Polymorphic Variations in the Neurogenic Differentiation-1, Neurogenin-3, and Hepatocyte Nuclear Factor-1α Genes Contribute to Glucose Intolerance in a South Indian Population

  1. Alan E. Jackson1,
  2. Paul G. Cassell1,
  3. Bernard V. North1,
  4. Shanti Vijayaraghavan1,
  5. Susan V. Gelding1,
  6. Ambady Ramachandran2,
  7. Chamukuttan Snehalatha2 and
  8. Graham A. Hitman1
  1. 1Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, London, U.K
  2. 2Diabetes Research Centre, Chennai, India
  1. Address correspondence and reprint requests to Graham A. Hitman, Department of Diabetes and Metabolic Medicine, Royal London Hospital, Whitechapel, London E1 1BB, U.K. E-mail: g.a.hitman{at}qmul.ac.uk

Abstract

The neurogenic differentiation-1 (NEUROD1), neurogenin-3 (NEUROG3), and hepatic nuclear factor-1α (TCF1) genes are interacting transcription factors implicated in controlling islet cell development and insulin secretion. Polymorphisms of these genes (Ala45Thr [NEUROD1], Ser199Phe [NEUROG3], and Ala98Val [TCF1]) have been postulated to influence the development of type 2 diabetes. We have investigated the role and interaction between these variants using PCR/restriction fragment–length polymorphism assays in 454 subjects recruited as part of a population survey in South India. Additionally, 97 South Indian parent-offspring trios were studied. Polymorphisms of all three genes were associated with either fasting blood glucose (FBG) and/or 2-h blood glucose (BG) in either the total dataset or when restricted to a normoglycemic population. A monotonically increasing effect, dependent on the total number of risk-associated alleles carried, was observed across the whole population (P < 0.0001 for FBG and 2-h BG), raising FBG by a mean of 2.9 mmol/l and 2-h BG by a mean of 4.3 mmol/l. Similarly, an ascending number of the same risk alleles per subject increased the likelihood of type 2 diabetes (P = 0.002). In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population.

Footnotes

    • Accepted April 26, 2004.
    • Received July 24, 2003.
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