Promoter and 3'-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study.
Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be associated with several complex diseases, including osteoporosis, but the mechanisms are unknown and study results have been inconsistent. We therefore determined sequence variation across the major relevant parts of VDR, including construction of linkage disequilibrium blocks and identification of haplotype alleles. We analyzed 15 haplotype-tagging SNPs in relation to 937 clinical fractures recorded in 6,148 elderly whites over a follow-up period of 7.4 years. Haplotype alleles of the 5' 1a/1e, 1b promoter region and of the 3' untranslated region (UTR) were strongly associated with increased fracture risk. For the 16% of subjects who had risk genotypes at both regions, their risk increased 48% for clinical fractures (P = .0002), independent of age, sex, height, weight, and bone mineral density. The population-attributable risk varied between 1% and 12% for each block and was 4% for the combined VDR risk genotypes. Functional analysis of the variants demonstrated 53% lower expression of a reporter construct with the 1e/1a promoter risk haplotype (P = 5 x 10(-7)) in two cell lines and 15% lower mRNA level of VDR expression constructs carrying 3'-UTR risk haplotype 1 in five cell lines (P = 2 x 10(-6)). In a further analysis, we showed 30% increased mRNA decay in an osteoblast cell line for the construct carrying the 3'-UTR risk haplotype (P = .02). This comprehensive candidate-gene analysis demonstrates that the risk allele of multiple VDR polymorphisms results in lower VDR mRNA levels. This could impact the vitamin D signaling efficiency and might contribute to the increased fracture risk we observed for these risk haplotype alleles.
Fang
Yue
Y
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
van Meurs
Joyce B J
JB
d'Alesio
Arnold
A
Jhamai
Mila
M
Zhao
Hongyan
H
Rivadeneira
Fernando
F
Hofman
Albert
A
van Leeuwen
Johannes P T
JP
Jehan
Frédéric
F
Pols
Huibert A P
HA
Uitterlinden
André G
AG
D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D050723:Fractures, Bone / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D010024:Osteoporosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D018167:Receptors, Calcitriol