Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis
Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis
复制标题
DOI：
10.1001/jama.299.11.1277
复制
发表时间：
2008-03-19
影响因子：
120.7
通讯作者：
Uitterlinden, Andre G.
中科院分区：
文献类型：
--
作者：
van Meurs, Joyce B. J.;Trikalinos, Thomas A.;Uitterlinden, Andre G.
研究背景低密度脂蛋白受体相关蛋白5（LRP 5）基因突变引起以骨矿物质密度（BMD）改变为特征的罕见综合征。更常见的LRP 5变体可能会影响普通人群的骨质疏松症风险。目的提供大规模证据来证明LRP 5的2种常见变体是否存在（Val 667 Met，Ala 1330 Val）和LRP 6的1种变体（Ile 1062 Val）与BMD和骨折风险相关。对来自欧洲和北美18个参与团队的37534名个人的个人水平数据进行了合作研究。数据收集于2004年9月至2007年1月之间;对收集到的数据进行分析的时间为2007年2月至5月。骨密度采用双能X线吸收法测定.通过问卷调查、医疗记录或影像学文件确定骨折;通过常规监测方法确定某些队列的骨折事件数据，包括椎骨骨折的影像学检查。结果LRP 5的Met 667等位基因与腰椎BMD降低相关，（n= 25 052 [有可用数据的参与者数量];每个Met 667等位基因拷贝的BMD降低20 mg/ cm（2）; P= 3.3 x 10（-8）），Val 1330等位基因也是如此（n= 24 812;每个Val 1330拷贝的BMD降低14 mg/ cm（2）; P= 2.6 x 10（-9））。对股骨颈BMD也观察到类似的影响，Met 667和Val 1330等位基因分别降低11 mg/ cm 2（P= 3.8 x 10（-5））和8 mg/cm 2（P= 5.0 x 10（-6））（n= 25 193）。两种LRP 5等位基因的研究结果一致。两个等位基因均与椎骨骨折相关（Met 667 [ 2001例骨折，20488例患者]的比值比[ OR]为1.26; 95%置信区间[ CI]为1.08-1.47; Val 1330 [ 1988例骨折，20096例患者]的比值比[ OR]为1.12; 95% CI为1.01- 1.24）。Met 667（OR，1.14; 95%CI，1.05- 1.24/等位基因[31435例患者中7876例骨折]）和Val 1330（OR，1.06; 95%CI，1.01- 1.12/等位基因[31199例患者中7802例骨折]）也增加了所有骨折的风险。当对年龄、体重、身高、绝经状态和激素治疗的使用进行调整时，效果相似。骨折风险部分减弱了骨密度的调整。单倍型分析表明，Met 667和Val 1330变异都独立影响BMD。LRP 6 Ile 1062 Val多态性与任何骨质疏松表型无关。除了Val 1330和所有骨折和椎骨骨折之间的所有上述协会仍然显着多重比较调整后。结论常见的LRP 5变异体始终与不同的白色人群的BMD和骨折风险。影响的程度是适度的。LRP 5可能是第一个达到与骨质疏松症相关的表型的全基因组显著性水平（保守的显著性水平[本文中，未调整的P < 10（-7）]，其解释了人类基因组中许多可能的比较）的基因。
Context Mutations in the low- density lipoprotein receptor - related protein 5 ( LRP5) gene cause rare syndromes characterized by altered bone mineral density ( BMD). More common LRP5 variants may affect osteoporosis risk in the general population.Objective To generate large- scale evidence on whether 2 common variants of LRP5 ( Val667Met,Ala1330Val) and 1 variant of LRP6( Ile1062Val) are associated with BMD and fracture risk.Design and Setting Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual- energy x- ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.Main Outcome Measures Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.Results The Met667 allele of LRP5 was associated with reduced lumbar spine BMD ( n= 25 052 [ number of participants with available data]; 20- mg/ cm(2) lower BMD per Met667 allele copy; P= 3.3 x 10(-8)), as was the Val1330 allele ( n= 24 812; 14- mg/ cm(2) lower BMD per Val1330 copy; P= 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/ cm(2) ( P= 3.8 x 10(-5)) and 8 mg/ cm2 ( P= 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively ( n= 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures ( odds ratio [ OR], 1.26; 95% confidence interval [ CI], 1.08-1.47 for Met667 [ 2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01- 1.24 for Val1330 [ 1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 ( OR, 1.14; 95% CI, 1.05- 1.24 per allele [ 7876 fractures among 31 435 individuals)]) and Val1330 ( OR, 1.06; 95% CI, 1.01- 1.12 per allele [ 7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.Conclusions Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome- wide significance level ( a conservative level of significance [ herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.