Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly
Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly
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DOI：
10.1359/jbmr.2003.18.9.1632
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发表时间：
2003-09-01
影响因子：
6.2
通讯作者：
Uitterlinden, AG
中科院分区：
文献类型：
--
作者：
Fang, Y;Van Meurs, JBJ;Uitterlinden, AG
在人类维生素D受体（VDR）基因的启动子区域，肠道特异性转录因子Cdx-2结合位点内的单核苷酸多态性（SNP）已被报道。在一小群日本绝经后妇女中发现，它可以调节hVDR基因的转录，并与骨矿物质密度下降有关。在这项研究中，我们研究了VDR Cdx-2基因型与骨折风险之间的关系。方法：我们首先通过测序分析确定该SNP在VDR基因中的位置，并开发了等位基因特异性多重聚合酶链反应试验来确定Cdx-2基因型。然后，我们对8个种族进行了生态研究，并对2848名55岁的荷兰白人男性和女性进行了关联分析。结果与结论：在VDR基因外显子le （1e-G-1739A）的启动子区发现了G- to - A的替换位点。通过比较8个不同种族a等位基因的频率，我们观察到a等位基因的患病率与这些种族中公布的髋部骨折发病率呈负相关（男性p = 0.006，女性p = 0.02），表明该等位基因对骨折风险有保护作用。随后，在关联研究中，a等位基因（群体频率19%）被观察到对骨质疏松性骨折的发生具有保护作用，特别是对女性的非椎体骨折（AA与GG基因型的相对风险为0.2;95% Cl, 0.05-0.8）。在调整了年龄、体重和骨密度后，这种影响仍然存在。我们得出结论，VDR Cdx-2多态性的a等位基因存在于白人中，尽管频率较低，并显示出该等位基因对骨折风险的保护作用。
Introduction: A single nucleotide polymorphism (SNP) within a binding site of the intestinal-specific transcription factor Cdx-2 in the promoter region of the human vitamin D receptor (VDR) gene was previously reported. It was found to modulate the transcription of the hVDR gene and to be associated with decreased bone mineral density in a small group of postmenopausal Japanese women. In this study, we investigated the relationship between the VDR Cdx-2 genotype and risk of fracture.Methods: We first determined the location of this SNP in the VDR gene by sequencing analysis, and we developed an allele-specific multiplex polymerase chain reaction test to determine the Cdx-2 genotype. We then performed an ecological study in eight ethnic groups and an association analysis in a large epidemiological cohort of 2848 Dutch white men and women, :55 years old.Results and Conclusions: The location of the G to A substitution was found in the promoter region of exon le (1e-G-1739A) of the VDR gene. By comparing the frequency of the A-allele in eight different ethnic groups, we observed a negative correlation between prevalence of the A-allele and published hip fracture incidence rates in these ethnic groups (p = 0.006 for men and p = 0.02 for women), suggesting a protective effect of this allele on fracture risk. Subsequently, in the association study, the A-allele (population frequency 19%) was observed to have a protective effect on occurrence of osteoporotic fractures, especially for nonvertebral fracture in women (relative risk of AA versus GG genotype is 0.2; 95% Cl, 0.05-0.8). This effect remained after adjustment for age, weight, and bone mineral density. We conclude that the A-allele of the VDR Cdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.