2 diabetes mellitus in the Indian population. We genotyped type 2 diabetes patients (n = 955) and ethnically matched control subjects (n = 399) by sequencing three single nucleotide polymorphisms (SNPs) (rs7903146, rs12255372 and rs4506565) in TCF7L2. We observed a strong association with all the polymorphisms, including rs12255372 (odds ratio [OR] 1.50 [95% CI = 1.24-1.82], p = 4.0 x 10(-5)), rs4506565 (OR 1.48 [95% CI = 1.24-1.77], p = 2.0 x 10(-5)) and rs7903146 (OR 1.46 [95% CI = 1.22-1.75], p = 3.0 x 10(-5)). All three variants showed increased relative risk when homozygous rather than heterozygous, with the strongest risk for rs12255372 (OR 2.28 [95% CI = 1.40-3.72] vs OR 1.43 [95% CI = 1.11-1.83]). We found no association of the TCF7L2 genotypes with age at diagnosis, BMI or WHR, but the risk genotype at rs12255372 was associated with higher fasting plasma glucose (p = 0.001), higher 2-h plasma glucose (p = 0.0002) and higher homeostasis model assessment of insulin resistance (HOMA-R; p = 0.012) in non-diabetic subjects. Our study in Indian subjects replicates the strong association of TCF7L2 variants with type 2 diabetes in other populations. It also provides evidence that variations in TCF7L2 may play a crucial role in the pathogenesis of type 2 diabetes by influencing both insulin secretion and insulin resistance. TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity.