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

Springer Science and Business Media LLC - 2019
Na Zhu1,2, Michael W. Pauciulo3,4, Carrie L. Welch5, Katie A. Lutz6, Alan Coleman6, Claudia Gonzaga‐Jauregui7, Jiayao Wang1,2, Joseph M. Grimes5, Lisa J. Martin4,3, Hua He6, Pah Biobank Enrolling Centers’ Investigators8, Yufeng Shen2, Wendy K. Chung9, William C. Nichols4,3
1Columbia University Medical Center, Department of Pediatrics, New York, USA
2Columbia University, Department of Systems Biology, New York, USA
3Cincinnati Children’s Hospital Medical Center, Division of Human Genetics, Cincinnati, USA
4University of Cincinnati, Department of Pediatrics, College of Medicine, Cincinnati, USA
5Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
6Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue MLC 7016, Cincinnati, OH, USA.
7Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
8Department of Systems Biology, Columbia University, New York, USA
9Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, New York, USA

Tóm tắt

AbstractBackgroundGroup 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. Empiricalpvalues 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 genesKLK1andGGCXwith 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.

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