Estrogen signaling and portopulmonary hypertension: the Pulmonary Vascular Complications of Liver Disease Study (PVCLD2)

Al-Naamani, N. et al. (2021) Estrogen signaling and portopulmonary hypertension: the Pulmonary Vascular Complications of Liver Disease Study (PVCLD2). Hepatology, 73(2), pp. 726-737. (doi: 10.1002/hep.31314) (PMID:32407592) (PMCID:PMC8115214)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacLean, Professor Margaret
• Authors: 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. R., Fallon, M. B., and Kawut, S. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Hepatology
• Publisher: Wiley
• ISSN: 0270-9139
• ISSN (Online): 1527-3350
• Published Online: 14 May 2020