Genetic Variation at the Proprotein Convertase Subtilisin/Kexin Type 5 Gene Modulates High-Density Lipoprotein Cholesterol Levels

Genetic Variation at the Proprotein Convertase Subtilisin/Kexin Type 5 Gene Modulates High-Density Lipoprotein Cholesterol Levels Iulia Iatan, MSc ; Zari Dastani, MD, PhD ; Ron Do, MSc ; Daphna Weissglas-Volkov, PhD ; Isabelle Ruel, PhD ; Jenny C. Lee, PhD ; Adriana Huertas-Vazquez, PhD ; Marja-Riitta Taskinen, MD, PhD ; Annik Prat, PhD ; Nabil G. Seidah, PhD ; Päivi Pajukanta, MD, PhD ; James C. Engert, PhD and Jacques Genest, MD From the Departments of Biochemistry (I.I., I.R., J.C.E., J.G.) and Human Genetics (Z.D., R.D., I.R., J.C.E., J.G.), Cardiovascular Research Laboratories, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada; Department of Human Genetics (D.W.-V., J.C.L., A.H.-V., P.P.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; Department of Medicine (M.-R.T.), Helsinki University Central Hospital, Helsinki, Finland; and Laboratory of Biochemical Neuroendocrinology (A.P., N.G.S.), Clinical Research Institute of Montreal, Montreal, Quebec, Canada. Correspondence to Jacques Genest, MD, Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Ave W, Room M4/76, Montreal, Quebec, Canada H3A 1A1. E-mail jacques.genest{at}muhc.mcgill.ca Received May 14, 2009; accepted June 23, 2009. Background— A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. HDL particles are modulated by a variety of lipases, including endothelial lipase, a phospholipase present on vascular endothelial cells. The proprotein convertase subtilisin/kexin type 5 ( PCSK5 ) gene product is known to directly inactivate endothelial lipase and indirectly cleave and activate angiopoetin-like protein 3, a natural inhibitor of endothelial lipase. We therefore investigated the effect of human PCSK5 genetic variants on plasma HDL-C levels. Methods and Results— Haplotypes at the PCSK5 locus were examined in 9 multigenerational families that included 60 individuals with HDL-C