COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.

Background/Objectives: Genetic variants in cytokine genes such as IL1B, IL6, and TNF may influence inflammatory responses to SARS-CoV-2 and affect disease severity. This study investigates the role of these variants in relation to COVID-19 outcomes, including hospitalization, ICU admission, and mortality. Methods: A total of 500 unvaccinated individuals from southern Brazil diagnosed with COVID-19 via RT-PCR were analyzed. DNA was extracted from nasopharyngeal swabs and genotyped for functional variants selected based on evidence of regulatory function and prior associations with inflammatory outcomes—IL1B (rs4848306, rs1143623, rs16944, rs1143627), IL6 (rs1800795, rs2069832, rs2069840, rs2069845), and TNF (rs1799964, rs1800630, rs1799724, rs1800629, rs361525). Multivariate logistic regression analysis, adjusted for sex and age, was employed to assess the association between these genetic variants and severe clinical outcomes. Results: The results indicated that the IL1B rs16944-AG (OR: 1.98 [95% CI: 1.22–3.23], p = 0.006) and TNF rs1799964-CT (OR: 1.97 [95% CI: 1.22–3.22], p = 0.006) genotypes were associated with the need for hospitalization, while TNF rs1800630-AA (OR: 2.37 [95% CI: 1.08–5.33], p = 0.034) was associated with ICU admission. Additionally, the CC genotype of TNF rs1799964 was associated with a higher risk of mortality (OR: 3.73 [95% CI: 1.21–14.37], p = 0.034). Conclusions: Genetic variants—specifically IL1B rs16944 and rs1143627, and TNF rs1799964 and rs1800630—were associated with COVID-19 severity and should be further investigated in larger studies to evaluate their potential as predictive markers of severe outcomes in COVID-19.

The P1104A variant in the TYK2 gene is recognized as the first common monogenic cause of tuberculosis, and recent studies also suggest a potential role in COVID-19 severity. However, its frequency and impact in admixed Latin American populations remain underexplored. Therefore, we investigated the P1104A/TYK2 variant in a cohort comprising 1826 RT-PCR-confirmed COVID-19 patients from Southern Brazil. Cases were stratified by severity into non-severe (n = 1190) and severe (n = 636). Three homozygous individuals were identified—one non-severe and two severe cases—although no statistically significant association with disease severity was observed. The frequency of the C allele in the COVID-19 cohort (2.85%) was significantly higher than in Brazilian population databases, including “DNA do Brasil” (1.81%, p < 0.001) and ABraOM (2.34%, p = 0.03), but lower than in the multi-ancestry gnomAD database (3.71%, p = 0.01), possibly reflecting ancestry bias. We also observed associations between COVID-19 severity and sex (p = 0.003), age (p < 0.001), obesity (p < 0.001), diabetes (p < 0.001), and hypertension (p < 0.001). Future studies in larger and more diverse cohorts are needed to characterize the prevalence of the variant in admixed populations and assess its contribution to COVID-19 susceptibility.