Investigation of <i>PDCD1</i> Gene Polymorphisms and Haplotypes in COVID‐19 Severity and Outcome in a Brazilian Population

COVID-19 severity and survival are influenced by the host immune response to SARS-CoV-2. Programmed cell death 1 (PD-1), a key immune checkpoint, regulates T-cell activation and antiviral immune balance. Since genetic variability can modulate these responses, we investigated whether the PDCD1 polymorphisms rs11568821 C > T, rs2227982 G > A, rs2227981 G > A and rs10204525 C > T are associated with COVID-19 severity and mortality in a Brazilian cohort. A total of 366 COVID-19 patients (165 mild, 72 moderate, and 129 severe cases) were genotyped for the four PDCD1 SNPs, and their haplotype structures were estimated. Significant differences were observed in the allele frequencies of rs11568821, and in genotypes and allele frequencies of the exonic rs2227982, among mild, moderate, and severe cases. Multinomial logistic regression identified associations between rs2227982 (dominant and overdominant models) and moderate COVID-19, and between the rs2227981 AA genotype (genotypic and recessive models) and severe COVID-19. The rs10204525 polymorphism (CT genotype under genotypic dominant and overdominant models) also presented an association with severe COVID-19. However, none of these associations remained independent. Haplotype analysis identified five major haplotypes with significantly different frequencies among the groups (p = 0.02); however, no association was found between the haplotypes and disease severity or outcome. This is the first study to evaluate SNP rs2227982 in COVID-19 patients, and the first to evaluate the four aforementioned SNPs in a Brazilian population. Overall, our findings suggest that these polymorphisms, although involved in COVID-19 immunopathogenesis, are not suitable biomarkers for predicting COVID-19 severity or clinical outcomes.