Evidence for an association between the Leu¹⁶²Val polymorphism of the PPARα gene and decreased fasting serum triglyceride levels in glucose tolerant subjects

The aim of the study was to investigate whether genetic variation in the peroxisome proliferator-activated receptor-α (PPARα) is associated with type 2 diabetes and altered lipid or carbohydrate metabolism in glucose tolerant subjects. Mutation analyses of PPARα were performed in 56 type 2 diabetic patients. Six variants were identified: IVS3 + 76T>C, IVS3-19C>T, IVS4 + 35C>T, Leu¹⁶²Val, Arg¹⁷⁸Gly and Ala²⁶⁸Val. In a case-control study comprising 738 type 2 diabetic patients and 524 glucose tolerant subjects, the three exon variants did not show any significant differences in allele frequencies between type 2 diabetic patients and control subjects. The functional Leu¹⁶²Val polymorphism was further investigated in genotype-phenotype studies involving 340 young, healthy subjects and 502 middle-aged glucose tolerant subjects. The young, healthy subjects who were heterozygous for the Leu1⁶²Val variant had, on average, a 20% decrease in fasting serum triglyceride levels (P = 0.014). This finding was replicated in middle-aged subjects (P = 0.023). The Leu¹⁶²Val polymorphism was not related to alterations in insulin sensitivity, insulin release or level of glycaemia. In conclusion, the Leu¹⁶²Val polymorphism of PPARα is associated with a decreased level of fasting serum triglyceride in glucose tolerant white subjects.