Direct sequencing for comprehensive screening of LDLR genetic polymorphisms among five ethnic populations

Low density lipoprotein receptor (LDLR) plays an important role in plasma lipoprotein metabolism and pharmacological responses. Although mutations of LDLR and their functional associations with plasma LDL cholesterol concentrations have been described, no comprehensive comparisons of LDLR variants among populations are established. The aim of this study is to define the distribution of single nucleotide polymorphisms (SNPs) of LDLR and to discover novel variants across population groups. A total of 288 DNAs from 96 Korean, 48 Chinese, 48 Japanese, 48 African-American, and 48 European-American subjects were resequenced. A total of 59 SNPs (18 in the coding regions, 37 in the introns, and 4 in the 3′-untranslated region) were identified, including eight novel variants. Polymorphisms of LDLR showed significantly different distributions in comparisons among ethnic population groups (P < 0.05, Fisher’s exact test). Moreover, almost all of these differently distributed SNPs were common variants. Notably, prevalent variations—rs1003723, rs1799898, rs688, rs5925, rs6413504 in Europeans, nonsynonymous rs11669576 (Ala391Thr) in Africans, and rs14158 in Asians—were observed. In further in silico analyses for the novel SNPs, 2 intronic variants (+17716G>A in the intron 5 and +38569A>C in the intron 16) were predicted as potential branch point sites for alternative splicing. Although this study is not free from limitations such as insufficient sample size and no functional studies on the novel SNPs, our findings provides supporting information about LDLR genetic variability among ethnic groups and pharmacogenetics studies for plasma lipoprotein metabolism.