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Estrogen receptor alpha gene variant, PvuII (rs2234693), as a potential pharmacogenetic biomarker for aneurysmal subarachnoid hemorrhage in postmenopausal women

The Pharmacogenomics Journal volume 20, pages 655–663 (2020)Cite this article

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Abstract

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.

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Fig. 1: Relative expression of estrogen receptor alpha mRNA levels (ESR1 gene expression) and the correlation between ESR1 gene expression and estradiol levels.
Fig. 2: The proposed model for the association between ESR1 gene variant, estradiol levels, ER gene expression, and aSAH in postmenopausal women.

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Acknowledgements

We thank the Indian Council of Medical Research (ICMR), New Delhi, India and the Department of Science and Technology (DST), New Delhi, India for the funding, and the Vision Group on Science and Technology (VGST), Karnataka, India for providing qRT-PCR equipment. We also thank all the volunteers who consented to participate in this study.

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  1. Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru, 560029, India

    Shruthi Shimoga Ramesh & Rita Christopher

  2. Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bengaluru, 560029, India

    Bhagavatula Indira Devi, Dhananjaya Ishwar Bhat & Dhaval Shukla

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  1. Shruthi Shimoga Ramesh
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Correspondence to Rita Christopher.

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Ramesh, S.S., Christopher, R., Devi, B.I. et al. Estrogen receptor alpha gene variant, PvuII (rs2234693), as a potential pharmacogenetic biomarker for aneurysmal subarachnoid hemorrhage in postmenopausal women. Pharmacogenomics J 20, 655–663 (2020). https://doi.org/10.1038/s41397-020-0155-4

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