Cold medicine-related Stevens–Johnson syndrome/toxic epidermal necrolysis with severe ocular complications–phenotypes and genetic predispositions

Stevens–Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, such as the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called toxic epidermal necrolysis (TEN). Severe ocular complications (SOCs) appear in some–but not all–SJS/TEN patients who are diagnosed by dermatologists, and cold medicines including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs are the main causative drugs particularly for SJS/TEN with SOCs and all SJS and TEN. In this review, we focus on the genetic predisposition of cold medicine-related SJS/TEN (CM-SJS/TEN) with SOCs. CM-SJS/TEN with SOCs was strongly associated with HLA-A*02:06 and significantly associated with HLA-B*44:03 in Japanese individuals, significantly associated with HLA-B*44:03 in Indian and Brazilian individuals, and associated with HLA-A*02:06 in Korean individuals. In the first genome-wide association study (GWAS), we found an association between the prostaglandin E receptor 3 (PTGER3) gene and SJS/TEN with SOCs. In this study, we focused on CM-SJS/TEN with SOCs and found that the association of CM-SJS/TEN with SOCs became stronger than all SJS/TEN with SOCs. In the second GWAS, we found an association between the IKZF1 gene and CM-SJS/TEN with SOCs not only in Japanese, but also in Korean and Indian populations. Moreover, we found that TSHZ2 gene single nucleotide polymorphisms (SNPs) also showed especially low p values in the Japanese population; however, this association was not found in the Korean population. Furthermore, we investigated the interaction between susceptibility genes, and found multiplicative interactions of HLA-A*02:06 and TLR3 SNPs and additive interactions of HLA-A*02:06 and PTGER3 SNPs.