BACKGROUND: Recurrent COVID-19 remains a major public health challenge, yet the host factors driving susceptibility are poorly understood. Although genetic determinants of COVID-19 severity have been explored, their role in infection recurrence particularly in genetically diverse populations such as Malaysia has received limited attention. This study represents the first Malaysian assessment of the combined impact of ACE (I/D), TNF-alpha (-308G>A), and IL-6 (-572G/C) polymorphisms on susceptibility to recurrent COVID-19. METHODS: A total of 120 participants were recruited, comprising 60 individuals with documented recurrent COVID-19 (RT-PCR positive >90 days apart) and 60 matched SARS-CoV-2-negative controls. Genotyping was performed using PCR-based approaches. Genotype and allele frequencies were compared using Chi-square Tests, and odds ratios (ORs) were calculated to estimate relative risks. RESULTS: A significant association was observed for the ACE (I/D) polymorphism at both genotype (x(2)=25.94, df=2, P<0.001) and allele levels (x(2)=17.01, df=1, P<0.001). The D allele was more frequent in recurrent cases (50.8%) than controls (25%), with an OR of 0.50 (95% CI: 0.37-0.68). For TNF-alpha (-308G>A), no significant genotype association was found (x(2)=4.92, P=0.086), though the A allele was more common in recurrent cases (31.7%) vs. controls (19.2%), indicating a modest association (x(2)=4.95, p=0.037; OR=0.62, 95% CI: 0.41-0.93). The IL-6 (-572G/C) variant showed strong associations at both genotype (x2=18.31, P<0.001) and allele levels (x(2)=15.67, P<0.001), with the C allele more frequent in recurrent cases (45.8%) than controls (21.7%; OR=0.59, 95% CI: 0.43-0.82). CONCLUSIONS: ACE and IL-6 polymorphisms appear to be key genetic contributors to recurrent COVID-19 risk, with a suggestive role for TNF-alpha. This study provides novel evidence that pro-inflammatory genetic variants may predispose individuals to repeated SARS-CoV-2 infections, emphasising the importance of host genetic profiling in understanding COVID-19 recurrence.
