Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru, 560029, India.
Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bengaluru, 560029, India.
Pharmacogenomics J. 2020 Oct;20(5):655-663. doi: 10.1038/s41397-020-0155-4. Epub 2020 Feb 4.
Aneurysmal subarachnoid hemorrhage (aSAH) occurs more often in postmenopausal women than in men. Estrogen plays an important role in vascular homeostasis. Our aim was to elucidate whether a drop in circulating estradiol in conjunction with variants of estrogen receptor genes have a role in female gender susceptibility to aSAH. A total of 709 subjects were enrolled (349 aSAH patients, 360 controls) and genotyped for rs2234693 or PvuII (intron 1, T>C) in the ESR1 gene and rs4986938 or AluI (exon 8, 1730G>A) of ESR2 gene by PCR-RFLP. Serum estradiol was estimated by ELISA. Estrogen receptor gene expression was studied by qRT-PCR. Logistic regression analysis indicated a significant recessive effect of the T allele of PvuII on aSAH in females, and this association remained statistically significant even after adjusting for confounders (OR 1.702, CI 95% 1.062, 2.726, P value = 0.027). ESR1 gene expression was significantly reduced (P value = 0.0089) in subjects carrying PvuII T allele. In postmenopausal women with TT genotype and low serum estradiol, the odds for developing aSAH were found to be 3.5-fold increase compared with premenopausal women (CI 95% 1.424-8.828, P value = 0.0074). However, this variant showed no significant association with aSAH in men. No significant difference was found in genotype and allelic distribution of AluI polymorphism in ESR2 gene, between patients and controls. We propose that the PvuII T allele could be a potential pharmacogenetic marker for strategizing personal medicine for preventing aSAH in postmenopausal women with low circulating estradiol. Further larger studies in other population are warranted.
颅内动脉瘤性蛛网膜下腔出血（aSAH）在绝经后女性中比男性更常见。雌激素在血管稳态中发挥着重要作用。我们的目的是阐明循环雌二醇水平下降与雌激素受体基因变异是否在女性易患 aSAH 中起作用。共纳入 709 例受试者（349 例 aSAH 患者，360 例对照），采用 PCR-RFLP 法检测 ESR1 基因中的 rs2234693 或 PvuII（内含子 1，T>C）以及 ESR2 基因中的 rs4986938 或 AluI（外显子 8，1730G>A）的基因型。采用 ELISA 法检测血清雌二醇水平。采用 qRT-PCR 法研究雌激素受体基因表达。Logistic 回归分析表明，女性 PvuII T 等位基因对 aSAH 存在显著的隐性效应，即使在调整混杂因素后，这种相关性仍具有统计学意义（OR 1.702，95%CI 1.0622.726，P 值=0.027）。携带 PvuII T 等位基因的受试者 ESR1 基因表达显著降低（P 值=0.0089）。在 TT 基因型和低血清雌二醇的绝经后女性中，与绝经前女性相比，发生 aSAH 的几率增加了 3.5 倍（95%CI 1.4248.828，P 值=0.0074）。然而，这种变异在男性中与 aSAH 无显著相关性。ESR2 基因中的 AluI 多态性在患者和对照组之间，基因型和等位基因分布无显著差异。我们提出，PvuII T 等位基因可能是一个潜在的药物遗传学标志物，有助于制定策略，为低循环雌二醇的绝经后女性预防 aSAH 提供个体化医学治疗。需要在其他人群中进行更大规模的研究。
