Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

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.

• Authors: 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 Fallon, Steven M Kawut, , for the Pulmonary Vascular Complications of Liver Disease Study Group
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 73 Issue 2 Pg. 726-737 (02 2021) ISSN: 1527-3350 [Electronic] United States
• PMID: 32407592 (Publication Type: Journal Article, Multicenter Study, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Association for the Study of Liver Diseases.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• Estrogens
• Aromatase
• CYP19A1 protein, human
• CYP1B1 protein, human
• Cytochrome P-450 CYP1B1

Topics

• Aged
• Aromatase (genetics, metabolism)
• Case-Control Studies
• Cytochrome P-450 CYP1B1 (genetics, metabolism)
• Echocardiography
• End Stage Liver Disease (blood, complications, genetics, metabolism)
• Estrogen Receptor alpha (genetics, metabolism)
• Estrogens (blood, metabolism, urine)
• Female
• Humans
• Hypertension, Portal (blood, genetics, metabolism, urine)
• Hypertension, Pulmonary (blood, genetics, metabolism, urine)
• Liver Function Tests
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Prospective Studies
• Signal Transduction (genetics)
• Vascular Resistance (genetics)