The term primary hyperaldosteronism (PHA) describes the overproduction of aldosterone (a mineralocorticoid steroid hormone) by the adrenal cortex. PHA is the leading cause of secondary arterial hypertension, underlying high blood pressure in up to 10% of patients with it. The primary form of hyperaldosteronism (there is also a secondary form) is caused by bilateral adrenal hyperplasia, adenomas (Conn's syndrome) or carcinomas. Left untreated, PHA can lead to arterial hypertension treatment resistance and increased cardiovascular risks. Thus, the possibility of PHA in patients with arterial hypertension must be rapidly verified to avoid these risks and enable specific medical or surgical interventions. Although PHA guidelines have brought some standardization to patient management, the disorder remains underdiagnosed due to inadequate first-line screening. Identifying novel genetic contributors would greatly empower early detection and improve knowledge on the pathophysiological mechanisms of the disease.
With these goals in mind, the CNRGH's Mathematics & Statistics team partnered with colleagues from the Paris-Cardiovascular Research Center (PARCC) to perform a genome-wide association study1 in a French cohort of 562 patients with PHA and 950 controls. In their work published in Nature Communications, the researchers identified three main loci associated with PHA risk on chromosomes 1 & 13 and on the X chromosome.
The associations on chromosomes 1 and 13 were replicated in a second, German cohort and further confirmed by a meta-analysis including the first two cohorts and two additional, smaller cohorts (Italian and French) for a total of 1,162 patients and 3,296 controls.
The association with the locus on chromosome 13 appeared to be specific to men and stronger in patients with PHA due to bilateral adrenal hyperplasia compared to those in whom the disorder is due to an adenoma.
The team identified CASZ1 and RXFP2 as candidate genes: the former, located in the chromosome 1 locus and the latter the chromosome 13 locus, are both expressed in human and mouse adrenal cell clusters. The researchers also reported that overexpression of these two genes in the adrenal cortex modifies mineralocorticoid hormone production under basal and stimulated conditions without modifying cortisol biosynthesis.
With its study, the CNRGH-PARCC team identified for the first time genome loci associated with primary hyperaldosteronism risks and shed light on novel mechanisms potentially involved in the excessive production of aldosterone.
1 : A genome-wide association study enables the analysis of genetic variations (variations in nucleotides) in a great number of individuals to establish correlations between those variations and phenotypic characteristics of interest.