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

  1. Paul G. Cassell1,
  2. Alan E. Jackson1,
  3. Bernard V. North2,
  4. Julie C. Evans3,
  5. Denise Syndercombe-Court4,
  6. Chris Phillips4,
  7. Ambady Ramachandran5,
  8. Chamukuttan Snehalatha5,
  9. Susan V. Gelding1,
  10. Shanti Vijayaravaghan1,
  11. David Curtis2 and
  12. Graham A. Hitman1
  1. 1Department of Diabetes and Metabolic Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
  2. 2Joint Academic Department of Psychological Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
  3. 3Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter
  4. 4Department of Haematology, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
  5. 5Diabetes 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. 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.

    Footnotes

    • 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: g.a.hitman{at}mds.qmw.ac.uk.

      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.

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