Abstract
17β-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 17β-estradiol levels. An in silico bioinformatics analysis was performed for single nucleotide polymorphisms (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 analysis 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 analyses being 5% and 7%, respectively. None of these polymorphisms was significantly associated with circulating 17β-estradiol levels. In conclusion, common genetic variations within the CYP19A1 gene are significantly associated with aBMD in postmenopausal Caucasian women.
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Prince RL, Dick I (1997) Estrogen effects on calcium membrane transport: a new view of the inter-relationship between estrogen deficiency and age-related osteoporosis. Osteoporos Int 7 Suppl 3:S150–S154
Gueguen R, Jouanny P, Guillemin F, Kuntz C, Pourel J, Siest G (1995) Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Miner Res 10:2017–2022
Krall EA, Dawson-Hughes B (1993) Heritable and life-style determinants of bone mineral density. J Bone Miner Res 8:1–9
Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults: a twin study. J Clin Invest 80:706–710
Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr (1973) Genetic factors in determining bone mass. J Clin Invest 52:2800–2808
Fisher CR, Graves KH, Parlow AF, Simpson ER (1998) Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci USA 95:6965–6970
Oz OK, Hirasawa G, Lawson J, Nanu L, Constantinescu A, Antich PP, Mason RP, Tsyganov E, Parkey RW, Zerwekh JE, Simpson ER (2001) Bone phenotype of the aromatase deficient mouse. J Steroid Biochem Mol Biol 79:49–59
Bilezikian JP, Morishima A, Bell J, Grumbach MM (1998) Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603
Maffei L, Rochira V, Zirilli L, Antunez P, Aranda C, Fabre B, Simone ML, Pignatti E, Simpson ER, Houssami S, Clyne CD, Carani C (2007) A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital estrogen deficiency, adiposity and the metabolic syndrome. Clin Endocrinol (Oxf) 67:218–224
Mullis PE, Yoshimura N, Kuhlmann B, Lippuner K, Jaeger P, Harada H (1997) Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab 82:1739–1745
Dick IM, Devine A, Prince RL (2005) Association of an aromatase TTTA repeat polymorphism with circulating estrogen, bone structure, and biochemistry in older women. Am J Physiol Endocrinol Metab 288:E989–E995
Gennari L, Masi L, Merlotti D, Picariello L, Falchetti A, Tanini A, Mavilia C, Del Monte F, Gonnelli S, Lucani B, Gennari C, Brandi ML (2004) A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism. J Clin Endocrinol Metab 89:2803–2810
Tofteng CL, Kindmark A, Brandstrom H, Abrahamsen B, Petersen S, Stiger F, Stilgren LS, Jensen JE, Vestergaard P, Langdahl BL, Mosekilde L (2004) Polymorphisms in the CYP19 and AR genes—relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: the Danish osteoporosis prevention study. Calcif Tissue Int 74:25–34
Masi L, Becherini L, Gennari L, Amedei A, Colli E, Falchetti A, Farci M, Silvestri S, Gonnelli S, Brandi ML (2001) Polymorphism of the aromatase gene in postmenopausal Italian women: distribution and correlation with bone mass and fracture risk. J Clin Endocrinol Metab 86:2263–2269
Riancho JA, Valero C, Naranjo A, Morales DJ, Sanudo C, Zarrabeitia MT (2007) Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis. J Clin Endocrinol Metab 92:660–665
Riancho JA, Sanudo C, Valero C, Pipaon C, Olmos JM, Mijares V, Fernandez-Luna JL, Zarrabeitia MT (2009) Association of the aromatase gene alleles with BMD: epidemiological and functional evidence. J Bone Miner Res 24:1709–1718
Bruce DG, Devine A, Prince RL (2002) Recreational physical activity levels in healthy older women: the importance of fear of falling. J Am Geriatr Soc 50:84–89
Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 166:869–875
Ireland P, Jolley D, Giles G, O’Dea K, Powles J, Ritishauser I, Wahlqvist ML, Williams J (1994) Development of the Melbourne FFQ: a food frequency questionnaire for use in an Australian prospective study involving an ethnically diverse cohort. Asia Pacific J Clin Nutr 3:19–31
Dick IM, Devine A, Marangou A, Dhaliwal SS, Laws S, Martins RN, Prince RL (2002) Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women. Bone 31:497–502
Bollerslev J, Wilson SG, Dick IM, Devine A, Dhaliwal SS, Prince RL (2004) Calcium-sensing receptor gene polymorphism A986S does not predict serum calcium level, bone mineral density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women. Calcif Tissue Int 74:12–17
The International HapMap Consortium (2003) The international HapMap project. Nature 426:789–796
Lee PH, Shatkay H (2009) An integrative scoring system for ranking SNPs by their potential deleterious effects. Bioinformatics 25:1048–1055
Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM (2002) PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 18:333–334
Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Carter KW, McCaskie PA, Palmer LJ (2008) SimHap GUI: an intuitive graphical user interface for genetic association analysis. BMC Bioinformatics 9:557
Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M (2003) The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol 86:219
Mahendroo MS, Mendelson CR, Simpson ER (1993) Tissue-specific and hormonally controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J Biol Chem 268:19463–19470
Demura M, Martin RM, Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K, Bryant M, Mendonca BB, Hanaki K, Kanzaki S, Rhoads DB, Misra M, Bulun SE (2007) Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. Hum Mol Genet 16:2529–2541
Gonda TJ, Leo P, Ramsay RG (2008) Estrogen and MYB in breast cancer: potential for new therapies. Expert Opin Biol Ther 8:713–717
Baba T, Mimura J, Nakamura N, Harada N, Yamamoto M, Morohashi K, Fujii-Kuriyama Y (2005) Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction. Mol Cell Biol 25:10040–10051
Cheng CK, Yeung CM, Hoo RL, Chow BK, Leung PC (2002) Oct-1 is involved in the transcriptional repression of the gonadotropin-releasing hormone receptor gene. Endocrinology 143:4693–4701
Simpson ER, Davis SR (2001) Aromatase and the regulation of estrogen biosynthesis—some new perspectives. Endocrinology 142:4589–4594
Nguyen TV, Center JR, Eisman JA (2000) Association between breast cancer and bone mineral density: the Dubbo osteoporosis epidemiology study. Maturitas 36:27–34
Sowers MR, Finkelstein JS, Ettinger B, Bondarenko I, Neer RM, Cauley JA, Sherman S, Greendale GA (2003) The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN. Osteoporos Int 14:44–52
Rendina D, Gianfrancesco F, De Filippo G, Merlotti D, Esposito T, Mingione A, Nuti R, Strazzullo P, Mossetti G, Gennari L (2010) FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women. Eur J Endocrinol 163:165–172
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We thank the staff of the Western Australian Bone and Cartilage group who contributed to patient recruitment, genotyping, and data analysis.
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B. H. Mullin and K. W. Carter contributed equally to this study.
The authors have stated that they have no conflict of interest.
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Mullin, B.H., Carter, K.W., Lewis, J.R. et al. Significant Association between Common Polymorphisms in the Aromatase Gene CYP19A1 and Bone Mineral Density in Postmenopausal Women. Calcif Tissue Int 89, 464–471 (2011). https://doi.org/10.1007/s00223-011-9535-8
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DOI: https://doi.org/10.1007/s00223-011-9535-8