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A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density

¹ Department of Internal Medicine and ² Unit of Legal Medicine, Hospital U.M. Valdecilla, University of Cantabria, 39008 Santander, Spain

(Correspondence should be addressed to J A Riancho; Email: rianchoj{at}unican.es)

Objective: The aromatization of androgenic precursors is the main source of estrogens in postmenopausal women. We tested the hypothesis that allelic variants of the genes coding for aromatase and estrogen receptors (ER) could interact to determine the estrogenic signals on the bone tissue and, consequently, bone mineral density (BMD).

Design: Cross-sectional study including 331 postmenopausal women.

Methods: BMD was measured by dual energy x-ray absorptiometry. A CG polymorphism of the aromatase gene as well as three polymorphisms of ER (a TA repeat in the promoter region, a C T single nucleotide polymorphism (SNP) in intron 1 and an AG SNP in exon 8) and a CA repeat polymorphism of ERß were studied.

Results: Age, body weight and the aromatase genotype were associated with BMD. Allelic variants of ERß and the exon 8 of ER did not show a significant association with BMD. The polymorphisms located on the promoter and intron 1 of ER interacted strongly with aromatase. Thus, in women TT homozygous for the ER gene, there was a marked influence of aromatase genotypes on BMD: spine BMD was 0.724±0.027 g/cm² in women with CC aromatase alleles and 0.926±0.032 g/cm² in those with GG alleles (P<0.001). Hip BMD in women with CC and GG aromatase genotypes was 0.722±0.020 and 0.842±0.026 g/cm² respectively (P=0.002). On the contrary, there were no aromatase-related differences in BMD in women with CT/CC alleles of ER. Similarly, aromatase-related differences in BMD were found in women with short alleles at the promoter region of ER, but not in those with long alleles. Both ER polymorphisms were in strong linkage disequilibrium (P<0.001).

Conclusion: These results suggest that the interaction between polymorphisms of genes involved in estrogen synthesis and estrogen signaling exerts an important influence on BMD in postmenopausal women, thus helping to explain, in part, its heritable component. Nevertheless, further studies are warranted to confirm this gene-to-gene interaction in other populations.

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				M. T Zarrabeitia, J. L Hernandez, C. Valero, A. Zarrabeitia, J. A Amado, J. Gonzalez-Macias, and J. A Riancho Adiposity, estradiol, and genetic variants of steroid-metabolizing enzymes as determinants of bone mineral density Eur. J. Endocrinol., January 1, 2007; 156(1): 117 - 122. [Abstract] [Full Text] [PDF]