A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population
A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population
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DOI：
10.18632/oncotarget.20459
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发表时间：
2017-09-26
期刊：
影响因子：
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通讯作者：
Sano, Motoaki
中科院分区：
文献类型：
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作者：
Kimura, Mai;Tamura, Yuichi;Sano, Motoaki
肺动脉高压（PAH）是一种致命的疾病，经常影响年轻人。虽然骨形态发生蛋白受体2型基因（BMPR2）突变与特发性和遗传性PAH相关，但PAH的低突变率和可变表达率提示存在其他遗传和/或环境因素。在这项研究中，我们的目的是确定与PAH相关的新的遗传因素，而不考虑BMPR2突变。我们在日本人群中进行了全基因组关联研究（GWAS），该人群包括44名特发性和遗传性PAH患者和2，993名对照。在全基因组研究中确定的7个位点被提交给验证研究，一个新的易感性位点PDE1A| DNAJC 10被鉴定为映射到2q32.1（rs71427857，P = 7.9 x 10（-9），验证研究中的比值比= 5.18; 95%CI 1.86 - 14.42）。我们还发现PDE1A蛋白在特发性PAH患者远端重塑的肺动脉壁中增加。鉴于磷酸二酯酶5抑制剂对特发性和遗传性PAH的治疗有效，我们的研究结果表明PDE1A可能是PAH的新治疗靶点。
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 x 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.