title: Association of a single-nucleotide variation (A1330V) in the low-density lipoprotein receptor-related protein 5 gene (LRP5) with bone mineral density in adult Japanese women.
abstract: Low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor of Wnt signaling, is an important regulator of bone development and maintenance. Recently we identified correlation between an intronic single-nucleotide polymorphism (SNP) in the LRP5 gene and vertebral bone mineral density (BMD), indicating that a genetic ground exists at this locus for determination of BMD. In the study reported here, we searched for nucleotide variation(s) that might confer susceptibility to osteoporosis among an extended panel of 387 healthy subjects recruited from the same hospital (Group-A), as well as among 384 subjects from the general population in eastern Japan (Group-B). We basically focused on two potentially functional variations, Q89R (c.266A > G) and A1330V (c.3989C > T), whose functional effects by the amino-acid changes were estimated by the SIFT software program; it predicted the 1330 V allele as deleterious ("intolerant") although the minor allele of Q89R was questionable. By analyzing associations between the variant alleles and the BMD, reproducible association of the minor variant of A1330V to lower adjusted BMD levels was detected; i.e., In Group-A subjects 1330-V significantly associated with the spinal BMD Z-score (P = 0.034), and in Group-B it associated with low radial BMD (P = 0.019). From haplotype and linkage disequilibrium (LD) analysis for 29 SNPs, we detected two separate LD blocks within the entire 137-kb LRP5 locus, basically consistent with a previous report on Caucasians. One of the second block haplotype significantly associated with adjusted BMD (r = 0.15, P = 0.004). Possible combined effect of Q89R and A1330V belonging to different LD blocks was denied by multiple regression analyses. Our results indicate that genetic variations in LRP5 are important factors affecting BMD in adult women and that 1330 V may contribute to osteoporosis susceptibility, at least in Japanese.
authors.affiliation: Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan. ezura.mph@mri.tmd.ac.jp
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ezura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sudo
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Kajita
authors.forename: Hideyo
authors.initials: H
authors.lastname: Yoshida
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hosoi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Masataka
authors.initials: M
authors.lastname: Shiraki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007564:Japan; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008875:Middle Aged; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5