Vitamin D receptor gene haplotype is associated with body height and bone size

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.