Peter Inga, Kelley-Hedgepeth Alyson, Fox Caroline S, Cupples L Adrienne, Huggins Gordon S, Housman David E, Karas Richard H, Mendelsohn Michael E, Levy Daniel, Murabito Joanne M
Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
J Clin Endocrinol Metab. 2008 Jul;93(7):2779-85. doi: 10.1210/jc.2008-0106. Epub 2008 Apr 29.
Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors alpha (ESR1) and beta (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to cardiovascular disease, we tested the hypothesis that the polymorphisms were associated with endogenous steroid hormone levels.
Multiple regression analysis was used to assess the relation between reported polymorphisms and total serum estradiol, testosterone, and dehydroepiandrosterone sulfate levels in 834 men and 687 women who attended the third and fourth Framingham Heart Study examination cycles.
In men, significant associations were detected between CYP19A1 polymorphisms and estradiol and testosterone levels, and the estradiol to testosterone ratio (P ranges 0.0005-0.01). Specifically, carriers of common haplotype rs700518[G]-(TTTA)(n) [L]-rs726547[C] had higher estradiol levels (5% per copy; P = 0.0004), lower testosterone levels (17% per copy; P = 0.036), and a higher estradiol to testosterone ratio (24% per copy; P < 0.0001) compared with the rs700518[A]-(TTTA)(n) [S]-rs726547[C] carriers. In addition, postmenopausal carriers of the ESR2 (CA)(n) long allele and rs1256031 [C] allele had moderately higher estradiol levels (P < or = 0.03). No significant associations with the ESR1 variants were detected.
Our findings suggest that variations in CYP19A1 correlate with steroid hormone levels in men. Knowledge that a specific carrier status may predispose to altered steroid hormone levels may lead to targeted intervention strategies to reduce health risks in genetically susceptible individuals.
绝经起始年龄较小以及循环雌激素水平较低是心血管疾病的危险因素。在弗雷明汉心脏研究中，多项研究已检测到编码雌激素受体α（ESR1）和β（ESR2）的基因变异以及调节雌激素与睾酮比例的酶芳香化酶（CYP19A1）与心血管表型之间的关联。为探究这些基因变异可能导致心血管疾病的潜在机制，我们检验了多态性与内源性甾体激素水平相关的假设。
采用多元回归分析评估参加弗雷明汉心脏研究第三和第四次检查周期的834名男性和687名女性中报告的多态性与血清总雌二醇、睾酮和硫酸脱氢表雄酮水平之间的关系。
在男性中，检测到CYP19A1多态性与雌二醇和睾酮水平以及雌二醇与睾酮比例之间存在显著关联（P值范围为0.0005 - 0.01）。具体而言，与rs700518[A]-(TTTA)(n)[S]-rs726547[C]携带者相比，常见单倍型rs700518[G]-(TTTA)(n)[L]-rs726547[C]的携带者雌二醇水平更高（每拷贝增加5%；P = 0.0004），睾酮水平更低（每拷贝降低17%；P = 0.036），雌二醇与睾酮比例更高（每拷贝增加24%；P < 0.0001）。此外，ESR2 (CA)(n)长等位基因和rs1256031[C]等位基因的绝经后携带者雌二醇水平适度升高（P ≤ 0.03）。未检测到与ESR1变异的显著关联。
我们的研究结果表明，CYP19A1的变异与男性甾体激素水平相关。了解特定的携带者状态可能易导致甾体激素水平改变，这可能会带来针对性干预策略，以降低遗传易感性个体的健康风险。
