Journal
ATHEROSCLEROSIS
Volume 196, Issue 1, Pages 29-36Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2006.12.035
Keywords
PCSK9; plasma LDL cholesterol; rare genetic variants; general population; missense mutation
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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. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
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