Molecular scanning of the human PPAR alpha gene: association of the L162V mutation with hyperapobetalipoproteinemia

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a member o f the steroid hormone receptor super family involved in the control of cell ular lipid utilization. This makes PPAR alpha a candidate gene for type 2 d iabetes and dyslipidemia, The aim of this study was to investigate whether genetic variation in the human PPAR alpha gene can influence the risk of ty pe 2 diabetes and dyslipidemia among French Canadians. We therefore first d etermined the genomic structure of human pPAR alpha, and then designed intr onic primers to sequence the coding region and the exon-intron boundaries o f the gene in 12 patients with type 2 diabetes and iu 2 nondiabetic subject s. Sequence analysis revealed the presence of a L162V missense mutation in exon 5 of one diabetic patient. Leucine 162 is contained within the DNA bin ding domain of the human PPAR alpha gene, and is conserved among humans, mi ce, rats, and guinea pigs. We subsequently screened a sample of 121 patient s newly diagnosed with type 2 diabetes and their age and sex-matched nondia betic controls, recruited from the Saguenay-Lac-St-Jean region of Northeast ern Quebec, for the presence of the L162V mutation by a PCR-RFLP based meth od. There was no difference in L162 homozygote or V162 earlier frequencies between diabetics and nondiabetics. However, whether diabetic or not, carri ers of the V162 allele had higher plasma apolipoprotein B levels compared t o noncarriers (P = 0.05). To further this association, we screened another sample of 193 nondiabetic subjects recruited in the greater Quebec City are a. Carriers of the V162 allele compared with homozygotes of the L162 allele had significantly higher concentrations of plasma total and LDL-apolipopro tein B as well as LDL cholesterol (P less than or equal to 0.02), These res ults suggest an association between the PPAR alpha V162 allele and the athe rogenic/hyperapolipoprotein B dyslipidemia.