UNLABELLED: 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.
UNLABELLED: A Cdx-2 binding site polymorphism (G to A) in the promoter region of the humanvitamin 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 humanvitamin 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 VDRCdx-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 VDRCdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.
Authors: J Brent Richards; Fotini K Kavvoura; Fernando Rivadeneira; Unnur Styrkársdóttir; Karol Estrada; Bjarni V Halldórsson; Yi-Hsiang Hsu; M Carola Zillikens; Scott G Wilson; Benjamin H Mullin; Najaf Amin; Yurii S Aulchenko; L Adrienne Cupples; Panagiotis Deloukas; Serkalem Demissie; Albert Hofman; Augustine Kong; David Karasik; Joyce B van Meurs; Ben A Oostra; Huibert A P Pols; Gunnar Sigurdsson; Unnur Thorsteinsdottir; Nicole Soranzo; Frances M K Williams; Yanhua Zhou; Stuart H Ralston; Gudmar Thorleifsson; Cornelia M van Duijn; Douglas P Kiel; Kari Stefansson; André G Uitterlinden; John P A Ioannidis; Tim D Spector Journal: Ann Intern Med Date: 2009-10-20 Impact factor: 25.391
Authors: Mariël L te Winkel; Robert D van Beek; Sabine M P F de Muinck Keizer-Schrama; André G Uitterlinden; Wim C J Hop; Rob Pieters; Marry M van den Heuvel-Eibrink Journal: Haematologica Date: 2009-12-16 Impact factor: 9.941
Authors: B Frederiksen; E Liu; J Romanos; A K Steck; X Yin; M Kroehl; T E Fingerlin; H Erlich; G S Eisenbarth; M Rewers; J M Norris Journal: J Steroid Biochem Mol Biol Date: 2012-09-07 Impact factor: 4.292
Authors: Yue Fang; Joyce B J van Meurs; Pascal Arp; Johannes P T van Leeuwen; Albert Hofman; Huibert A P Pols; André G Uitterlinden Journal: Calcif Tissue Int Date: 2009-06-02 Impact factor: 4.333