Haplotype Combinations of Calpain 10 Gene Polymorphisms Associate With Increased Risk of Impaired Glucose Tolerance and Type 2 Diabetes in South Indians
- Paul G. Cassell1,
- Alan E. Jackson1,
- Bernard V. North2,
- Julie C. Evans3,
- Denise Syndercombe-Court4,
- Chris Phillips4,
- Ambady Ramachandran5,
- Chamukuttan Snehalatha5,
- Susan V. Gelding1,
- Shanti Vijayaravaghan1,
- David Curtis2 and
- Graham A. Hitman1
- 1Department of Diabetes and Metabolic Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 2Joint Academic Department of Psychological Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 3Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter
- 4Department of Haematology, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 5Diabetes Research Centre, Chennai, India
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. However, the relative infrequency of the “at-risk” combinations in the South Indian population suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes.
Address correspondence and reprint requests to Professor Graham A. Hitman, Department of Diabetes and Metabolic Medicine, the Royal London Hospital, Whitechapel Road, London E1 1BB, U.K. E-mail:.
Received for publication 18 June 2001 and accepted in revised form 6 February 2002.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LD, linkage disequilibrium; OHA, oral hypoglycemic agent; OR, odds ratio; SNP, single-nucleotide polymorphism; TDT, transmission disequilibrium test; WHO, World Health Organization; WHR, waist-to-hip ratio.