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Increased HDAC9 Expression is Associated with Decreased Estrogen in Female Patients with Intracranial Aneurysm
Author(s) -
Lansdell Theresa A,
Fisher Courtney,
Demel Stacie,
Dorrance Anne
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.828.5
Subject(s) - estrogen receptor , allele , estrogen receptor alpha , biology , population , medicine , endocrinology , immunology , genetics , gene , breast cancer , cancer , environmental health
Background and purpose Subarachnoid hemorrhage is a devastating consequence of intracranial aneurysm (IA) rupture. Therefore early identification of patients with IA is important. Identification of biomarkers for IA will help improve diagnosis, the understanding of IA pathogenesis, and patient management. A risk allele (rs10230207), located nearby the histone deacetylase 9 (HDAC9) gene on chromosome 7, has been associated with IA incidence. HDAC9 can repress the transcription of estrogen receptors α and β (ESR1 and ESR2). We tested the hypothesis that lymphocytes from patients with IA will have increased HDAC9 and decreased estrogen receptor gene transcription compared to controls. Methods Immortalized B‐lymphocytes from male and female patients with un‐ruptured IA (N=109) and population controls (N=85) were obtained from the NINDS repository and cultured in RPMI‐1640 medium supplemented with 10% fetal calf serum. Subject genomic DNA was genotyped for presence of the risk allele using TaqMan SNP genotyping assays directed toward rs10230207. HDAC9 and ESR gene expression were analyzed using TaqMan expression assays. In a separate study using subject case (N=23) and control (N=10) blood samples, HDAC9 and ESR2 transcriptional differences were confirmed in peripheral blood mononuclear cells. Plasma estrogen levels were also measured in these subjects. Results HDAC9 expression was increased in IA patient lymphoblasts compared to population controls (P= 0.0311) and was associated with the presence of the rs10230207 risk allele (P=0. 0235). Patients harboring the risk allele had an increased risk for IA (OR 9.1, 95% CI 3.6–23.1). While the risk allele puts both males and females at risk for IA, the risk of IA is larger for females (OR 23.9, 95% CI 5.4–105.4) compared to males (OR 5.9, 95% CI 2.7–13.2). Lymphoblasts from female subjects between 19–50 years (premenopausal) were further analyzed (N= 17 cases and 22 population controls). HDAC9 gene expression was increased (P=0.0243) and ESR2 expression was decreased (P= 0.0351) in premenopausal females with IA compared to premenopausal female population controls. Decreased plasma estrogen levels were also detected in the premenopausal female cases (N=7) compared to control (N=5) subjects (P =0.0015). Conclusions The presence of the rs10230207 risk allele was associated with increased expression of HDAC9 and decreased expression of ESR2 in case and control immortalized lymphoblasts. Furthermore, we found that female IA patients that had not yet undergone menopause had decreased plasma estrogen levels. Future studies are aimed at defining the positive and negative predictive values of estrogen levels and IA in female patients. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .