Host Genetic Determinants of SARS-CoV-2 Susceptibility in Transplant Recipients and Donor Candidates: A Multicohort Analysis of HLA Variation

Background: Host genetic variation plays a key role in susceptibility to SARS-CoV-2 infection. Human leukocyte antigen (HLA) variation influences antiviral immune responses; however, allele-level associations with SARS-CoV-2 infection have varied across populations and clinical groups. This study aimed to evaluate HLA associations with SARS-CoV-2 positivity among transplant recipients and immunocompetent donor candidates representing different clinical and immunological settings. Methods: A retrospective multicohort genetic association study was conducted using data from a single-center tissue typing laboratory during the COVID-19 pandemic. The study included n = 158 pediatric transplant recipients, n = 159 pediatric donor candidates, n = 311 adult transplant recipients, and n = 336 adult donor candidates. SARS-CoV-2 infection was defined by documented positive real-time polymerase chain reaction testing. HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci were analyzed using a predefined carrier threshold (≥5). Associations with SARS-CoV-2 positivity were evaluated using Fisher’s exact test with false discovery rate correction and multivariable logistic regression adjusted for age, sex, vaccination status, and antiviral use. Results: HLA-DRB1*11 showed a consistent direction of association with higher odds of SARS-CoV-2 positivity across several cohorts, with the strongest statistical support observed in the pediatric transplant and pediatric donor cohorts. In adult solid organ transplant recipients, the association met only the predefined exploratory threshold (q = 0.12). HLA-B*51 and HLA-A*32 were associated with higher odds of positivity in pediatric and adult transplant recipients, respectively, whereas HLA-DRB1*14 was associated with lower odds of positivity in pediatric donor candidates and adult transplant recipients; both HLA-DRB1*14 findings met the predefined exploratory threshold (q < 0.20). Exploratory subgroup analyses indicated that HLA-B*38 was associated with higher vaccination uptake and lower infection frequency (p = 0.043); however, these observations were based on small carrier numbers and should be interpreted cautiously. No allele reached the predefined exploratory threshold in healthy adult donor candidates. Conclusions: The observed HLA associations differed across the four study cohorts, with several exploratory signals identified among transplant recipients. Because the cohorts also differed in demographic and clinical characteristics, these findings do not establish modification of HLA effects by immune status and require validation in appropriately matched independent populations.