Genetic Association of Low-density Lipoprotein Receptor-related Protein 2 (LRP2) with Plasma Lipid Levels

Abstract

Not all genetic factors predisposing phenotypic features of dyslipidemia have been identified. We studied the association between the low density lipoprotein-related protein 2 gene (LRP2) and levels of plasma total cholesterol (T-Cho) and LDL-cholesterol (LDL-C) among 352 adults in Japan. Subjects were obtained from among participants in a cohort study that was carried out with health-check screening in an area of east-central Japan. We selected 352 individuals whose LDL-C levels were higher than 140 mg/dL from the initially screened 22,228 people. We assessed the relation between plasma cholesterol levels and single-nucleotide polymorphisms (SNPs) in the LRP2 gene. We identified significant correlations between plasma cholesterol levels and two of 19 examined SNPs in LRP2, c.+193826T/C and IVS55 - 147A/G. In particular, the association of c.+193826T/C with the T-Cho level was prominent (p=0.003), showing a co-dominant effect of the minor C-allele on lowering T-Cho and LDL-C levels: for 24 homozygous C-allele carriers, T-Cho=240.7 +/- 24.2 mg/dL and LDL-C=166.1 +/- 21.0 mg/dL); for 130 heterozygous carriers, 248.5 +/- 23.5 mg/dL and 166.6 +/- 19.3 mg/dL; and for 196 homozygous T-allele carriers, 253.9 +/- 23.5 mg/dL and 172.0 +/- 21.0 mg/dL. Linkage disequilibrium (LD) analyses based on 19 selected SNPs showed that c.+193826T/C and IVS55 - 147A/G were in tight LD and that both were located in an LD block covering the genomic sequence from exon 55 to exon 61. We confirm the association between LRP2 and levels of T-Cho and LDL-C in human plasma. The results suggest that genetic variations in LRP2 are important factors affecting lipoprotein phenotypes of patients with hypercholesterolemia.