van Meurs Joyce B J, Rivadeneira Fernando, Jhamai Mila, Hugens Wendy, Hofman Albert, van Leeuwen Johannes P T M, Pols Huibert A P, Uitterlinden André G
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
J Bone Miner Res. 2006 Jan;21(1):141-50. doi: 10.1359/JBMR.050904. Epub 2005 Sep 6.
Both LRP5 and LRP6 genes have been implicated to play a role in bone metabolism. In a large population-based study, we related common variation in both genes to bone parameters and fractures. LRP5 variation was associated to both BMD and frame size, whereas both LRP5 and 6 variations were associated with an increased fracture risk in males.
The low-density lipoprotein receptor-related protein 5 (LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5 and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis.
We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects.
In men, the LRP5 1330-valine variant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele-dose effect (p = 0.001 and 0.01, respectively). The Val allele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6 Ile1062Val polymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330-valine variant had a 60% increased risk for fragility fractures, and the LRP6 1062-valine allele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5 and 6 had a 140% (p = 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues.
低密度脂蛋白受体相关蛋白5（LRP5）基因和低密度脂蛋白受体相关蛋白6（LRP6）基因均被认为在骨代谢中起作用。在一项基于大规模人群的研究中，我们将这两个基因的常见变异与骨参数和骨折情况联系起来。LRP5变异与骨密度（BMD）和体格大小均相关，而LRP5和LRP6变异均与男性骨折风险增加相关。
低密度脂蛋白受体相关蛋白5（LRP5）基因在罕见的骨密度性状以及峰值骨密度的正常变异中均有明确作用。我们研究了LRP5及其紧密同源基因LRP6的常见变异在老年骨密度及骨折（骨质疏松的主要临床终点）中是否起作用。
在一项针对老年受试者的大规模前瞻性基于人群的队列研究中，我们分析了LRP5的四个变异以及LRP6基因的一个氨基酸变异。
在男性中，LRP5基因的1330缬氨酸变异与腰椎和股骨颈骨密度降低相关，存在等位基因剂量效应的证据（分别为p = 0.001和0.01）。缬氨酸等位基因也与椎体大小和股骨颈宽度减小相关。对所研究多态性的单倍型分析并未改善所发现的关联，并表明1330变异驱动了这种关联。我们观察到LRP6基因Ile1062Val多态性与男性身高和椎体大小存在临界显著关联。携带LRP5基因1330缬氨酸变异的男性发生脆性骨折的风险增加60%，LRP6基因1062缬氨酸等位基因也使风险提高60%。与非携带两种风险等位基因的男性相比，同时携带LRP5和LRP6风险等位基因的男性骨折风险高140%（p = 0.004），且占男性骨折病例的10%。骨折风险与年龄、身高、体重和骨密度无关。在女性中，与男性相比，所有这些关联均较弱且不太一致。所发现的相关多态性均位于受体的潜在重要结构域，且显示出相当程度的进化保守性，这证明了这些残基的功能重要性。
