Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility of fracture in the elderly
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. 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, > or = 55 years old. RESULTS AND CONCLUSIONS: 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.
|Keywords||*Polymorphism, Single Nucleotide, *Promoter Regions (Genetics), 0 (DNA, Complementary), 0 (Homeodomain Proteins), 0 (Receptors, Calcitriol), 156560-97-3 (Cdx-2-3 protein), Aged, Aged, 80 and over, Alleles, Base Sequence, Binding Sites/genetics, Bone disease, Cohort Studies, Comparative Study, DNA, Complementary/genetics, Ethnic Groups/genetics, European Continental Ancestry Group/genetics, Female, Fractures/*genetics, Gene Frequency, Homeodomain Proteins/*metabolism, Human, Male, Middle Aged, Netherlands, Receptors, Calcitriol/*genetics, Risk Factors, Support, Non-U.S. Gov't|
|Persistent URL||dx.doi.org/10.1359/jbmr.2003.18.9.1632, hdl.handle.net/1765/5950|
Fang, Y., Hofman, A., van Duijn, C.M., van Leeuwen, J.P.T.M., Pols, H.A.P., Uitterlinden, A.G., … Bergink, A.P.. (2003). Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility of fracture in the elderly. Journal of Bone and Mineral Research, 18(9), 1632–1641. doi:10.1359/jbmr.2003.18.9.1632