Riancho José A, Zarrabeitia María T, Valero Carmen, Sañudo Carolina, Mijares Verónica, González-Macías Jesús
Department of Internal Medicine, Hospital U.M. Valdecilla, University of Cantabria, 39008 Santander, Spain.
Eur J Endocrinol. 2006 Jul;155(1):53-9. doi: 10.1530/eje.1.02189.
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.
雄激素前体的芳香化是绝经后女性雌激素的主要来源。我们检验了这样一个假设，即编码芳香化酶和雌激素受体（ER）的基因的等位基因变异可能相互作用，以确定骨组织上的雌激素信号，从而决定骨矿物质密度（BMD）。
对331名绝经后女性进行横断面研究。
采用双能X线吸收法测量骨密度。研究了芳香化酶基因的CG多态性以及雌激素受体α的三种多态性（启动子区域的TA重复、内含子1中的C/T单核苷酸多态性（SNP）和外显子8中的AG SNP）以及雌激素受体β的CA重复多态性。
年龄、体重和芳香化酶基因型与骨密度相关。雌激素受体β和雌激素受体α外显子8的等位基因变异与骨密度无显著关联。雌激素受体α启动子和内含子1上的多态性与芳香化酶强烈相互作用。因此，在雌激素受体α基因TT纯合的女性中，芳香化酶基因型对骨密度有显著影响：芳香化酶CC等位基因的女性脊柱骨密度为0.724±0.027g/cm²，GG等位基因的女性为0.926±0.032g/cm²（P<0.001）。芳香化酶基因型为CC和GG的女性髋部骨密度分别为0.722±0.020和0.842±0.026g/cm²（P = 0.002）。相反，雌激素受体α的CT/CC等位基因女性的骨密度没有芳香化酶相关差异。同样，在雌激素受体α启动子区域有短等位基因的女性中发现了骨密度的芳香化酶相关差异，但长等位基因女性中未发现。两种雌激素受体α多态性处于强连锁不平衡状态（P<0.001）。
这些结果表明，雌激素合成和雌激素信号传导相关基因多态性之间的相互作用对绝经后女性的骨密度有重要影响，从而有助于部分解释其遗传成分。然而，有必要进行进一步研究以在其他人群中证实这种基因间相互作用。
