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

Oncotarget
Mai KimuraMotoaki Sano

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.

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Citations

Aug 14, 2019·Nature Reviews. Cardiology·Laura SouthgateNicholas W Morrell
Dec 1, 2017·European Journal of Pharmacology·Yi-Shuai ZhangChen Yan

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Methods Mentioned

BETA
PCA
genotyping
reverse transcription PCR
chips

Software Mentioned

ZEN
PLINK
Eigenstrat
ABI SeqScape
R
IMPUTE

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