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

作者：Riancho Jose A^*; Zarrabeitia Maria T; Valero Carmen; Sanudo Carolina; Mijares Veronica; Gonzalez Macias Jesus

来源：European Journal of Endocrinology, 2006, 155(1): 53-59.

DOI：10.1530/eje.1.02189

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 alpha (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 ER were studied.
Results: Age, body weight and the aromatase genotype were associated with BMD. Allelic variants of ER beta and the exon 8 of ER alpha did not show a significant association with BMD. The polymorphisms located on the promoter and intron 1 of ER alpha interacted strongly with aromatase. Thus, in women TT homozygous for the ER alpha gene, there was a marked influence of aromatase genotypes on BMD: spine BMD was 0.724 +/- 0.02 7 g/cm(2) in women with CC aromatase alleles and 0.92 +/- 0.032 g/cm(2) in those with GG alleles (P < 0.00 1). Hip BMD in women with CC and GG aromatase genotypes was 0.722 +/- 0.020 and 0.842 +/- 0.026 g/cm(2) respectively (P=0.002). On the contrary, there were no aromatase-related differences in BMD in women with CT/CC alleles of Er alpha. Similarly, aromatase-related differences in BMD were found in women with short alleles at the promoter region of ER alpha, but not in those with long alleles. Both ER alpha 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.

• 出版日期2006-7