PT  - JOURNAL ARTICLE
AU  - Na Zhu
AU  - Michael W. Pauciulo
AU  - Carrie L. Welch
AU  - Katie A. Lutz
AU  - Anna W. Coleman
AU  - Claudia Gonzaga-Jauregui
AU  - Jiayao Wang
AU  - Joseph M. Grimes
AU  - Lisa J. Martin
AU  - Hua He
AU  - PAH Biobank
AU  - Yufeng Shen
AU  - Wendy K. Chung
AU  - William C. Nichols
TI  - Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension
AID  - 10.1101/550327
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 550327
4099  - http://biorxiv.org/content/early/2019/02/14/550327.short
4100  - http://biorxiv.org/content/early/2019/02/14/550327.full
AB  - Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH. By statistical association of rare deleterious variants, we found tissue kallikrein 1 and gamma glutamyl carboxylase as new candidate risk genes for idiopathic PAH associated with a later age-of-onset and relatively moderate disease phenotype compared to bone morphogenetic receptor type 2. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms and therapeutic targets for this lethal vasculopathy.