DEPARTMENT FOR BUSINESS, ENERGY & INDUSTRIAL STRATEGY

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

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Description

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.

Objectives

The Newton Fund builds research and innovation partnerships with developing countries across the world to promote the economic development and social welfare of the partner countries.

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Location

The country, countries or regions that benefit from this Programme.

Malaysia

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