Peroxisome Proliferator-Activated Receptor α Gene Variation Influences Age of Onset and Progression of Type 2 Diabetes

  1. David M. Flavell1,
  2. Helen Ireland1,
  3. Jeffrey W. Stephens1,
  4. Emma Hawe1,
  5. Jay Acharya1,
  6. Hugh Mather2,
  7. Steven J. Hurel3 and
  8. Steve E. Humphries1
  1. 1Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, London, U.K
  2. 2Department of Medicine, Ealing Hospital, London, U.K
  3. 3Department of Diabetes & Endocrinology, University College London Hospital, London, U.K
  1. Address correspondence and reprint requests to Dr. David M. Flavell, Centre for Cardiovascular Genetics, The Rayne Building, 5 University St., London WC1E 6JF, U.K. E-mail: d.flavell{at}ucl.ac.uk

Abstract

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)α is a master regulator of fatty acid catabolism, and PPARα activators delay the onset of type 2 diabetes. We examined association between three PPARα gene polymorphisms (an A→C variant in intron 1, the L162V variant, and the intron 7 G→C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARα gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A→C (P < 0.001) and intron 7 G→C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARα haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis ≤45 years) of 3.75 (95% CI 1.65–8.56, P = 0.002). Intron 1 C-allele carriers also progressed more rapidly to insulin monotherapy (AA 9.4 ± 1.5 and AC + CC 5.3 ± 1.1 years, P = 0.002). These data indicate that PPARα gene variation influences the onset and progression of type 2 diabetes.

Footnotes

    • Accepted October 27, 2004.
    • Received June 2, 2004.
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