Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians

• Published in: Journal of human genetics Vol. 56; no. 10; pp. 695 - 700
• Main Authors: Chavali, Sreenivas, Mahajan, Anubha, Tabassum, Rubina, Dwivedi, Om Prakash, Chauhan, Ganesh, Ghosh, Saurabh, Tandon, Nikhil, Bharadwaj, Dwaipayan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2011; Nature Publishing Group
• Subjects: 631/208/726/649; 631/208/727/2000; 692/699/2743/137/773; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Beta cells; Beta2 protein; Biomedical and Life Sciences; Biomedicine; Body Mass Index; Case-Control Studies; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - ethnology; Diabetes Mellitus, Type 2 - genetics; Gene Expression; Gene Function; Gene Therapy; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Human Genetics; Humans; Indians, North American - genetics; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - physiology; Islet-1 protein; Linkage disequilibrium; Molecular Medicine; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nkx2.2 protein; Nkx6.1 protein; Obesity; original-article; Pancreas; Pax6 protein; Polymorphism, Single Nucleotide; association; type 2 diabetes; β-cell; obesity
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/jhg.2011.83

Variants in genes involved in pancreatic β-cell development and function are known to cause monogenic forms of type 2 diabetes and are also associated with complex form. In this study, we studied the genetic association of polymorphisms in such important genes with type 2 diabetes in the high-risk Indians. We genotyped 91 polymorphisms in 19 genes ( ABCC8, HNF1A, HNF1B, HNF4A, INS, INSM1 , ISL1, KCNJ11, MAFA, MNX1, NEUROD1, NEUROG3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1, USF1 and WFS1 ) in 2025 unrelated North Indians of Indo-European ethnicity comprising of 1019 diabetic and 1006 non-diabetic subjects. HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR)=1.37 (95% confidence interval (CI) 1.19–1.57), P =9.4 × 10 −6 for rs1884613 and OR=1.37 (95%CI 1.20–1.57), P =6.0 × 10 −6 for rs2144908), as previously shown in other populations. We observed body mass index-dependent association of these variants with type 2 diabetes in normal-weight/lean subjects. Variants in USF1 , ABCC8 , ISL1 and KCNJ11 showed nominal association, while haplotypes in these genes were significantly associated. rs3812704 upstream of NEUROG3 significantly increased risk for type 2 diabetes in normal-weight/lean subjects (OR=1.68 (95%CI 1.25–2.24), P =4.9 × 10 −4 ). Thus, pancreatic β-cell development and function genes contribute to susceptibility to type 2 diabetes in North Indians.