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
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
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DOI：
10.1016/j.bone.2005.06.025
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发表时间：
2007-04-01
期刊：
影响因子：
4.1
通讯作者：
Emi, Mitsuru
中科院分区：
文献类型：
--
作者：
Ezura, Yoichi;Nakajima, Toshiaki;Emi, Mitsuru
低密度脂蛋白受体相关蛋白5（LRP 5）是Writ信号的共受体，是骨发育和维持的重要调节因子。最近，我们确定了LRP 5基因的内含子单核苷酸多态性（SNP）和椎骨骨密度（BMD）之间的相关性，表明在这个位点存在一个遗传基础，用于确定BMD。在本文报告的研究中，我们在同一医院招募的387名健康受试者（A组）以及日本东部普通人群的384名受试者（B组）中寻找可能导致骨质疏松症易感性的核苷酸变异。我们主要关注两个潜在的功能变异，Q89 R（c.266A > G）和A1330 V（c.3989C > T），通过SIFT软件程序估计其氨基酸变化的功能效应;它预测1330 V等位基因是有害的（“不耐受”），尽管Q89 R的次要等位基因是可疑的。通过分析变异等位基因与BMD之间的关联，检测到A1330 V的次要变异与较低的校正BMD水平的可再现关联;即，在A组受试者中，1330-V与脊柱BMD Z评分显著相关（P = 0.034），在B组中，1330-V与低桡骨BMD相关（P = 0.019）。从单倍型和连锁不平衡（LD）分析的29个SNP，我们发现两个独立的LD块内的整个137 kb的LRP 5基因座，基本上与以前的报告一致的高加索人。其中第二块单倍型与校正后的BNID显著相关（r = 0.15，P0.004）.多元回归分析否定了Q89 R和A1330 V属于不同LD块的可能的联合作用。我们的研究结果表明，LRP 5的遗传变异是影响成年女性BMID的重要因素，1330 V可能有助于骨质疏松症的易感性，至少在日本。(c)2007年由Elsevier Inc.出版
Low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor of Writ 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 A 1330V (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 BNID (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 BMID in adult women and that 1330 V may contribute to osteoporosis susceptibility, at least in Japanese. (c) 2007 Published by Elsevier Inc.