Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly

被引:109
作者
Fang, Y
Van Meurs, JBJ
Bergink, AP
Hofman, A
Van Duijn, CM
Van Leeuwen, JP
Ap Pols, H
Uitterlinden, AG
机构
[1] Erasmus Univ, Med Ctr, Dept Internal Med, Genet Lab, NL-3000 DR Rotterdam, Netherlands
[2] Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands
关键词
osteoporosis; ethnic groups; genetics; allele-specific multiplex polymerase chain reaction;
D O I
10.1359/jbmr.2003.18.9.1632
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1632 / 1641
页数:10
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