title: Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly.
abstract: 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.
  
  
  BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fang
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: Arjan P
authors.initials: AP
authors.lastname: Bergink
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D000071616:CDX2 Transcription Factor; D015331:Cohort Studies; D018076:DNA, Complementary / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D005787:Gene Frequency; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D015534:Trans-Activators; D044465:White People / Q000235:genetics
chemical_list: D000071616:CDX2 Transcription Factor; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D018167:Receptors, Calcitriol; D015534:Trans-Activators