Haplotype Combinations of Calpain 10 Gene Polymorphisms Associate With Increased Risk of Impaired Glucose Tolerance and Type 2 Diabetes in South Indians

Haplotype Combinations of Calpain 10 Gene Polymorphisms Associate With Increased Risk of Impaired Glucose Tolerance and Type 2 Diabetes in South Indians Paul G. Cassell 1 , Alan E. Jackson 1 , Bernard V. North 2 , Julie C. Evans 3 , Denise Syndercombe-Court 4 , Chris Phillips 4 , Ambady Ramachandran 5 , Chamukuttan Snehalatha 5 , Susan V. Gelding 1 , Shanti Vijayaravaghan 1 , David Curtis 2 and Graham A. Hitman 1 1 Department of Diabetes and Metabolic Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London 2 Joint Academic Department of Psychological Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London 3 Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter 4 Department of Haematology, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London 5 Diabetes Research Centre, Chennai, India Abstract Haplotype combination 112/121 and its intrinsic variants (UCSNP43, -19, and -63) identified within the calpain 10 gene are associated with increased risk of type 2 diabetes in Mexican-Americans. We evaluated whether this haplotype combination and its constituent haplotypes and variants contribute to increased susceptibility to impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and type 2 diabetes in a South Indian population. Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey (69.1% with normal glucose tolerance, 12.8% with IFG/IGT, and 18.2% with type 2 diabetes). The four-locus haplotype combination 1112/1121 (UCSNP44, -43, -19, and -63) in South Indians conferred both a 10.7-fold increased risk for IFG/IGT ( P = 0.001) and a 5.78- to 6.52-fold increased risk for type 2 diabetes in the two study groups (families P = 0.025, urban survey P = 0.015). A combination of the 1112 haplotype with the 1221 haplotype also appeared to increase risk for both IFG/IGT and type 2 diabetes. Contrary to what might be expected, quantitative trait analysis in the families found that transmission of the disease-related 1121 and 1112 haplotypes was associated with a reduced hip size and lower waist-to-hip ratio, respectively. This study supports the paradigm that specific haplotype combinations of calpain 10 variants increase risk of both IFG/IGT and type 2 diabetes.