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Erschienen in: Osteoporosis International 6/2008

01.06.2008 | Original Article

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

verfasst von: C. Valero, J. L. Pérez-Castrillón, M. T. Zarrabeitia, J. L. Hernández, M. A. Alonso, J. del Pino-Montes, J. M. Olmos, J. González-Macías, J. A. Riancho

Erschienen in: Osteoporosis International | Ausgabe 6/2008

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Abstract

Summary

Two polymorphisms of the aromatase and estrogen receptor genes appeared to interact to influence the risk of hip fractures in women.

Introduction

Allelic variants of the aromatase gene have been associated with bone mineral density and vertebral fractures. Our objective was to analyze the relationship between two polymorphisms of the aromatase and estrogen receptor genes and hip fractures.

Methods

We studied 498 women with hip fractures and 356 controls. A C/G polymorphism of the aromatase gene and a T/C polymorphism of the estrogen receptor α gene were analyzed using Taqman assays. Aromatase gene expression was determined in 43 femoral neck samples by real-time RT-PCR.

Results

There were no significant differences in the overall distribution of genotypes between the fracture and control groups. However, among women with a TT genotype of the estrogen receptor, the CC aromatase genotype was more frequent in women with fractures than in controls (39 vs. 23%, p = 0.009). Thus, women homozygous for T alleles of estrogen receptor and C alleles of aromatase were at increased risk of fracture (odds ratio 2.0; 95% confidence interval 1.2–3.4). The aromatase polymorphism was associated with RNA levels in bone tissue, which were three times lower in samples with a CC genotype (p = 0.009).

Conclusions

These common polymorphisms of the aromatase and estrogen receptor genes appear to interact, influencing the risk of hip fractures in women.
Literatur
1.
Zurück zum Zitat Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506CrossRefPubMed Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506CrossRefPubMed
2.
Zurück zum Zitat Baldock PA, Eisman JA (2004) Genetic determinants of bone mass. Curr Opin Rheumatol 16:450–456CrossRefPubMed Baldock PA, Eisman JA (2004) Genetic determinants of bone mass. Curr Opin Rheumatol 16:450–456CrossRefPubMed
3.
Zurück zum Zitat Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23:303–326CrossRefPubMed Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23:303–326CrossRefPubMed
4.
Zurück zum Zitat Riggs BL, Khosla S, Melton LJ III (2002) Sex steroids and the construction and conservation of adult skeleton. Endocr Rev 23:279–302CrossRefPubMed Riggs BL, Khosla S, Melton LJ III (2002) Sex steroids and the construction and conservation of adult skeleton. Endocr Rev 23:279–302CrossRefPubMed
5.
Zurück zum Zitat Syed FS, Khosla S (2005) Mechanisms of sex steroid effects on bone. Biochem Biophys Res Commun 328:688–696CrossRefPubMed Syed FS, Khosla S (2005) Mechanisms of sex steroid effects on bone. Biochem Biophys Res Commun 328:688–696CrossRefPubMed
6.
Zurück zum Zitat Simpson ER (2000) Role of aromatase in sex steroid action. J Mol Endocrinol 25:1549–1556CrossRef Simpson ER (2000) Role of aromatase in sex steroid action. J Mol Endocrinol 25:1549–1556CrossRef
7.
Zurück zum Zitat McCloskey E (2006) Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 42:1044–1051CrossRefPubMed McCloskey E (2006) Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 42:1044–1051CrossRefPubMed
8.
Zurück zum Zitat Masi L, Becherini L, Gennari L et al (2001) Polymorphism of the aromatase gene in postmenopausal Italian women: distribution and correlation with bone mass and fracture risk. J Clin Endocrinol Metab 86:2263–2269PubMed Masi L, Becherini L, Gennari L et al (2001) Polymorphism of the aromatase gene in postmenopausal Italian women: distribution and correlation with bone mass and fracture risk. J Clin Endocrinol Metab 86:2263–2269PubMed
9.
Zurück zum Zitat Somner J, McLellan S, Cheung J et al (2004) Polymorphisms in the P450 c17(17-hydroxylase/17,20-lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women. J Clin Endocrinol Metab 89:344–351CrossRefPubMed Somner J, McLellan S, Cheung J et al (2004) Polymorphisms in the P450 c17(17-hydroxylase/17,20-lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women. J Clin Endocrinol Metab 89:344–351CrossRefPubMed
10.
Zurück zum Zitat Zarrabeitia MT, Hernandez JL, Valero C et al (2004) A common polymorphism in the 5′-untranslated region of the aromatase gene influences bone mass and fracture risk. Eur J Endocrinol 150:699–704CrossRefPubMed Zarrabeitia MT, Hernandez JL, Valero C et al (2004) A common polymorphism in the 5′-untranslated region of the aromatase gene influences bone mass and fracture risk. Eur J Endocrinol 150:699–704CrossRefPubMed
11.
Zurück zum Zitat Riancho JA, Zarrabeitia MT, Valero C, Sanudo C, Mijares V, Gonzalez-Macias J (2006) A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density. Eur J Endocrinol 155:53–59CrossRefPubMed Riancho JA, Zarrabeitia MT, Valero C, Sanudo C, Mijares V, Gonzalez-Macias J (2006) A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density. Eur J Endocrinol 155:53–59CrossRefPubMed
12.
Zurück zum Zitat Riancho JA, Zarrabeitia MT, Valero C et al (2005) Aromatase gene and osteoporosis: relationship of ten polymorphic loci with bone mineral density. Bone 36:917–925CrossRefPubMed Riancho JA, Zarrabeitia MT, Valero C et al (2005) Aromatase gene and osteoporosis: relationship of ten polymorphic loci with bone mineral density. Bone 36:917–925CrossRefPubMed
13.
Zurück zum Zitat Choi JY, Shin A, Park SK et al (2005) Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women. Calcif Tissue Int 77:152–159CrossRefPubMed Choi JY, Shin A, Park SK et al (2005) Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women. Calcif Tissue Int 77:152–159CrossRefPubMed
14.
Zurück zum Zitat Gennari L, Merlotti D, De Paola V et al (2005) Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review. Am J Epidemiol 161:307–320CrossRefPubMed Gennari L, Merlotti D, De Paola V et al (2005) Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review. Am J Epidemiol 161:307–320CrossRefPubMed
15.
Zurück zum Zitat Kobayashi N, Fujino T, Shirogane T et al (2002) Estrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen. Maturitas 41:193–201CrossRefPubMed Kobayashi N, Fujino T, Shirogane T et al (2002) Estrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen. Maturitas 41:193–201CrossRefPubMed
16.
Zurück zum Zitat Nam HS, Shin MH, Kweon SS et al (2005) Association of estrogen receptor-alpha gene polymorphisms with bone mineral density in postmenopausal Korean women. J Bone Miner Metab 23:84–89CrossRefPubMed Nam HS, Shin MH, Kweon SS et al (2005) Association of estrogen receptor-alpha gene polymorphisms with bone mineral density in postmenopausal Korean women. J Bone Miner Metab 23:84–89CrossRefPubMed
17.
Zurück zum Zitat Kjaergaard AD, Ellervik C, Tybjaerg-Hansen A (2007) Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture: cross-sectional, cohort, and case-control studies and a meta-analysis. Circulation 115:861–871CrossRefPubMed Kjaergaard AD, Ellervik C, Tybjaerg-Hansen A (2007) Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture: cross-sectional, cohort, and case-control studies and a meta-analysis. Circulation 115:861–871CrossRefPubMed
18.
Zurück zum Zitat Aerssens J, Dequeker J, Peeters J, Breemans S, Broos P, Boonen S (2000) Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women. Osteoporos Int 11:583–591CrossRefPubMed Aerssens J, Dequeker J, Peeters J, Breemans S, Broos P, Boonen S (2000) Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women. Osteoporos Int 11:583–591CrossRefPubMed
19.
Zurück zum Zitat Ioannidis JPA, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB et al (2004) Differential genetics effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114CrossRefPubMed Ioannidis JPA, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB et al (2004) Differential genetics effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114CrossRefPubMed
20.
Zurück zum Zitat Ioannidis JPA, Stavrou I, Trikalinos TA et al (2002) Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 17:2048–2060CrossRefPubMed Ioannidis JPA, Stavrou I, Trikalinos TA et al (2002) Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 17:2048–2060CrossRefPubMed
21.
Zurück zum Zitat 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 92:660–665CrossRefPubMed 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 92:660–665CrossRefPubMed
22.
Zurück zum Zitat Haiman CA, Dossus L, Setiawan VW et al (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67:1893–1897CrossRefPubMed Haiman CA, Dossus L, Setiawan VW et al (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67:1893–1897CrossRefPubMed
23.
Zurück zum Zitat Olson SH, Bandera EV, Orlow I (2007) Variants in estrogen biosynthesis genes, sex steroid hormone levels, and endometrial cancer: a HuGE review. Am J Epidemiol 165:235–245CrossRefPubMed Olson SH, Bandera EV, Orlow I (2007) Variants in estrogen biosynthesis genes, sex steroid hormone levels, and endometrial cancer: a HuGE review. Am J Epidemiol 165:235–245CrossRefPubMed
24.
Zurück zum Zitat 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–E995CrossRefPubMed 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–E995CrossRefPubMed
25.
Zurück zum Zitat Xiong DH, Zhao LJ, Xiao P et al (2006) Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 21:1678–1695CrossRefPubMedPubMedCentral Xiong DH, Zhao LJ, Xiao P et al (2006) Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 21:1678–1695CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Riancho JA (2007) Polymorphisms in the CYP19 gene that influence bone mineral density. Pharmacogenomics 8:339–352CrossRefPubMed Riancho JA (2007) Polymorphisms in the CYP19 gene that influence bone mineral density. Pharmacogenomics 8:339–352CrossRefPubMed
27.
Zurück zum Zitat Herrington DM, Howard TD, Brosnihan KB et al (2002) Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 105:1879–1882CrossRefPubMed Herrington DM, Howard TD, Brosnihan KB et al (2002) Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 105:1879–1882CrossRefPubMed
28.
Zurück zum Zitat Acha O, Hernandez JL, Penado S, Cano M, Riancho JA (2003) Factores de riesgo de ictus en pacientes de diferentes edades. Rev Clin Esp 203:189–192CrossRefPubMed Acha O, Hernandez JL, Penado S, Cano M, Riancho JA (2003) Factores de riesgo de ictus en pacientes de diferentes edades. Rev Clin Esp 203:189–192CrossRefPubMed
29.
Zurück zum Zitat Cummings SR, Nevitt MC, Browner WS et al (1995) Risk factors for hip fracture in white women. N Engl J Med 332:767–773CrossRefPubMed Cummings SR, Nevitt MC, Browner WS et al (1995) Risk factors for hip fracture in white women. N Engl J Med 332:767–773CrossRefPubMed
30.
Zurück zum Zitat Kanis JA, Johansson H, Oden A et al (2004) A family history of fracture and fracture risk: a meta-analysis. Bone 35:1029–1037CrossRefPubMed Kanis JA, Johansson H, Oden A et al (2004) A family history of fracture and fracture risk: a meta-analysis. Bone 35:1029–1037CrossRefPubMed
31.
Zurück zum Zitat Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen NL (2005) Genetic liability to fractures in the elderly. Arch Intern Med 165:1825–1830CrossRefPubMed Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen NL (2005) Genetic liability to fractures in the elderly. Arch Intern Med 165:1825–1830CrossRefPubMed
Metadaten
Titel
Association of aromatase and estrogen receptor gene polymorphisms with hip fractures
verfasst von
C. Valero
J. L. Pérez-Castrillón
M. T. Zarrabeitia
J. L. Hernández
M. A. Alonso
J. del Pino-Montes
J. M. Olmos
J. González-Macías
J. A. Riancho
Publikationsdatum
01.06.2008
Verlag
Springer London
Erschienen in
Osteoporosis International / Ausgabe 6/2008
Print ISSN: 0937-941X
Elektronische ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-007-0491-0

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