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

Nadine Al-Naamani, Michael J. Krowka, Kimberly A. Forde, Karen L. Krok, Rui Feng, Gustavo A. Heresi, Raed A. Dweik, Sonja Bartolome, Todd M. Bull, Kari E. Roberts, Eric D. Austin, Anna R. Hemnes, Mamta J. Patel, Jae K. Oh, Grace Lin, Margaret F. Doyle, Nina Denver, Ruth Andrew, Margaret MacLean, Michael B. FallonSteven M. Kawut

Research output: Contribution to journalArticle

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.
Original languageEnglish
Number of pages28
JournalHepatology
Publication statusAccepted/In press - 27 Mar 2020

Keywords

  • pulmonary arterial hypertension
  • pulmonary artery pressure
  • portal hypertension
  • cirrhosis
  • liver disease
  • estrogen

Cite this

Al-Naamani, N., Krowka, M. J., Forde, K. A., Krok, K. L., Feng, R., Heresi, G. A., Dweik, R. A., Bartolome, S., Bull, T. M., Roberts, K. E., Austin, E. D., Hemnes, A. R., Patel, M. J., Oh, J. K., Lin, G., Doyle, M. F., Denver, N., Andrew, R., MacLean, M., ... Kawut, S. M. (Accepted/In press). Estrogen signaling and portopulmonary hypertension: the pulmonary vascular complications of liver disease study (PVCLD2). Hepatology.