This Article Full Text Full Text (PDF) All Versions of this Article: 92/8/3206    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Stolk, L. Articles by Uitterlinden, A. G. Search for Related Content PubMed PubMed Citation Articles by Stolk, L. Articles by Uitterlinden, A. G. Related Collections Calcium and Bone Metabolism Male Endocrinology

The Catechol-O-Methyltransferase Met¹⁵⁸ Low-Activity Allele and Association with Nonvertebral Fracture Risk in Elderly Men

Departments of Internal Medicine (L.S., J.B.J.v.M., M.J., P.P.A., J.P.T.v.L., F.H.d.J., H.A.P.P., A.G.U.) and Epidemiology and Biostatistics (A.H., H.A.P.P., A.G.U.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

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

Context: Because sex steroids play an important role in bone development, variants in genes encoding proteins involved in estrogen synthesis and metabolism could contribute to interindividual variation in bone parameters and fracture risk. An example is catechol-O-methyltransferase (COMT), an estrogen-degrading enzyme involved in inactivation of catechol-estrogens. Its gene contains a functional valine to methionine substitution at codon 158.

Objective: The aim of our study was to determine whether this polymorphism is associated with bone parameters and fracture risk in elderly subjects.

Methods: COMT genotypes were determined using TaqMan allelic discrimination in 2515 men and 3554 women from the Rotterdam Study, a population-based cohort study of individuals aged 55 and older. Associations with bone mineral density (BMD) and bone loss were analyzed using ANOVA or analysis of covariance, whereas fracture risk was analyzed using Cox’s proportional hazard regression analysis. COMT mRNA expression in three osteoblastic cell lines (SaOS, MG63, and SVHFO) was analyzed by RT-PCR.

Results: Male carriers of the Met¹⁵⁸ allele had an increased risk for osteoporotic fractures (hazard ratio = 1.6; 95% confidence interval, 1.0–2.4) and for fragility fractures (hazard ratio = 2.7; 95% confidence interval, 1.3–5.9), with evidence for a dominant effect. Adjustments for age, height, weight, and BMD did not change the risk estimates. In women, this association was weaker and not significant. BMD was not significantly associated with the variant in either men or women. COMT mRNA was expressed in all three osteoblastic cell lines tested.

Conclusion: The COMT Val158Met polymorphism is associated with fracture risk in elderly men, through a mechanism independent of BMD.