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Functional analysis for a leader sequence variation Trp16Ser in GnRH which is associated with low bone mineral density among adult women

GnRH 中与成年女性低骨密度相关的前导序列变异 Trp16Ser 的功能分析

基本信息

批准号：
18591680
负责人：
NAKAJIMA Toshiaki
金额：
$ 2.57万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591680/
关键词：
osteoporosis polymorphisms gonadotropin releasing hormone

项目摘要

To search for polymorphic alleles influencing individual genetic susceptibility for osteoporosis, we have been analyzing genetic association of polymorphisms from a large pool of candidates with adjusted areal bone mineral density (aBMD). By now, we detected several candidate alleles significantly associated with aBMD level in single cohort (n=384, adult women). However, none of those variants have been ascertained to substantially contribute to the susceptibility in general. Here, to examine the reproducibility of those observed associations, we analyzed 1315 missense single nucleotide polymorphisms (SNPs) selected as common variant (>5% in Japanese) in a second stage association study for vertebral aBMD Z-score (L2-4) using a group of 380 adult Japanese women recruited independently from former cohort. By genotyping subjects for all the 1315 missense SNPs, and comparing the correlation coefficient between the genotypes and aBMD Z-score with those obtained from previous study, the reproducibility of the association was evaluated. However among all the analyzed SNPs, no alleles showed significant correlation in both groups (p<0.01), except one variant (W16S) in gonadotropin releasing hormone (GnRH) gene (r=0.14 in previous study p=0.005, and r=0.14 in current study p=0.007). This variant resides in the leader sequence of GnRH, and alters hydrophobicity of the central core region of the signal peptide. Considering from the strong candidacy of this selected polymorphism possibly affecting the sex hormone status and thus for bone mineral status, we assume that our screening is working as we expected. In addition, when the significance level was reduced to p<0.05, another functionally strong candidate gene LRP5 was included (as reported at the 26th annual meeting), supporting our assumption.

为了寻找影响个体骨质疏松症遗传易感性的多态性等位基因，我们一直在分析来自大量候选人的多态性与校正的区域骨密度（aBMD）的遗传关联。到目前为止，我们在一个队列（n=384，成年女性）中检测到几个与aBMD水平显著相关的候选等位基因。然而，这些变体中没有一个被确定为对总体易感性有实质性贡献。在此，为了检查这些观察到的关联的可重复性，我们分析了1315个错义单核苷酸多态性（SNP），这些SNP被选为椎骨aBMD Z评分（L2-4）第二阶段关联研究中的常见变体（日本人>5%），使用了一组独立于前一队列招募的380名日本成年女性。通过对所有1315个错义SNPs进行基因分型，并将基因型与aBMD Z评分之间的相关系数与先前研究中获得的相关系数进行比较，评估关联的可重复性。然而，在所有分析的SNPs中，除促性腺激素释放激素（GnRH）基因的一个变体（W16 S）外，两组中没有等位基因显示出显著相关性（p<0.01）（先前研究中r=0.14 p=0.005，当前研究中r=0.14 p=0.007）。该变体存在于GnRH的前导序列中，并改变信号肽的中心核心区的疏水性。考虑到这种选择的多态性可能影响性激素状态，从而影响骨矿物质状态的强候选性，我们假设我们的筛选如我们预期的那样工作。此外，当显著性水平降低到p<0.05时，另一个功能强的候选基因LRP 5被包括在内（如在第26届年会上报道的），支持我们的假设。