Genetic variants in IRF2, STAT6, and TSLP are associated with eczema herpeticum in a European cohort of patients with atopic dermatitis

Eczema herpeticum (EH) is a disseminated severe herpes simplex virus infection that occurs in a subset of patients with atopic dermatitis (AD). EH is a complex multifactorial disease caused by immunological changes, environmental influences, and genetic aberrations. The latter is becoming increasingly apparent, and several single nucleotide polymorphisms (SNP) have been associated with triggering EH, including genes related to interferon signaling, the epidermal barrier, and Th2-mediated immunity. So far, genetic studies have not considered the severity of AD, which may have led to associations related to AD severity rather than EH. To investigate genetic risk factors for EH in a European cohort, we analyzed several SNPs of the genes STAT6, IFNG, IFNGR1, IRF2 , and TSLP in AD patients with (ADEH+) versus a carefully matched control group of AD patients consisting of 44 patients matched for age, sex, and severity of AD (SCORAD) without a history of eczema herpeticum (ADEH-) by pyrosequencing. We confirmed an association of rs2416259 ( TSLP ), rs167769 ( STAT6 ), and rs11132242 ( IRF2 ) with ADEH + in our European cohort. However, the risk alleles for rs167769 and rs11132242 were contrary to previous reports that did not take age, sex, and disease severity into account. We could not confirm an association for several loci (rs3024975 (STAT6); rs2069705, rs2069718, rs2069727, and rs2430561 (IFNG); rs3799488 and rs9376269 (IFNGR1) ; rs1342852 ( IRF2 )) previously described in other cohorts. Moreover, linkage disequilibrium (LD) analysis revealed gametic LD and epistatic effects between STAT6 , IFNGR , and IFNG genes. Better knowledge of genetic factors predisposing to eczema herpeticum may allow the early identification of patients at increased risk and disease prevention. Our study provides important clues to possible key factors in the antiviral immunity in herpes simplex virus infection and thus to potential therapeutic interventions.