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

J Bone Miner Res. 2003 Sep;18(9):1632-41. doi: 10.1359/jbmr.2003.18.9.1632.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • CDX2 Transcription Factor
  • DNA, Complementary
  • Homeodomain Proteins
  • Receptors, Calcitriol
  • Trans-Activators