Sibling pair linkage and association studies between peak bone mineral density and the gene locus for the osteoclast-specific subunit (OC116) of the vacuolar proton pump on chromosome 11p12-13
Sibling pair linkage and association studies between peak bone mineral density and the gene locus for the osteoclast-specific subunit (OC116) of the vacuolar proton pump on chromosome 11p12-13
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DOI：
10.1210/jc.87.8.3819
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发表时间：
2002-08-01
影响因子：
5.8
通讯作者：
Econs, MJ
中科院分区：
文献类型：
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作者：
Carn, G;Koller, DL;Econs, MJ
骨质疏松症风险的一个主要决定因素是峰值骨密度(BMD)，它已被证明具有很大的遗传性。3种骨密度相关表型(常染色体显性高骨量、常染色体隐性遗传性骨质疏松-假性胶质瘤、常染色体隐性隐性骨质疏松症-假性胶质瘤、常染色体隐性隐性骨化症)的基因均位于染色体11q12-13区域。我们报告了大量健康的绝经前姐妹对的峰值骨密度与同一染色体区域的关联，这表明这三种疾病背后的基因也可能在决定正常人群的峰值骨密度方面发挥作用。为了验证这一假说，我们研究了导致一种常染色体隐性遗传性骨化症的基因TCIRG1，它编码空泡质子泵的破骨细胞特异性亚单位(OC116)。我们在TCIRG1中发现了3个变异体，但只有一个，即单核多态906713，具有足够的杂合度，可以用于遗传分析。在995对健康的绝经前姐妹样本中，我们的发现与股骨颈骨密度有关，但与脊柱骨密度无关。然而，使用人群和基于家庭的不平衡方法的进一步分析，没有显示TCIRG1与脊柱或股骨颈骨密度相关的任何证据。因此，我们的连锁数据表明，包含OC116的染色体区域包含一个影响峰值骨密度的基因，但我们的关联结果表明，OC116基因的多态不影响峰值骨密度。
A major determinant of the risk of osteoporosis is peak bone mineral density (BMD), which has been shown to have substantial heritability. The genes for 3 BMD-related phenotypes (autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessives osteopetrosis) are all in the chromosome 11q12-13 region. We reported linkage of peak BMD in a large sample of healthy premenopausal sister pairs to this same chromosomal region, suggesting that the genes underlying these 3 disorders may also play a role in determining peak BMD within the normal population. To test this hypothesis, we examined the gene responsible for 1 form of autosomal recessive osteopetrosis, TCIRG1, which encodes an osteoclast-specific subunit (OC116) of the vacuolar proton pump. We identified 3 variants in the sequence of TCIRG1, but only one, single nuclear polymorphism 906713, had sufficient heterozygosity for use in genetic analyses. Our findings were consistent with linkage to femoral neck BMD, but not to spine BMD, in a sample of 995 healthy premenopausal sister pairs. However, further analysis, using both population and family-based disequilibrium approaches, did not demonstrate any evidence of association between TCIRG1 and the spine or femoral neck BMD. Therefore, our linkage data suggest that the chromosomal region that contains OC116 harbors a gene that affects peak BMD, but our association results indicate that polymorphisms in the OC116 gene do not affect peak BMD.