Abstract 17494: Exome Sequencing Reveals a Novel SNP in TRPC6 in Pulmonary Arterial Hypertension
Introduction: The Ca2+ sensing receptor TRPC6 has been reported to promote pulmonary vascular disease. A functional promoter SNP (-254(C/G) has also been previously reported to be over-represented in patients with PAH. We hypothesized that there may be other novel SNPs associated with PAH in TRPC6.
Methods: Whole-exome sequencing (WES) was performed on lung tissue DNA collected at the time of transplant or autopsy from 12 patients with PAH (WHO Group I). Standard BWA, SAMTOOLS, and GATK protocols were used to analyze WES data. Filtered SNPs on were compared against 1000 genomes and dbSNP databases for case-control analysis. In a separate PAH cohort (n=47, WHO Group I) with available clinical data, genotyping of a top candidate SNP, rs191383391, was performed via PCR. Association between genotype [wild-type (GG), homozygous recessive (TT)] and clinical phenotypes including right heart catheterization-defined pulmonary vascular resistance (PVRi), cardiac index (CI), cardiac MRI-defined right ventricular ejection value (RVEF), as well as 6 minute walk distance (6MWD) was evaluated using univariate and multivariate analysis (adjusting for age, gender, patient PAH medication status, and PVRi).
Results: In histological-proven Group I PAH cases, rs191383391 was over-represented, observed in 25% (n=12) of cases compared to a minor allele frequency of 0.256% in the general population. In the validation cohort, 27 patients genotyped (TT) while 11 had the wild-type genotype (GG). In univariate analysis comparing GG vs TT genotype, patients with the TT genotype had significantly higher CI values (3.4 95%CI 3.0-3.8L/m/m2, P=0.036), with a trend toward higher 6MWD in patients with the GG genotype. Both parameters, CI (3.8 95%CI 2.2-4.3L/m/m2 in TT vs 2.975 95%CI 3.05-3.80 GG, P=0.0009) and 6MWD (618 95%CI 362-874m TT vs 199.5 95%CI 31.32-249.81 GG, P=0.035) became significantly predictive of PAH severity after multi-variable analysis.
Conclusion: rs191383391 is a novel SNP in TRPC6, more prevalent in PAH cases, and associated with improved RV function and functional status. We speculate that the SNP may alter expression levels of TRPC6 which could contribute to altered Ca2+ sensing in PAH.
Author Disclosures: H. Lynn: None. A. Desai: None. V. Nair: None. A. Gupta: None. A. Cordery: None. R. Sprissler: None. K. Knox: None. B. Larson: None. J.G. Garcia: None. J.X. Yuan: Consultant/Advisory Board; Modest; Actelion Sterring Committee for Young Investigator Program, Bayer HealthCare US Medical Affairs Cardiopulmonary Franchise Scientific Advisory Council. Research Grant; Significant; NIH grant.
- © 2016 by American Heart Association, Inc.