BACKGROUND Group 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. METHODS To 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. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing. RESULTS Tissue 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. CONCLUSIONS We report robust association of novel genes KLK1 and GGCX with 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.

中文翻译：

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对 2572 名肺动脉高压患者进行外显子组测序，发现新的风险基因和机制。

背景 1 组肺动脉高压（PAH）是一种罕见疾病，尽管最近的治疗取得了进展，但死亡率却很高。肺小动脉的致病性重塑导致肺动脉压力增加、右心室肥厚和心力衰竭。2 型骨形态发生蛋白受体和其他风险基因的突变容易导致疾病，但绝大多数非家族性病例在遗传上仍然不确定。方法 为了识别新的风险基因，我们对国家 PAH 生物样本和数据存储库（PAH Biobank，n = 2572）的一个大队列进行了外显子组测序。然后，我们进行了罕见的有害变异鉴定，然后进行基于病例对照基因的关联分析。为了控制人口结构，关联测试中仅使用了不相关的欧洲病例（n = 1832）和对照（n = 12,771）。经验 p 值通过排列分析确定，显着性阈值通过多重检验的 Bonferroni 校正定义。结果 组织激肽释放酶 1 (KLK1) 和 γ 谷氨酰羧化酶 (GGCX) 被确定为特发性 PAH (IPAH) 的新候选风险基因，具有全基因组意义。我们注意到，与骨形态发生受体2型变异携带者相比，变异携带者的平均发病年龄较晚，疾病表型相对温和。我们还证实了最近报道的生长分化因子 (GDF2) 与 IPAH 的全基因组关联，并进一步表明 T-box 4 (TBX4) 与儿童发病的 PAH 相关。结论 我们报告了新基因 KLK1 和 GGCX 与 IPAH 的强相关性，分别占 PAH Biobank 病例的约 0.4% 和 0.9%。这两个基因在血管血流动力学和炎症中发挥着重要作用，但之前并未涉及 PAH。这些数据提出了这种致命性血管病的新基因、致病机制和治疗靶点。