Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density
Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density
复制标题
DOI：
10.1359/jbmr.2002.17.4.678
复制
发表时间：
2002-04-01
影响因子：
6.2
通讯作者：
Recker, RR
中科院分区：
文献类型：
--
作者：
Deng, HW;Shen, H;Recker, RR
骨矿物质密度（BMD）是骨质疏松性骨折（OFs）的主要决定因素。BMD在人群中的遗传率为50% ~ 90%。通过传统的连锁或关联方法进行了广泛的分子遗传分析，以测试和鉴定BMD变异的基因或基因组区域。研究结果，特别是关于维生素D受体（VDR）基因的研究结果，一直不一致且有争议。在这项研究中，我们同时测试了来自53个人类家系的630名受试者的VDR、骨钙素（也称为骨玻璃蛋白[BGP]）和甲状旁腺激素（PTH）基因与骨密度的联系和/或关联。每个谱系都是通过在髋部或脊柱处具有极端骨密度值的先证者确定的（Z值小于或等于-1.28）。对于原始骨密度值，对年龄、性别和体重的显著协变量效应进行调整，我们分别对关联、关联以及关联和关联进行了测试。对于脊柱骨密度，在VDR基因内的两个标记（Apal和Fokl）上，我们发现了连锁的证据（p < 0.05），并且通过传递不平衡检验发现了连锁和关联的证据（TDT, p < 0.05）；通过方差分析（ANOVA）进行常规统计检验，发现相关性（p < 0.07）。此外，在单独关联（p < 0.05）、单独连锁（p = 0.0005）以及髋部骨密度BGP基因的基因内标记HindIII的连锁和关联（p = 0.0019）方面均有显著结果。通过关联、连锁、连锁和关联同时检测，我们的数据支持VDR基因是脊柱骨密度变异的数量性状位点（QTL）， BGP基因是髋关节骨密度变异的数量性状位点（QTL）。然而，我们的数据不支持PTH基因作为髋关节或脊柱骨密度变异的QTL。这是骨遗传学广泛领域的第一个研究，通过同时检测单独的关联、单独的连锁以及关联和连锁（通过TDT）来检测候选基因作为BMD的qtl。
Bone mineral density (BMD) is a major determinant of osteoporotic fractures (OFs). The heritability of BMD ranges from 50% to 90% in human populations. Extensive molecular genetic analyses have been performed through traditional linkage or association approaches to test and identify genes or genomic regions underlying BMD variation. The results, particularly those concerning the vitamin D receptor (VDR) gene, have been inconsistent and controversial. In this study, we simultaneously test linkage and/or association of the genes for VDR, osteocalcin (also known as bone Gla protein [BGP]), and parathyroid hormone (PTH) with BMD in 630 subjects from 53 human pedigrees. Each of these pedigrees was ascertained through a proband with an extreme BMD value at the hip or spine (Z score less than or equal to -1.28). For the raw BMD values, adjusting for significant covariate effects of age, sex, and weight, we performed tests for linkage alone, association alone, and then both linkage and association. For the spine BMD, at the two markers (Apal and Fokl) inside the VDR gene we found evidence for linkage (p < 0.05) and for both linkage and association by the transmission disequilibrium test (TDT; p < 0.05); association was detected (p < 0.07) with regular statistical testing by analyses of variance (ANOVA). In addition, significant results were found for association alone (p < 0.05), linkage alone (p = 0.0005), and for linkage and association (p = 0.0019) for the intragenic marker HindIII of the BGP gene for the hip BMD. Through testing for association, linkage, and linkage and association simultaneously, our data support the VDR gene as a quantitative trait locus (QTL) underlying spine BMD variation and the BGP gene as a QTL underlying hip BMD variation. However, our data do not support the PTH gene as a QTL underlying hip or spine BMD variation. This is the first study in the broad field of bone genetics that tests candidate genes as QTLs for BMD by testing simultaneously for association alone, for linkage alone, and for association and linkage (via the TDT).