Abstract
Abstract Disclosure: N.S. Mohd Rizam: None. F.A. Pauzi: None. M. Choy: None. S. Williams: None. A. Aminuddin: None. F. Abdul Latif: None. S. Syed Mohammed Nazri: None. M. Mustangin: None. G. Tan: None. X. Wu: None. E. Ng: None. K. Laycock: None. N. Sukor: None. A.B. Nasruddin: None. M.J. Brown: None. B. Keavney: None. E.A. Azizan: None. Primary aldosteronism (PA) is a common curable cause of hypertension (5-10% cases) yet markedly underdiagnosed. Heredity contributes 25-64% of inter-individual blood pressure variation. Genome-wide association studies have identified a proportion of these genetic factors, whole-genome sequencing (WGS) could provide deeper genetic resolution. We therefore performed WGS on PA patients to elucidate genetic contributors for aldosterone related hypertension. In PA patients of Malay or Black ethnicity, missense mutations in NOTCH4 were frequently encountered (21 of 100). Four of the seven mutations identified were rare (gnomAD allele frequency = 0) and damaging (CADD score >20). The protein is a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 that regulates cell-fate determination. Whereas in Black PA patients or PA patients with no apparent adenoma, an enrichment of two rare missense mutations in GBP7 occurred compared to the global population (7 of 100). The mutations in GBP7 were verified as the encoded protein hydrolyzes GTP to GMP associated with the aldosterone synthesis pathway. Bulk adrenal expression of NOTCH4 and GBP7 were 11.7 and 1.145 transcript per million (TPM) respectively (data acquired from GTex). Single-cell analysis of human adrenals identified NOTCH4 to be expressed mainly in endothelial cells. Co-culturing of the endothelial cell line (HCMEC) with an adrenocortical cell line (HAC15) increased expression of CYP11B2, encoding the aldosterone synthase enzyme, by 1.82+0.37-fold (n=6, p=0.03). Overexpressing NOTCH4 and GBP7 in HAC15 increased CYP11B2 expression by 1.74+0.08-fold (n=16, p=0.000003) and 1.57+0.21-fold (n=24, p=0.001) respectively. In summary, NOTCH4 and GBP7 may highlight a novel pathway in PA pathology. Presentation: 6/2/2024
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