背景:骨质疏松症是一种全身性骨骼疾病,其特征是骨矿物质密度降低和骨折易感性增加;这些特征具有高度遗传性。常见和罕见拷贝数变异(CNV)都可能影响基因的功能,并可能影响疾病风险。
目的:确定与骨质疏松性骨折风险相关的CNV。
方法:我们在荷兰的一个前瞻性队列中对5178名个体进行了全基因组CNV关联研究,包括809例骨质疏松性骨折,并在几个独立的研究中进行计算机查找和从头基因分型以复制。
结果:罕见(人群患病率0.14%,95%CI0.03%至0.24%)位于染色体6p25.1上的210kb缺失与骨折风险相关(OR32.58,95%CI3.95至1488.89;p=8.69×10(-5))。我们在4项研究中使用CNV微阵列数据进行了计算机荟萃分析,并重复了与骨折风险的关联(OR3.11,95%CI1.01至8.22;p=0.02)。这种缺失的患病率显示出地理多样性,在来自澳大利亚的额外样本中不存在,加拿大,波兰,冰岛,丹麦,瑞典,但目前在荷兰(0.34%),西班牙(0.33%),美国(0.23%),英格兰(0.15%),苏格兰(0.10%),爱尔兰(0.06%),与骨折风险相关的证据不足。
结论:这些结果表明,6p25.1位点的缺失可能导致一部分欧洲裔人群发生骨折的风险较高;需要进行更大规模和地理限制的研究来确认这种区域关联。这是评估稀有CNV在骨质疏松症中的作用的第一步。
BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.
OBJECTIVE: To identify CNVs associated with osteoporotic bone fracture risk.
METHODS: We performed a genome-wide CNV association
study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.
RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.
CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.