Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II
Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II
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DOI：
10.1210/jc.2005-2017
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发表时间：
2006-03-01
影响因子：
5.8
通讯作者：
de Vernejoul, MC
中科院分区：
文献类型：
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作者：
Kornak, U;Ostertag, A;de Vernejoul, MC
背景：遗传因素是骨密度（BMD）的重要决定因素。ClC-7氯离子通道突变导致常染色体显性骨硬化症（ADOII）的事实使得CLCN 7基因成为调节骨密度的有吸引力的候选者。目的：本研究的目的是调查CLCN 7基因多态性与绝经后妇女BMD之间的关联以及ADOII的临床变异性。设计：这是一项使用CLCN 7基因中5个单核苷酸多态性和可变数目串联重复序列（VNTR）多态性的遗传关联研究。参与者：共有425名年龄为64 +/- 7岁的绝经后妇女参加了这项研究。我们还调查了一个ADOII家族，包括18个突变carriers.Main结果Measure（S）的低突变率：在我们的绝经后队列，个人的单核苷酸多态性基因型和单倍型进行了分析，与BMD在腰椎和股骨颈和骨吸收标记物脱氧吡啶啉（D-Pyr/Crea）。相同的多态性nonmutated CLCN 7等位基因进行了调查与ADOII phenotype.Results的变异性：多元线性回归分析显示，SS基因型的VNTR和较高的Z-评分值（P = 0.029）之间的显着关联。单倍型4，其中包括长等位基因的VNTR，被发现与较低的股骨颈Z评分值（P = 0.011）。此外，我们发现VNTR的ss基因型与较低水平的骨吸收标志物D-Pyr/Crea相关（P = 0.015），而单倍型4与较高的D-Pyr/Crea水平相关（P = 0.039）。在ADOII家族中，我们可以证明单倍型3，其中包含VNTR的s-等位基因，与突变携带者发生石骨症的概率略高相关（P = 0.029）。在这两种情况下，该协会似乎在很大程度上是由VNTR基因型驱动，但进一步加强，如果周围的多态性被添加到analysis.Conclusion：我们观察到一个显着的关联CLCN 7多态性与绝经后妇女的BMD和骨吸收标志物水平的方差和ADOII表型的变异。
Context: Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density.Objective: The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII.Design: This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene.Participants: A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers.Main Outcome Measure(s): In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype.Results: Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis.Conclusion: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.