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 R. MacLean, Michael B. FallonSteven M. Kawut

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Background and Aims: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. Approach and Results: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm −5, and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (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
Pages (from-to)726-737
Number of pages12
JournalHepatology
Volume73
Issue number2
Early online date14 May 2020
DOIs
Publication statusPublished - 28 Feb 2021

Keywords

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

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