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Interaction between Vitamin D Receptor Genotype and Estrogen Receptor Genotype Influences Vertebral Fracture Risk

Departments of Internal Medicine (E.M.C., A.G.U., J.B.J.M., A.P.B., Y.F., P.P.A., J.P.T.M.v.L., H.A.P.P.) and Epidemiology and Biostatistics (A.G.U., M.v.d.K., Y.F., A.H., H.A.P.P.), Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Prof. Dr. H. A. P. Pols, Erasmus Medical Center, Department of Internal Medicine, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: h.pols{at}erasmusmc.nl.

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ER haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ER haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9–4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ER haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ER haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6–9.9) for heterozygous and 10.3 (95% CI, 2.7–40) for homozygous carriers of ER haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ER and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density.

Abbreviations: ANCOVA, Analysis of covariance; BMD, bone mineral density; BMI, body mass index; CI, confidence interval(s); E₂, 17ß-estradiol; ER, estrogen receptor; 1,25-(OH)₂D₃, 1,25-dihydroxyvitamin D₃; OR, odds ratio; RFLP, restriction fragment length polymorphisms; VDR, vitamin D receptor.

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