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

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).

Cross-sectional study including 331 postmenopausal women.

BMD was measured by dual energy x-ray absorptiometry. A CG polymorphism of the aromatase gene as well as three polymorphisms of ERalpha (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 ERbeta were studied.

Age, body weight and the aromatase genotype were associated with BMD. Allelic variants of ERbeta and the exon 8 of ERalpha did not show a significant association with BMD. The polymorphisms located on the promoter and intron 1 of ERalpha interacted strongly with aromatase. Thus, in women TT homozygous for the ERalpha 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 ERalpha. Similarly, aromatase-related differences in BMD were found in women with short alleles at the promoter region of ERalpha, but not in those with long alleles. Both ERalpha polymorphisms were in strong linkage disequilibrium (P < 0.001).

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.