ORIGINAL RESEARCH Significant Association between Common Polymorphisms in the Aromatase Gene CYP19A1 and Bone Mineral Density in Postmenopausal Women B. H. Mullin • K. W. Carter • J. R. Lewis • E. Ingley • S. G. Wilson • R. L. Prince Received: 30 May 2011 / Accepted: 27 August 2011 / Published online: 28 September 2011 Ó Springer Science+Business Media, LLC 2011 Abstract 17b-Estradiol is important in maintaining bone structure, and regulation of its synthesis plays an important role in the development of postmenopausal osteoporosis. We and others have demonstrated associations between variation in the CYP19A1 gene (encoding aromatase) and areal bone mineral density (aBMD) phenotypes in women. In the present study 33 tag polymorphisms were genotyped across the CYP19A1 gene in a population of 1,185 Caucasian postmenopausal women to test the association between sequence variations, total DXA hip aBMD, and circulating 17b-estradiol levels. An in silico bioinformatics analysis was performed for single nucleotide polymor- phisms (SNPs) associated with aBMD to identify putative functional effects, while linkage disequilibrium analysis of these SNPs was undertaken with previously published sequence variants. Five SNPs located in the central third of the gene were strongly associated with total-hip aBMD after adjustment for age (P = 0.006–0.013). A haplotype anal- ysis of these five SNPs revealed an association between the haplotype C-G-G-G-C and increased aBMD (P = 0.008) and the haplotype A-A-A-A-A and a decreased aBMD (P = 0.021). The haplotype frequency was 9.0% for C-G-G-G-C and 15.4% for A-A-A-A-A, with the variation in mean total-hip aBMD explained by the haplotype anal- yses being 5% and 7%, respectively. None of these poly- morphisms was significantly associated with circulating 17b-estradiol levels. In conclusion, common genetic vari- ations within the CYP19A1 gene are significantly associated with aBMD in postmenopausal Caucasian women. Keywords Areal bone mineral density Á Elderly women Á Cytochrome P-450 family 19 Á Aromatase Á Gene variation Postmenopausal osteoporosis is a systemic bone disease characterized by low bone mass and disturbed microar- chitecture of bone, resulting in increased fragility and risk of fracture. Peak bone mass is achieved in early adult life, but declines in postmenopausal women due to a reduction in estrogen production. This decrease in estrogen produc- tion has direct effects on bone as well as intestinal and renal calcium handling [1]. However, in addition to the influence of estrogen, calcium, and environmental factors, B. H. Mullin and K. W. Carter contributed equally to this study. The authors have stated that they have no conflict of interest. B. H. Mullin Á J. R. Lewis Á S. G. Wilson Á R. L. Prince Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia B. H. Mullin School of Biomedical Sciences, Curtin University of Technology, Bentley, WA, Australia K. W. Carter Telethon Institute for Child Health Research, UWA Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia J. R. Lewis (&) Á S. G. Wilson Á R. L. Prince School of Medicine and Pharmacology, University of Western Australia, Nedlands, Perth WA 6009, Australia e-mail: joshua.lewis@uwa.edu.au E. Ingley Cell Signalling Group, Laboratory for Cancer Medicine, Western Australia Institute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia S. G. Wilson Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK 123 Calcif Tissue Int (2011) 89:464–471 DOI 10.1007/s00223-011-9535-8