1. ¹Department of Internal Medicine II, Nippon Medical School, Tokyo, Japan
2. ²Department of Molecular Biology-Institute of Gerontology, Nippon Medical School, Kawasaki, Japan
3. ³Departments of Genome Research and Clinical Application, and, of Clinical Cell Biology, Chiba University Graduate School, Chiba, Japan
4. ⁴Awa Medical Association Hospital, Chiba, Japan
5. ⁵Department of Molecular Pharmacology, Institute of Medical Research, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan

Correspondence: Yoichi Ezura, Department of Molecular Pharmacology, Institute of Medical Research, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Fax: +81-3-52808067. E-mail: ezura.mph@mri.tmd.ac.jp

Received 1 December 2004; Accepted 28 January 2005; Published online 14 April 2005.

Abstract

Factors predisposing to the phenotypic features of high total cholesterol (T-Cho) in human plasma have not been clearly defined. Here we report an association between two variations in the apolipoprotein B48 receptor gene (APOB48R) and plasma T-Cho levels among 352 adult individuals in Japan. By analyzing phenotypic associations between age- and gender-adjusted levels of plasma T-Cho, low-density lipoprotein (LDL) cholesterol (LDL-C), and high-density lipoprotein (HDL) cholesterol (HDL-C), we detected a significant correlation between genotypes of the A419P variation and adjusted T-Cho levels. Among homozygous G-allele carriers (n=265), heterozygous carriers (n=78), and homozygous minor C-allele carriers (n=9), T-Cho levels were 2.430.21 mg/cm³, 2.480.24 mg/cm³, and 2.630.21 mg/cm³, respectively, indicating a codominant T-Cho-elevating effect of the minor C-allele (r=0.15, P=0.007). A similar effect was detected for c.934-960/del (r=0.13, P=0.015). Linkage disequilibrium (LD) analysis detected significant LD among eight variant sites that included neighboring loci. Our results indicate that variations in APOB48R and nearby genes are among the many factors involved in hypercholesterolemia. The etiological studies should now include consideration of this novel aspect of the mechanism(s) leading to hypercholesterolemic disease.