GEnetic and mechanistic studies of primary Aldosteronism

动脉高血压是一种主要的心血管危险因素，影响工业化国家10%至40%的人口。原发性醛固酮增多症（PA）是继发性高血压的最常见形式，在转诊患者中估计患病率约为10%。在PA的亚型中，醛固酮腺瘤（阿帕）和双侧肾上腺增生（BAH）共占约95%的病例。钾通道KCNJ 5的体细胞和遗传突变与醛固酮腺瘤的形成和家族性醛固酮增多症3型有关。我们已经表明，体细胞KCNJ 5突变存在于约40%的阿帕。最近，我们在有限数量的阿帕中进行了全外显子组测序，并鉴定了ATP 1A 1和ATP 2B 3的体细胞突变，这些突变存在于约7%的肿瘤中。所有这些突变都会影响肾上腺皮质肾小球细胞膜电位，这是醛固酮产生的主要触发因素。该建议的总体假设是，体细胞或生殖系突变是不同形式的散发性和家族性PA的原因。本项目的目的是：1）填补我们对KCNJ 5、ATP 1A 1和ATP 2B 3基因无突变的阿帕患者以及FH 2和BAH患者PA遗传病因认识上的差距; 2）进行机制研究，了解PA与细胞增殖和醛固酮产生相关的致病机制;（3）将这些发现转化为临床研究。为了实现这些目标，我们将使用最新的基因组技术应用于散发性和家族性PA患者的独特队列，获得标准化的临床和生物学信息，肿瘤和DNA样本，整合在欧洲肾上腺肿瘤研究网络（ENS@T）中，以及该疾病的原始小鼠模型。我们的策略将整合互补的高通量方法，以：（1）确定阿帕中不携带KCNJ 5和ATP酶突变的其他基因;（2）评估PA的疾病风险;（3）测试一个或几个基因中的罕见外显子变异导致小鼠2型家族性醛固酮增多症（FH 2）和PA的假设;（4）明确阿帕中突变的候选基因促进细胞生长和诱导肿瘤形成的机制;（5）验证钾通道和ATP酶的异常调节导致无突变患者PA的假设;明确KCNJ 5/ATP 1A 1/ATP 2B 3等突变对PA诊断和预后的影响。因此，该项目将扩展我们对PA的遗传和机制决定因素的知识，以转化为临床研究，并为识别最常见的继发性动脉高血压的新的潜在治疗靶点开辟新的视角。

Arterial hypertension is a major cardiovascular risk factor that affects between 10 and 40% of the population in industrialized countries. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. Among subtypes of PA, aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) together account for ~95% of cases. Somatic and inherited mutations of the potassium channel KCNJ5 have been implicated in the formation of aldosterone producing adenoma and in familial hyperaldosteronism type 3. We have shown that somatic KCNJ5 mutations are present in ~40% of APA. More recently, we have performed whole exome sequencing in a limited number of APA and identified somatic mutations in ATP1A1 and ATP2B3, which are present in ~7% of tumors. All these mutations affect the adrenal zona glomerulosa cell membrane potential, the major trigger for aldosterone production. The overall hypothesis of this proposal is that somatic or germ-line mutations are responsible for different forms of sporadic and familial PA. The aim of our program is 1) to fill the gap in our understanding of the genetic causes of PA in patients with APA not harboring mutations in the KCNJ5, ATP1A1 and ATP2B3 genes, as well as in patients with FH2 and BAH; 2) to perform mechanistic studies allowing to understand the pathogenic mechanisms of PA in relation to cell proliferation and aldosterone production; and 3) to translate these findings into clinical investigation. To achieve these objectives we will use the most recent genomic technologies available applied on unique cohorts of patients with sporadic and familial PA, with access to standardized clinical and biological information, tumor and DNA samples, integrated within the European network for the study of adrenal tumors (ENS@T), as well as original mouse models of the disease. Our strategy will integrate complementary high throughput approaches to: (1) identify further genes in APA not harboring KCNJ5 and ATPase mutations; (2) assess disease risk in PA; (3) test the hypothesis that rare exonic variants within one or few genes cause familial hyperaldosteronism type 2 (FH2) and PA in mice; (4) define the mechanisms by which candidate genes mutated in APA increase cell growth and induce tumor formation; (5) test the hypothesis that abnormal regulation of potassium channels and ATPases cause PA in patients without mutations; and (6) define the clinical impact of KCNJ5/ATP1A1/ATP2B3 and other mutations on diagnosis and outcome of patients with PA. Thereby, this project will extend our knowledge on the genetic and mechanistic determinants of PA to be translated into clinical investigation, and open new perspectives for the identification of novel potential therapeutic targets for the most frequent secondary form of arterial hypertension.