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

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 pa...

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Published in:	Hepatology (Baltimore, Md.) Vol. 73; no. 2; pp. 726 - 737
Main Authors:	Al‐Naamani, Nadine, Krowka, Michael J., Forde, Kimberly A., Krok, Karen L., Feng, Rui, Heresi, Gustavo A., Dweik, Raed A., Bartolome, Sonja, Bull, Todd M., Roberts, Kari E., Austin, Eric D., Hemnes, Anna R., Patel, Mamta J., Oh, Jae K., Lin, Grace, Doyle, Margaret F., Denver, Nina, Andrew, Ruth, MacLean, Margaret R., Fallon, Michael B., Kawut, Steven M., Timmerman, Kasi, Mottram, C.D., Scanlon, Paul D., Miller, Adam, Visnaw, Karen, Homer, Natalie, Abbott, Cheryl, Palevsky, Harold I., Rajender Reddy, K., Goldberg, David S., Khungar, Vandana, Akaya Smith, K., Fritz, Jason S., Lynch, Marita, Sharkoski, Tiffany, Pinder, Diane, Machicao, Victor, Rubin, Moises Nevah, Walker, Kim, Cranford, Stacy, Varing, Jordan, Banga, Namrata, Igenoza, Oluwatosin, LaRochelle, Celeste
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-02-2021
Subjects:	17β-Estradiol Aged Aromatase Aromatase - genetics Aromatase - metabolism Blood pressure Case-Control Studies Cytochrome P-450 CYP1B1 - genetics Cytochrome P-450 CYP1B1 - metabolism Cytochrome P450 Dehydroepiandrosterone Echocardiography End Stage Liver Disease - blood End Stage Liver Disease - complications End Stage Liver Disease - genetics End Stage Liver Disease - metabolism Estrogen Receptor alpha - genetics Estrogen Receptor alpha - metabolism Estrogen receptors Estrogens Estrogens - blood Estrogens - metabolism Estrogens - urine Female Genetic diversity Genomes Heart Hepatology Humans Hypertension Hypertension, Portal - blood Hypertension, Portal - genetics Hypertension, Portal - metabolism Hypertension, Portal - urine Hypertension, Pulmonary - blood Hypertension, Pulmonary - genetics Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - urine Liver diseases Liver Function Tests Male Metabolites Middle Aged Plasma levels Polymorphism, Single Nucleotide Prospective Studies Pulmonary arteries Pulmonary artery Signal transduction Signal Transduction - genetics Single-nucleotide polymorphism Vascular Resistance - genetics Ventricle
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Summary:	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.
Bibliography:	A list of additional members of the Pulmonary Vascular Complications of Liver Disease Study Group are included in the Appendix at the end of the article. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 Equal contribution Author contributions All authors collected data, provided critical revisions to the study manuscript and approved the final version submitted for publication. MJK, MBF, SMK contributed to the study design. NA, RF, MJP, ND, RA, MRM and SMK analyzed the data. NA, MJK, KAF, KLK, GAH, RAD, SB, TMB, KER, EDA, ARH, JKO, GL, MFD, RA, MRM, MBF and SMK contributed to the interpretation of the results and the drafting of the manuscript.
ISSN:	0270-9139 1527-3350
DOI:	10.1002/hep.31314