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A Cdx-2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A-allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism.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.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, > or = 55 years old.The location of the G to A substitution was found in the promoter region of exon le (le-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% CI, 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.

Original publication

DOI

10.1359/jbmr.2003.18.9.1632

Type

Journal article

Journal

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Publication Date

09/2003

Volume

18

Pages

1632 - 1641

Addresses

Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.

Keywords

Humans, Homeodomain Proteins, Trans-Activators, Receptors, Calcitriol, DNA, Complementary, Risk Factors, Cohort Studies, Binding Sites, Base Sequence, Gene Frequency, Polymorphism, Single Nucleotide, Alleles, Aged, Aged, 80 and over, Middle Aged, European Continental Ancestry Group, Ethnic Groups, Netherlands, Female, Male, Fractures, Bone, Promoter Regions, Genetic, CDX2 Transcription Factor