title: Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population.
abstract: The aim of this study was to investigate whether plasma low-density lipoprotein cholesterol (LDL-C) levels in the general population are influenced by rare sequence variations in the PCSK9 gene. We sequenced the promoter and coding regions of the PCSK9 gene in individuals from the general population (n=3655) with the lowest (n=78) and highest (n=96) LDL-C levels and in individuals taking antihypercholesterolemia medication (n=96). We identified 33 sequence variants in the PCSK9 gene among which 24 were specific for Japanese. Statistical analysis showed that one missense mutation, R93C, was associated with low LDL-C levels. The other variants had no association with LDL-C levels or the numbers of individuals with the variants were too small for statistical analysis. A comparison of the numbers of individuals with nonsynonymous mutations between the low LDL-C and high LDL-C/treatment groups found that four missense mutations and one nonsense mutation were identified only in the low LDL-C group and six missense mutations were identified only in the high LDL-C/treatment group. As we have analyzed groups at opposite ends of the LDL-C spectrum, it is likely that some of these nonsynonymous mutations may be associated with either low or high LDL-C in the Japanese population. Based on the extremely high frequencies of the nonsynonymous mutations in PCSK9 compared with those of LDLR or apoB-100, PCSK9 mutations could be important factors that cumulatively influence plasma LDL-C levels in the general population.
authors.affiliation: Department of Etiology and Pathophysiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: ymiyake@ri.ncvc.go.jp.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: Department of Etiology and Pathophysiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Kimura
authors.affiliation: Division of Preventive Cardiology, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.affiliation: Division of Preventive Cardiology, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Okayama
authors.affiliation: National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.affiliation: Division of Health Sciences, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Yamamura
authors.affiliation: Department of Etiology and Pathophysiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000208:ethnology / Q000235:genetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases