Discerning the genetic contributors to autonomous aldosterone production through whole genome sequencing

通过全基因组测序辨别自主醛固酮产生的遗传因素

• 批准号: MR/T018941/1
• 负责人: Bernard Keavney
• 金额: $ 33.64万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT018941%2F1
• 关键词: Discerning; genetic; contributors; autonomous; aldosterone

Malaysia, like the rest of the world, has a high prevalence of high blood pressure (hypertension), 32.7% for aged >18 years. Difficult to control hypertension can lead to co-morbidities and mortality as it is a major risk factor for stroke and heart diseases. Primary aldosteronism (PA), showing excess production of the hormone aldosterone from the adrenal glands, is probably the commonest curable cause of hypertension. While a recent report suggested that 60% of patients with hypertension have PA, a more conservative estimate, with concentration on curable patients, might suggest 5-10% of all patients, but in much higher proportions among those with treatment resistant hypertension, and ethnic groups with low-renin hypertension. In many patients, the discovery of a unilateral aldosterone-producing adenoma (APA) of the adrenal gland offers the opportunity for complete cure of hypertension. However developing country like Malaysia lacks the resources to identify these patients. Even making a reliable diagnosis of PA is currently fraught, requiring withdrawal of most first-line antihypertensive drugs from high-risk patients for the hormone (renin and aldosterone) measurements, often on more than one occasion if a confirmatory test (e.g saline or captopril suppression) is required. Hence, <1% of patients with PA are currently diagnosed. However, preventing excessive aldosterone is not only essential to attenuate high blood pressure which can lead to cardiovascular diseases, but also to prevent direct cardiac damage. We therefore aim in this proposal to identify the genetic contributors for autonomous aldosterone production, using the powerful whole genome sequencing technology, with the hope of developing a low-cost high-throughput peripheral blood assay that will allow mass diagnosis and targeted treatment of autonomous aldosterone production. Whole genome sequencing, a powerful technology to detect all the genetic sequences in an individual, will be able to identify heritable mutations associated with PA. Heredity is estimated to contribute 25-64% of inter-individual variation in blood pressure, yet currently genome-wide association studies have only identified ~3.5% of the genetic contribution with most hits occurring in the non-coding regions. This work will provide deeper genetic understanding of the disease development especially on the non gene-coding regulatory sequences and interplay between heritable germline mutations and somatic mutations that occur in the adrenal. Interestingly, one of the top hit GWAS polymorphism associated with PA in the recently released UK Biobank data is SMUG1, a DNA repair gene where the signature for its failure is C/T or G/A mutations. To note, almost half of aldosterone-producing cell clusters and micro-aldosterone-producing adenomas in PA patients have this signature. We hypothesize that WGS will discover informative, causal variants, e.g. in enhancer regions, which are rare (<1%) in control population databases, but >10-fold more frequent in documented PA with somatic mutation in aldosterone-driver genes. Such discovery may be rewarded by the potential for a clinically useful diagnostic test, a potential which is never realised by the common SNPs used in GWAS. We postulate that much of low-renin hypertension is due to undiagnosed autonomous aldosterone production and the low tech high throughput assay that can be developed from this study will cut cost of diagnosis and justify cheap preventive treatment despite spironolactone's known plethora of side effects. With the new information generated from this project, a simple genotyping test may be developed to identify hypertensive patients due to autonomous aldosterone production, which can then be treated by the cheap aldosterone receptor antagonist spironolactone, decreasing blood pressure and risk of cardiovascular diseases.

与世界其他地区一样，马来西亚的高血压患病率很高，18 岁以上人群的患病率为 32.7%。难以控制高血压可能导致合并症和死亡，因为它是中风和心脏病的主要危险因素。原发性醛固酮增多症 (PA) 表现为肾上腺产生过多的醛固酮激素，可能是高血压最常见的可治愈原因。虽然最近的一份报告表明 60% 的高血压患者患有 PA，但更保守的估计（重点关注可治愈患者）可能占所有患者的 5-10%，但在难治性高血压患者和低肾素高血压的种族群体中比例要高得多。在许多患者中，单侧肾上腺产生醛固酮腺瘤（APA）的发现为彻底治愈高血压提供了机会。然而，像马来西亚这样的发展中国家缺乏识别这些患者的资源。即使对 PA 做出可靠的诊断，目前也充满挑战，需要从高危患者中撤回大多数一线抗高血压药物来进行激素（肾素和醛固酮）测量，如果需要验证性测试（例如盐水或卡托普利抑制），通常会不止一次。因此，目前仅有<1% 的 PA 患者得到诊断。然而，防止醛固酮过量不仅对于减轻可导致心血管疾病的高血压至关重要，而且对于防止直接的心脏损伤也至关重要。因此，我们在本提案中的目的是利用强大的全基因组测序技术来确定自主醛固酮产生的遗传因素，希望开发出一种低成本高通量的外周血检测方法，以实现自主醛固酮产生的大规模诊断和靶向治疗。全基因组测序是一种检测个体所有基因序列的强大技术，将能够识别与 PA 相关的遗传突变。据估计，遗传因素对血压的个体间变异有 25-64% 的影响，但目前全基因组关联研究仅确定了约 3.5% 的遗传因素，其中大多数命中发生在非编码区域。这项工作将为疾病的发展提供更深入的遗传学理解，特别是关于非基因编码调控序列以及可遗传的种系突变和肾上腺中发生的体细胞突变之间的相互作用。有趣的是，最近发布的英国生物银行数据中与 PA 相关的最热门 GWAS 多态性之一是 SMUG1，这是一种 DNA 修复基因，其失败的特征是 C/T 或 G/A 突变。值得注意的是，PA 患者中几乎一半的醛固酮生成细胞簇和微醛固酮生成腺瘤具有这种特征。我们假设 WGS 将发现信息丰富的因果变异，例如在增强子区域中，这种情况在对照群体数据库中很少见（<1%），但在记录的醛固酮驱动基因体细胞突变的 PA 中频率要高出 10 倍以上。这种发现可能会因临床上有用的诊断测试的潜力而得到回报，而 GWAS 中使用的常见 SNP 从未实现过这种潜力。我们假设大部分低肾素高血压是由于未确诊的自主醛固酮产生所致，并且本研究开发的低技术高通量检测将降低诊断成本，并证明廉价的预防性治疗是合理的，尽管螺内酯已知有大量副作用。利用该项目产生的新信息，可以开发一种简单的基因分型测试来识别由于自主醛固酮产生而导致的高血压患者，然后可以通过廉价的醛固酮受体拮抗剂螺内酯进行治疗，从而降低血压和心血管疾病的风险。

项目成果

Somatic intramembranous mutations of CADM1 in aldosterone-producing adenomas and gap-junction dependent regulation of aldosterone production

醛固酮生成腺瘤中 CADM1 的体细胞膜内突变和醛固酮生成的间隙连接依赖性调节

• 发表时间: 2023
• 期刊: Nature Genetics
• 影响因子: 30.8
• 作者: Wu X

PS-BPB06-9: PREVALENCE OF KCNJ5 MUTANT ALDOSTERONE-PRODUCING ADENOMAS AMONG MALAYSIAN PATIENTS WITH PRIMARY ALDOSTERONISM

PS-BPB06-9：马来西亚原发性醛固酮增多症患者中 KCNJ5 突变型醛固酮腺瘤的患病率

• DOI: 10.1097/01.hjh.0000915604.94784.48
• 发表时间: 2023
• 期刊: Journal of Hypertension
• 影响因子: 4.9
• 作者: Rizam N

PS-BPB06-10: DISTRIBUTION OF CACNA1D SOMATIC MUTATIONS AMONG CYP11B2 IMMUNOHISTOCHEMISTRY-GUIDED SAMPLES OF ALDOSTERONE-PRODUCING ADENOMA (APA)

PS-BPB06-10：CACNA1D 体细胞突变在 CYP11B2 免疫组织化学引导的醛固酮腺瘤 (APA) 样本中的分布

• DOI: 10.1097/01.hjh.0000915608.20633.e6
• 发表时间: 2023
• 期刊: Journal of Hypertension
• 影响因子: 4.9
• 作者: Pauzi F

S-55-4: HISTOPATHOLOGY-GENOTYPE CORRELATION OF ALDOSTERONE- PRODUCING ADENOMAS

S-55-4：产生醛固酮的腺瘤的组织病理学-基因型相关性

• DOI: 10.1097/01.hjh.0000913932.53564.fe
• 发表时间: 2023
• 期刊: Journal of Hypertension
• 影响因子: 4.9
• 作者: Azizan E

Functional Characteristic and Significance of Aldosterone-Producing Cell Clusters in Primary Aldosteronism and Age-Related Hypertension.

• DOI: 10.3389/fendo.2021.631848
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Pauzi FA;Azizan EA
• 通讯作者: Azizan EA