Prevalence of KCNJ5 mutations in aldosterone-producing adenomas among Malaysian primary aldosteronism patients: Genotype-phenotype correlation.

Primary aldosteronism (PA) is a common cause of secondary hypertension characterised by autonomous aldosterone hypersecretion independent of the renin-angiotensin-aldosterone system. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 are commonly linked to aldosterone overproduction in unilateral aldosterone-producing adenomas (APAs). Interestingly, KCNJ5 mutations have been reported to be more frequent in APAs from Asian PA patients (60-70%) compared to Western PA patients (30-40%). However, a previous study done at a university hospital in Malaysia found a lower prevalence of KCNJ5 mutations (31.5%) in 54 APAs, aligning with Western data. Herein, this study aimed to verify KCNJ5 mutation prevalence in Malaysian PA patients treated at a government hospital. Adrenal samples (n=99) from adrenalectomies performed at Hospital Putrajaya (2010-2020) were analyzed. Using CYP11B2 immunohistochemistry (IHC), 85 APAs were identified, and DNA sequencing was performed for known aldosterone-driver KCNJ5 mutations. Patients' demographics were compared across genotypes using chi-square test. Among the 85 APAs, 42 (49.4%) harboured a KCNJ5 mutation: G151R (25.9%), L168R (18.8%), and T158A/E145Q (2.4%). Mutant APAs were more frequent in females (69%), similarly for wild-type APAs (56%). Significant female gender bias for mutation was seen with Malay patients (p=0.049). No association between age at adrenalectomy and mutation status was found. One KCNJ5-mutant APA with aldosterone-producing diffused ZG hyperplasia also harboured a mutation in CACNA1H R1253H. In conclusion, this study supports a lower prevalence of KCNJ5 mutations in Malaysian PA patients (<50%) compared to other Asian cohorts (>50%) consistent with prior Malaysian data, and suggest that co-existing aldosterone-driver mutations with KCNJ5 may occur.