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.
|Number of pages||28|
|Publication status||Accepted/In press - 27 Mar 2020|
- pulmonary arterial hypertension
- pulmonary artery pressure
- portal hypertension
- liver disease