Impact of HLA-B*58:01 allele and allopurinol-induced cutaneous adverse drug reactions: evidence from 21 pharmacogenetic studies

Abstract

Allopurinol is widely used for hyperuricemia and gouty arthritis, but is associated with cutaneous adverse drug reactions (CADRs). Recently, HLA-B*58:01 allele was identified as a strong genetic marker for allopurinol-induced CADRs in Han Chinese. However, the magnitude of association and diagnosis value of HLA-B*58:01 in allopurinol-induced CADRs remain inconclusive. To investigate this inconsistency, we conducted a meta-analysis of 21 pharmacogenetic studies, including 551 patients with allopurinol-induced CADRs, and 2,370 allopurinol-tolerant controls as well as 9,592 healthy volunteers. The summary OR for allopurinol-induced CADRs among HLA-B*58:01 carriers was 82.77 (95% CI: 41.63 – 164.58, P < 10⁻⁵) and 100.87 (95% CI: 63.91 – 159.21, P < 10⁻⁵) in matched and population based studies, respectively. Significant results were also observed when stratified by outcomes and ethnicity. Furthermore, the summary estimates for quantitative analysis of HLA-B*58:01 allele carriers in allopurinol-induced CADRs screening were as follows: sensitivity, 0.93 (95% CI: 0.85 – 0.97); specificity, 0.89 (95% CI: 0.87 – 0.91); positive likelihood ratio, 8.24 (95% CI: 6.92 – 9.81); negative likelihood ratio, 0.084 (95% CI: 0.039 – 0.179); and diagnostic odds ratio, 98.59 (95% CI: 43.31 – 224.41). The AUSROC was 0.92 (95% CI: 0.89–0.94), indicating the high diagnostic performance. Our results indicated that allopurinol–SCAR is strongly associated with HLA-B*58:01, and HLA-B*58:01 is a highly specific and effective genetic marker for the detection allopurinol-induced CADRs, especially for Asian descents.