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.