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Vitamin D Receptor Gene Haplotype Is Associated with Body Height and Bone Size

Departments of Internal Medicine (Y.F., J.B.J.v.M., F.R., J.P.T.v.L., H.A.P.P., A.G.U.), and Epidemiology and Biostatistics (F.R., H.A.P.P., A.G.U.), Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; Institute for Research in Extramural Medicine (N.M.v.S.), VU University Medical Center, 1081 BT Amsterdam, The Netherlands; and Department of Endocrinology (P.L.), VU University Medical Center, 1007 MB Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: André G. Uitterlinden, Genetic Laboratory, Room Ee575, Department of Internal Medicine, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: a.g.uitterlinden{at}erasmusmc.nl.

Context: Adult stature is a complex genetic trait. The vitamin D endocrine system has pleiotropic effects on several physiological processes, especially on skeletal metabolism. We recently identified promoter and 3'-untranslated region (UTR) haplotype alleles that influence vitamin D receptor (VDR) mRNA expression.

Objective: We studied whether VDR gene variants contribute to the genetic variation in height.

Design and Subjects: We studied VDR haplotype alleles and body height in two independent populations (n = 7187). In a meta-analysis (n = 14,157 from 27 studies and our current data), we evaluated the effect of the Bsm I polymorphism.

Results: Haplotypes of the linkage disequilibrium block 3 and block 5 were associated with body height differences with evidence for additive effects in the Rotterdam Study (P = 0.00002) and the Longitudinal Aging Study Amsterdam study (P = 0.001). Height differences between the extreme genotypes were 1.4 and 2.7 cm, respectively. The relationship was independent of age, gender, presence of vertebral fractures, and age-related height loss. In the Rotterdam population, we found the combined genotype to be associated with decreased vertebral area (P = 0.03) and femoral narrow neck width (P = 0.002). In the meta-analysis, subjects with the "BB" genotype were 0.6 cm (95% confidence interval, 0.2–1.1 cm) taller than those with the "bb" genotype (P = 0.006).

Conclusion: VDR gene variants are associated with differences in body height as evidenced by our study and by a meta-analysis. It remains for further studies to confirm whether the underlying mechanism of the association involves lower VDR expression in cells important for determining bone size.