Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Abstract

BackgroundGroup 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.MethodsTo identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni’s correction for multiple testing.ResultsTissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.ConclusionsWe report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. 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.

Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension

“…The National Institute for Health Research BioResource -Rare Diseases study (NIHRBR-RD), the Rare Disease pilot for Genomics England Ltd. 100,000 Genomes Project, was established to identify genetic causes, improve rates of molecular diagnosis and develop new treatments for rare diseases through whole-genome sequencing and deep phenotyping 14 . Of the 18 domains, 15 were defined either as a single rare disease or a group of rare disorders (Table S1) Patients with rare diseases recruited to domains other than PAH were used as non-PAH controls in the genetic analysis (Table 1).…”

“…Isaac Aligner version SAAC00776. 15.01.27 17 with bcftools and loaded into our Hbase database to produce multi-sample variant calls to undertake the genetic association studies 14 .…”

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

“…carriers (6,11,12), with an enrichment of predicted deleterious missense (D-Mis) variants with younger age-of-onset (6,13). Notably, BMPR2 variants contribute almost exclusively to FPAH and idiopathic PAH (IPAH), and rarely to other subclasses.…”

“…Variants in two other genes in the transforming growth factor-beta (TGF-b) superfamily, activin A receptor type II-like 1 (ACVRL1) and endoglin (ENG) contribute to ~0.8% of PAH cases (6), especially PAH associated with hereditary hemorrhagic telangiectasia (APAH-HHT). Variants in growth differentiation factor 2 (GDF2), encoding the ligand of BMPR2/ACVRL1 (BMP9), contribute to ~1% of PAH cases in European-enriched cohorts (6,7) and are more frequent in Chinese patients (~6.7%) (14). Variants in mothers against decapentaplegic (SMAD) genes, encoding downstream mediators of BMP signaling, contribute rarely.…”

“…A number of genes outside of the TGF-b signaling pathway have also been identified as PAH risk genes. Variants in developmental transcription factors, TBX4 and SOX17, are enriched in pediatric patients (6,(15)(16)(17). Variants in TBX4 cause a variety of developmental lung disorders (18), including persistent pulmonary hypertension of the newborn with recurrent PAH in childhood (19).…”