Introduction: Pulmonary arterial hypertension (PAH) is a rare and fatal disease associated with variable therapeutic response, suggesting a genetic contribution. Vasodilator-responsive PAH accounts for a minority of PAH cases and is associated with dramatically improved survival over vasodilator-nonresponsive PAH. The objective of our study was to identify genetic influences on vasodilator drug response in PAH.
Methods: Two cohorts of patients with Group I PAH confirmed by right heart catheterization were derived from the PAH Biobank (NHLBI R24HL105333), representing over 40 US institutions. Differences between hemodynamics at rest (baseline mean pulmonary arterial pressure, mPAP) and after vasodilator (nitric oxide, prostacyclin) administration were determined to define acute vasodilator drug response (with unchanged cardiac index) as a continuous measure. All cases were genotyped using HumanOmni5 with single nucleotide polymorphism (SNP) call rate >99%, minor allele frequency (MAF)>3%, and Hardy-Weinberg p-value>0.01. Analysis was restricted to cases with European ancestry. We performed linear regressions in an additive model for acute vasodilator drug response with adjustment for baseline mPAP, age, gender, and first 3 principal components. A Bonferroni-corrected alpha=5x10-8 was used in the discovery cohort and alpha=0.05 was used in the replication cohort.
Results: The discovery cohort included 434 PAH cases and the replication cohort included 49 less severe PAH cases. QQ-plots showed no evidence of genomic inflation (lambda=1.00). Association of the intronic SNP rs8057488 (MAF 0.05) in the sorting nexin 29 gene (SNX29) with acute vasodilator drug response reached genome-wide significance in the discovery cohort (beta= -7.03 mmHg, p=3.39x10-8). A significant association between rs8057488 and acute vasodilator drug response was also observed in the replication cohort (beta = -6.48 mmHg, p=0.03).
Conclusion: These findings implicate a novel association between SNX29 variation and differential responses to vasodilator treatment in Group I PAH. While requiring further replication in a larger independent cohort, these observations advance our understanding of the molecular underpinnings in PAH.