Genetic variants in TLR1, TIRAP and PSAPL1 are enriched in a specific subgroup of adult atopic dermatitis showing persistent skin manifestation on the face and neck area

Atopic dermatitis (AD) is a multifactorial disease, and the heterogeneity of clinical characteristics in AD might be partly based on difference in genetic factors. In this study, we focused on a clinically-characteristic AD subgroup and investigated genetic variants enriched in the subgroup. We named the subgroup as face and neck type adult AD (FNaAD) based on the tendency of skin eruptions on the face and neck to persist even after standard AD treatment. Among 94 AD patients who regularly visited our clinic,18 patients screened positive for FNaAD. By using genomic DNA of FNaAD patients, we performed target re-sequencing of 648 genes known to be associated with AD, skin barrier, inflammation, and innate immune responses. The allele frequency comparison with Japanese controls (n = 1,208) from the Human Genetic Variation Database indicated 12 variants as candidates. Further multivariate analysis using genotypes of these 12 variants in FNaAD and other AD patients revealed that 3 variants in Toll like receptor 1 (TLR1), Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), and prosaposin like 1 (PSAPL1) were significantly enriched in the 18 FNaAD patients (p < 0.003). TLR1 and TIRAP are known as members of the TLR pathway that play an important role in innate immune responses. PSAPL1 is an uncharacterized protein specially expressed in the epidermis. Among the 3 variants, the TLR1 p.L144P variant was isolated in 6 FNaAD patients (33.3%) while p.L144P is non-common variant in the Japanese population (minor allele frequency: 0.038), which is excluded from targets in a conventional genome-wide association study. Altogether, we identified 3 enriched variants in a specific AD subgroup by using a combination approach of clinical subgrouping and screening for genetic variants which would enable to detect even non-common variants associated with AD subgroups.