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

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>HLA-class II (HLA-DRB1, DQB1)</jats:italic> in addition to <jats:italic>HLA-class I (HLA-A, B, C)</jats:italic>. We studied the histocompatibility antigen genes <jats:italic>HLA-DRB1</jats:italic> and <jats:italic>DQB1</jats:italic> in addition to <jats:italic>HLA-A, B</jats:italic>, and <jats:italic>C</jats:italic> 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 <jats:italic>HLA-DRB1</jats:italic> and <jats:italic>DQB1</jats:italic>, and 639 healthy volunteers for <jats:italic>HLA-A, B, and C</jats:italic>. <jats:italic>HLA-DRB1*08:03</jats:italic> and <jats:italic>DRB1*12:02</jats:italic> were associated with acetaminophen-related SJS/TEN with SOC, although the results ceased to be significant when we corrected the <jats:italic>p</jats:italic>-value for the number of alleles detected. <jats:italic>HLA-A*02:06</jats:italic> was strongly associated with acetaminophen-related SJS/TEN with SOC (carrier frequency: <jats:italic>p</jats:italic> = 4.7 × 10<jats:sup>−12</jats:sup>, Pc = 6.6 × 10<jats:sup>−11</jats:sup>, OR = 6.0; gene frequency: <jats:italic>p</jats:italic> = 8.0 × 10<jats:sup>−13</jats:sup>, Pc = 1.1 × 10<jats:sup>−11</jats:sup>, OR = 4.9). <jats:italic>HLA-B*13:01</jats:italic> (carrier frequency: <jats:italic>p</jats:italic> = 2.0 × 10<jats:sup>−3</jats:sup>, Pc = 0.042, OR = 4.1; gene frequency: <jats:italic>p</jats:italic> = 2.2 × 10<jats:sup>−3</jats:sup>, Pc = 0.047, OR = 3.9)<jats:italic>, HLA-B*44:03</jats:italic> (carrier frequency: <jats:italic>p</jats:italic> = 2.1 × 10<jats:sup>−3</jats:sup>, Pc = 0.045, OR = 2.4) and <jats:italic>HLA-C*14:03</jats:italic> (carrier frequency: <jats:italic>p</jats:italic> = 3.4 × 10<jats:sup>−3</jats:sup>, Pc = 0.045, OR = 2.3) were also significantly associated, while <jats:italic>HLA-A*24:02</jats:italic> was inversely associated (gene frequency: <jats:italic>p</jats:italic> = 6.3 × 10<jats:sup>−4</jats:sup>, Pc = 8.8 × 10<jats:sup>−3</jats:sup>, OR = 0.5). Acetaminophen-related SJS/TEN with SOC was not associated with <jats:italic>HLA-class II (HLA-DRB1, DQB1)</jats:italic>. However, for acetaminophen-related SJS/TEN with SOC, we found an association with <jats:italic>HLA-B*13:01</jats:italic> and <jats:italic>HLA- C*14:03</jats:italic> in addition to <jats:italic>HLA-A*02:06</jats:italic> and <jats:italic>HLA-B*44:03</jats:italic>, which have been described previously.</jats:p>