Evidence for an association between the Leu162Val polymorphism of the PPARalpha 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-a (PPARa) 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, Leu 162 Val, Arg 178 Gly and Ala 268 Val. 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 Leu 162 Val 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 Leu 162 Val 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 Leu 162 Val polymorphism was not related to alterations in insulin sensitivity, insulin release or level of glycaemia. In conclusion, the Leu 162 Val polymorphism of PPARa is associated with a decreased level of fasting serum triglyceride in glucose tolerant white subjects.