HLA-B*58:01 is an Incomplete Predictor of Allopurinol-Induced Severe Cutaneous Adverse Reactions.

Carriage of HLA-B*58:01 has been shown to have a strong association with the development of allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction and eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to determine if this is generalizable to varying populations including those in the United States (US). To perform HLA class I and II association studies in a cohort of US patients diagnosed with allopurinol-induced SJS/TEN or DRESS compared to allopurinol tolerant and population controls. We enrolled consenting individuals who had specialist adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-SCAR). HLA carriage in these cases was compared to allopurinol tolerant and population controls identified through Vanderbilt University Medical Center (VUMC) BioVU, a biobank which includes 94,489 individuals with imputed human leukocyte antigen (HLA) class I and II typing from genotyping array data. We performed HLA class I and II conditional logistic regression case-control analyses between allopurinol-SCAR cases and both population controls and allopurinol tolerant controls matched on age, sex, and self-identified race. We reported odds ratio (OR) and 95% confidence interval (CI) with Bonferroni corrected P ( Pc ) <.05. The conditional logistic regression analyses included allopurinol-SCAR cases (n=16) and 10:1 matched allopurinol tolerant controls (n=160). We found two HLA class I alleles independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR 28 [95% CI, 8.6 - 100.6]) and HLA-A*34:02 (OR 20.6 [95% CI, 3.3 - 131.1]). We did not identify any HLA class II alleles meeting the Pc level of significance. We found HLA-B*58:01 to be strongly associated with allopurinol-induced SCAR, generalizing findings from previous studies. Additionally, we found HLA-A*34:02 to be a second independent genetic risk factor for allopurinol-SCAR. These findings underscore the need to conduct specific population-based studies that both reproduce known and uncover novel HLA associations in order to reduce harm through contributions to screening, risk stratification, and diagnosis.

Conclusions: Question: Is the association between HLA-B*58:01 and allopurinol-SCAR generalizable to admixed populations in the US or are additional HLA associations involved?Findings: In this HLA association study with 16 patients of primarily self-identified Black race of adjudicated allopurinol-induced SJS/TEN or DRESS, we demonstrate a strong association with the established risk allele, HLA-B*58:01, and, for the first time, identified HLA-A*34:02 as an additional independent risk factor.Meaning: HLA-B*58:01 is absent in more than one-third of our US cohort of allopurinol-SCAR cases suggesting that more comprehensive screening and diagnostic approaches are necessary to prevent additional cases in genetically heterogenous populations.