Estrogen signaling and portopulmonary hypertension : the pulmonary vascular complications of liver disease study (PVCLD2)

Al-Naamani, Nadine and Krowka, Michael J. and Forde, Kimberly A. and Krok, Karen L. and Feng, Rui and Heresi, Gustavo A. and Dweik, Raed A. and Bartolome, Sonja and Bull, Todd M. and Roberts, Kari E. and Austin, Eric D. and Hemnes, Anna R. and Patel, Mamta J. and Oh, Jae K. and Lin, Grace and Doyle, Margaret F. and Denver, Nina and Andrew, Ruth and MacLean, Margaret and Fallon, Michael B. and Kawut, Steven M. (2020) Estrogen signaling and portopulmonary hypertension : the pulmonary vascular complications of liver disease study (PVCLD2). Hepatology. ISSN 0270-9139 (In Press)

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    Abstract

    Objectives: Portopulmonary hypertension (POPH) was previously associated with a single nucleotide polymorphism (SNP) rs7175922 in aromatase (CYP19A1). We sought to determine if genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. Methods: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure > 25 mmHg, pulmonary vascular resistance > 240 dynes•s•cm-5, and pulmonary artery wedge pressure ≤ 15 mmHg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure < 40 mmHg and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in ESR1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. Main Results: There were 37 patients with POPH and 290 controls. The mean age was 57 years and 36% were female. The risk allele rs7175922 in CYP19A1 was significantly associated with higher levels of estradiol (p = 0.02) and an increased risk of POPH (OR 2.36, 95% CI 1.12-4.91, p = 0.02) whereas other SNPs were not. Higher urinary 2-hydroxyestrogen/16-α-hydroxyestrone (2-OHE/16α-OHE1) (OR per 1 ln increase = 2.04, 95%CI 1.16-3.57, p = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (DHEA-S) (OR per 1 ln decrease = 2.38, 95%CI 1.56-3.85, p < 0.001) and higher plasma levels of 16-α-hydroxyestradiol (16α-OHE2) (OR per 1 ln increase = 2.16, 95%CI 1.61-2.98, p < 0.001) were associated with POPH. Conclusions: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.