The association of selected genetic polymorphisms with adverse events following COVID-19 vaccination: a single-centre prospective observational cohort study

Objectives: The study investigated whether selected genetic polymorphisms are linked to adverse reactions after Pfizer-BioNTech BNT162b2 vaccination. Methods: A prospective observational cohort of 354 hospital employees who received two doses of BNT162b2 vaccination was analysed. Adverse effects were recorded after each dose using standardized surveys and graded by severity. Genotyping was performed for variants in ACE2, TMPRSS2, HLA-E, IFNG, MICA, NKG2A, NKG2C, TLR4, and TLR7. Statistical analyses included Fisher's exact test and proportional odds logistic regression with Bonferroni correction. Results: The KLRC2/NKG2C del/del genotype was associated with higher frequencies of selected reactions. After the first dose, skin redness occurred in 100% (5/6) of del/del carriers versus 32% (35/110) of wt/del and 31% (72/229) of wt/wt (p = 0.0105 and p = 0.0129, respectively); swelling in 100% (5/5) versus 33% (36/109) and 35% (8/229) (p = 0.0153; p = 0.0177); and headache in 100% (5/5) versus 26% (29/110) and 36% (82/229) (p = 0.0054; p = 0.0198). After dose 2, diarrhea occurred in 40% (2/5) of del/del carriers versus 2% (2/110) of wt/del and 2% (4/227) of wt/wt (OR 34.85, 95% CI 3.35-300.59; p = 0.0264). Severity was associated with NKG2C del/del (dose 1 OR 0.16, 95% CI 0.04-0.71; p = 0.0371; dose 2 OR 0.07, 0.01-0.59; p = 0.0323) and showed a borderline association for TLR4 rs4986790 AG versus AA (OR 0.38, 0.16-0.87; p = 0.0508). No significant associations were observed for the remaining variants. Conclusions: Genetic variability in KLRC2/NKG2C and TLR4 may influence the risk and severity of adverse events following mRNA COVID-19 vaccination, supporting a role for host genetics in vaccine reactogenicity.