Research Papers:

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

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

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Oncotarget. 2017; 8:74917-74926. https://doi.org/10.18632/oncotarget.20459

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Mai Kimura1,*, Yuichi Tamura1,2,3,4,5,*,**, Christophe Guignabert2,4, Makoto Takei1, Kenjiro Kosaki6, Nobuhiro Tanabe7,8, Koichiro Tatsumi7, Tsutomu Saji9, Toru Satoh10, Masaharu Kataoka1, Shigeo Kamitsuji11, Naoyuki Kamatani11, Raphaël Thuillet2,4, Ly Tu2,4, Marc Humbert2,3,4, Keiichi Fukuda1 and Motoaki Sano1,**

1Department of Cardiology, Keio University School of Medicine, Tokyo, Japan

2Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

3AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

4Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

5Department of Cardiology, International University of Health and Welfare Mita Hospital, Tokyo, Japan

6Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan

7Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan

8Department of Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University, Chiba, Japan

9Department of Pediatrics, Toho University, Medical Center, Omori Hospital, Tokyo, Japan

10Department of Cardiology, Kyorin University School of Medicine, Tokyo, Japan

11StaGen Co. Ltd., Tokyo, Japan

*These authors have contributed equally to this work

**These authors are co-corresponding authors

Correspondence to:

Yuichi Tamura, email: [email protected]

Keywords: pulmonary arterial hypertension, genome-wide association study, novel therapeutic target

Abbreviations: BMPR2: Bone Morphogenetic Protein Receptor Type 2; I/HPAH: idiopathic and heritable pulmonary arterial hypertension; GWAS: genome-wide association study; PAH: pulmonary arterial hypertension; PDE: phosphodiesterase

Received: January 10, 2017     Accepted: July 25, 2017     Published: August 24, 2017


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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