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Diabetes 54:582-586, 2005
© 2005 by the American Diabetes Association, Inc.

Brief Genetics Report

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

David M. Flavell1, Helen Ireland1, Jeffrey W. Stephens1, Emma Hawe1, Jay Acharya1, Hugh Mather2, Steven J. Hurel3, and Steve E. Humphries1

1 Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, London, U.K
2 Department of Medicine, Ealing Hospital, London, U.K
3 Department of Diabetes & Endocrinology, University College London Hospital, London, U.K

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR){alpha} is a master regulator of fatty acid catabolism, and PPAR{alpha} activators delay the onset of type 2 diabetes. We examined association between three PPAR{alpha} 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, PPAR{alpha} 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 PPAR{alpha} 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 PPAR{alpha} gene variation influences the onset and progression of type 2 diabetes.

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

Abbreviations: EDSC, Ealing Diabetic Study of Coagulation; PPAR, peroxisome proliferator-activated receptor; UDACS, University College Diabetes and Cardiovascular Study


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