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Journal of Lipid Research, Vol. 41, 945-952, June 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

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

Correspondence to: Marie-Claude Vohl

Correspondence to: Thomas J. Hudson

Peroxisome proliferator-activated receptor alpha (PPAR) is a member of the steroid hormone receptor super family involved in the control of cellular lipid utilization. This makes PPAR a candidate gene for type 2 diabetes and dyslipidemia. The aim of this study was to investigate whether genetic variation in the human PPAR gene can influence the risk of type 2 diabetes and dyslipidemia among French Canadians. We therefore first determined the genomic structure of human PPAR, and then designed intronic primers to sequence the coding region and the exon;–intron boundaries of the gene in 12 patients with type 2 diabetes and in 2 nondiabetic subjects. Sequence analysis revealed the presence of a L162V missense mutation in exon 5 of one diabetic patient. Leucine 162 is contained within the DNA binding domain of the human PPAR gene, and is conserved among humans, mice, rats, and guinea pigs. We subsequently screened a sample of 121 patients newly diagnosed with type 2 diabetes and their age and sex-matched nondiabetic controls, recruited from the Saguenay-Lac-St-Jean region of Northeastern Quebec, for the presence of the L162V mutation by a PCR-RFLP based method. There was no difference in L162 homozygote or V162 carrier frequencies between diabetics and nondiabetics. However, whether diabetic or not, carriers of the V162 allele had higher plasma apolipoprotein B levels compared to noncarriers (P 5 0.05). To further this association, we screened another sample of 193 nondiabetic subjects recruited in the greater Quebec City area.

Carriers of the V162 allele compared with homozygotes of the L162 allele had significantly higher concentrations of plasma total and LDL-apolipoprotein B as well as LDL cholesterol (P 0.02). These results suggest an association between the PPAR V162 allele and the atherogenic/hyperapolipoprotein B dyslipidemia.—Vohl, M-C., P. Lepage, D. Gaudet, C. G. Brewer, C. Bétard, P. Perron, G. Houde, C. Cellier, J. M. Faith, J-P. Després, K. Morgan, and T. J. Hudson. Molecular scanning of the human PPAR gene: association of the L162V mutation with hyperapobetalipoproteinemia. J. Lipid Res. 2000. 41: 945;–952.

Supplementary key words: PPAR, L162V mutation, type 2 diabetes, apolipoprotein B, hyperapobetalipoproteinemia, genetics

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