A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population

Mai Kimura,Raphaël Thuillet,Christophe Guignabert,Tsutomu Saji,Yuichi Tamura,Toru Satoh,Kenjiro Kosaki,Keiichi Fukuda,Marc Humbert,Koichiro Tatsumi,Masaharu Kataoka,Motoaki Sano,Shigeo Kamitsuji,Naoyuki Kamatani,Makoto Takei,Nobuhiro Tanabe,Ly Tu

doi:10.18632/oncotarget.20459

Abstract

Pulmonary arterial hypertension (PAH) is a lethal disease that often affects the young. Although Bone Morphogenetic Protein Receptor Type 2 gene (BMPR2) mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors. In this study, we aimed to identify novel genetic factors associated with PAH, irrespective of BMPR2 mutation.We performed genome-wide association study (GWAS) in a Japanese population comprising 44 individuals with idiopathic and heritable PAH, and 2,993 controls.Seven loci identified in the genome-wide study were submitted to the validation study, and a novel susceptibility locus, PDE1A|DNAJC10, was identified that maps to 2q32.1 (rs71427857, P = 7.9 × 10-9, odds ratio in the validation study = 5.18; 95% CI 1.86 – 14.42). We also found the augmentation of PDE1A protein in distal remodeled pulmonary artery walls in idiopathic PAH patients.Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH.

Highlights

Pulmonary arterial hypertension (PAH) is a rare but fatal disease, with an estimated mean survival period in untreated patients of approximately 3 years [1]
Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH
To perform genome-wide association study (GWAS) analyses, 1,347,690 single-nucleotide polymorphisms (SNPs) were selected because they showed minor allele frequencies (MAF) of > 0.01 in controls, a Hardy-Weinberg equilibrium (HWE) P-value of > 0.001 in controls, and a SNP call rate of > 0.95

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a rare but fatal disease, with an estimated mean survival period in untreated patients of approximately 3 years [1]. Pulmonary vascular remodeling, occurring mostly in the small to mid-sized pulmonary arterioles (≤ 500μm), is a hallmark of PAH This process is ascribed to the increased proliferation, migration and survival of pulmonary vascular cells within the pulmonary artery wall, i.e. pulmonary arterial smooth muscle cells (PASMCs), endothelial cells, myofibroblasts and pericytes [2]. Many familial cases of heritable PAH exhibit an autosomal dominant mode of inheritance, with the majority having mutations in the Bone Morphogenetic Protein Receptor, Type 2 gene (BMPR2), [3] the penetrance of BMPR2 pathogenic variants is low and estimated to be 14% for males and 42% for females [4]. This low PAH penetrance in BMPR2 mutation carriers likely results from a combination of currently unknown genetic, environmental, and lifestyle factors [5]

Objectives

Methods

Results

Conclusion