title: Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes.
abstract: 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 PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha 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, PPARalpha 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 PPARalpha 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 PPARalpha gene variation influences the onset and progression of type 2 diabetes.
authors.affiliation: Centre for Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, London, UK. d.flavell@ucl.ac.uk
authors.forename: David M
authors.initials: DM
authors.lastname: Flavell
authors.forename: Helen
authors.initials: H
authors.lastname: Ireland
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Stephens
authors.forename: Emma
authors.initials: E
authors.lastname: Hawe
authors.forename: Jay
authors.initials: J
authors.lastname: Acharya
authors.forename: Hugh
authors.initials: H
authors.lastname: Mather
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hurel
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D017668:Age of Onset; D000368:Aged; D001794:Blood Pressure; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D018450:Disease Progression; D005838:Genotype; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007438:Introns; D008055:Lipids / Q000097:blood; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D006442:Glycated Hemoglobin; D008055:Lipids; D047493:PPAR alpha