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A variant of human aromatase predicts increased circulating estradiol and bone health in post-menopausal women

Payne, E.J., Wilson, S.G., Mullin, B.H., Ingley, E.ORCID: 0000-0002-8112-9134 and Prince, R.L. (2009) A variant of human aromatase predicts increased circulating estradiol and bone health in post-menopausal women. Bone, 44 (Supp.1). S19-S20.

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The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. Work from our group has shown that a microsatellite in intron 4 is associated with bone density and estrogen levels. Moreover a threonine to methionine missense mutation at amino acid position 201 in exon 6 of the aromatase gene causes a 5 fold increase in aromatase activity in an in-vitro assay. In this study we have characterized the effect of this variant on a large population of elderly women. A cohort of 1257 post-menopausal Western Australian women aged 75 ± 2.5 years in 1998 were recruited from the Western Australian electoral roll. Bone mineral density (BMD) at the hip and spine sites was measured by DXA (Hologic QDR 4500). Serum estradiol was measured by RIA (Orion Diagnostica, Finland). Genotyping of the T201M site was by Taqman (Applied Biosystems, Foster City, CA). Spinal deformity was calculated from morphometric x-ray calculations. The frequencies of the genotypes in the population were CC = 0.83, CT = 0.16, TT = 0.01. Using a dominant model the variant (T) was associated with increased estradiol for the heterozygote and rarer homozygote combined (CC: 25.5 ± 14.9 pmol/L vs. CT, TT: 38.3 ± 27.4 pmol/L; P = 4.5 × 10− 21). In addition, the variant allele was associated with increased BMD at the total hip (CC: 806 ± 126 mg/cm2 vs. CT, TT: 831 ± 129 mg/cm2; P = 0.015), femoral neck (CC: 686 ± 104 mg/cm2 vs. CT, TT: 706 ± 109 mg/cm2; P = 0.021). This variant was also associated with a reduction in spinal deformity (L4–T12) (CC: 37.6% vs. CT, TT: 21.1%; P = 0.012). We found that carriers of the T allele (17% of the population) show increased circulating estrogen, increased DXA BMD and reduced spine deformity. The observed associations are in keeping with the molecular effects of the nucleotide change previously characterised in vitro. These findings serve as the basis for further examination of the regulatory mechanisms of aromatase expression in human bone tissue and suggest that this variant may be of clinical use in predicting propensity to disease.

Item Type: Journal Article
Publisher: Elsevier
Copyright: © 2009 Published by Elsevier Inc.
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