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Background: Human leukocyte antigen (<i>HLA</i>) genes are important in many immune processes and contribute to many adverse drug reactions. Whether genetic variations in the <i>HLA</i> region are associated with non-steroid anti-inflammatory drug (NSAID) hypersensitivity remains uncertain. Therefore, the aim of our study was to identify <i>HLA</i> genetic variations in patients with NSAID hypersensitivity in the Taiwanese population. Methods: This hospital-based, retrospective case-control study enrolled 37,156 participants with NSAID exposure from the Taiwan Precision Medicine Initiative (TPMI), who were all genotyped and imputed to fine map <i>HLA</i> typing. Our study assigned 1217 cases to the NSAID allergy group and 12,170 controls to a matched group. Logistic regression analyses were utilized to explore associations between <i>HLA</i> alleles and NSAID hypersensitivity. Results: Overall, 13,387 patients were genotyped for eight major <i>HLA</i> alleles. Allele frequencies were different between the two groups. In the NSAID allergy group, the genotype frequencies of <i>HLA-A*02:01</i>, <i>HLA-A*34:01</i>, and <i>HLA-DQA1*06:01</i> were found to be markedly elevated compared to the control group, a significance that persisted even after applying the Bonferroni correction. Furthermore, the risk of NSAID allergy demonstrated a significant association with <i>HLA-A*02:01</i> (OR = 1.29, <i>p</i> < 0.001) and <i>HLA-A*34:01</i> (OR = 9.90, <i>p</i> = 0.001), in comparison to their respective counterparts. Notably, the genotype frequency of <i>HLA-B*46:01</i> exhibited a significant increase in the severe allergy group when compared with the mild allergy group. Conclusions: We identified <i>HLA</i> genotypes linked to the onset and severity of NSAID hypersensitivity. Our findings establish a basis for precision prescription in future clinical applications.