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Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. We have reported that the main causative drugs for SJS/TEN with severe ocular complications (SOC) were cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs (NSAIDs). Moreover, we also reported that acetaminophen is the most frequent causative drug in various cold medicines. In this study, we focused on acetaminophen-related SJS/TEN with SOC and analyzed  HLA-class II (HLA-DRB1, DQB1)  in addition to  HLA-class I (HLA-A, B, C) . We studied the histocompatibility antigen genes  HLA-DRB1  and  DQB1  in addition to  HLA-A, B , and  C  in 80 Japanese patients with acetaminophen-related SJS/TEN with SOC. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO) using commercial bead-based typing kits. We also used genotyped data from 113 healthy volunteers for  HLA-DRB1  and  DQB1 , and 639 healthy volunteers for  HLA-A, B, and C .  HLA-DRB1*08:03  and  DRB1*12:02  were associated with acetaminophen-related SJS/TEN with SOC, although the results ceased to be significant when we corrected the  p -value for the number of alleles detected.  HLA-A*02:06  was strongly associated with acetaminophen-related SJS/TEN with SOC (carrier frequency:  p  = 4.7 × 10 −12 , Pc = 6.6 × 10 −11 , OR = 6.0; gene frequency:  p  = 8.0 × 10 −13 , Pc = 1.1 × 10 −11 , OR = 4.9).  HLA-B*13:01  (carrier frequency:  p  = 2.0 × 10 −3 , Pc = 0.042, OR = 4.1; gene frequency:  p  = 2.2 × 10 −3 , Pc = 0.047, OR = 3.9) , HLA-B*44:03  (carrier frequency:  p  = 2.1 × 10 −3 , Pc = 0.045, OR = 2.4) and  HLA-C*14:03  (carrier frequency:  p  = 3.4 × 10 −3 , Pc = 0.045, OR = 2.3) were also significantly associated, while  HLA-A*24:02  was inversely associated (gene frequency:  p  = 6.3 × 10 −4 , Pc = 8.8 × 10 −3 , OR = 0.5). Acetaminophen-related SJS/TEN with SOC was not associated with  HLA-class II (HLA-DRB1, DQB1) . However, for acetaminophen-related SJS/TEN with SOC, we found an association with  HLA-B*13:01  and  HLA- C*14:03  in addition to  HLA-A*02:06  and  HLA-B*44:03 , which have been described previously.

human genome variation

Association of HLA class I and II gene polymorphisms with acetaminophen-related Stevens–Johnson syndrome with severe ocular complications in Japanese individuals