Investigation of the Predisposing Factor of Pemphigus and its clinical subtype through a Genome-wide association and next generation sequence analysis.

Background Pemphigus is an autoimmune blistering disease with pemphigus vulgaris (PV) and foliaceus (PF) as the two major histological subtypes. Associations with HLA molecules have been suggested, but specific HLA risk variants as well as non-HLA risk variants remain to be discovered. Methods We performed a two-stage genome-wide association study in the Chinese Han population through a genome-wide discovery analysis and follow-up validation analysis in a total number of 210 PV, 159 PF and 2493 healthy controls. HLA imputation as well as high coverage next generation sequencing based HLA genotyping was employed to investigate the association of classical HLA alleles and amino acid change. Results We have discovered independent novel associations with PF at rs2178077 on 12q24.33, located next to RAN (P-PF = 1.57 x 10(-9)) and rs3888722 within the MHC region (P = 6.73 x 10(-9)). For the HLA variants, we confirmed independent genome-wide level risk associations in HLA-DQB1 and HLA-DRB1, with DQB1*05:03 to be the strongest association with PV (P = 8.59 x 10(-68), OR = 31.16) and PF (P = 4.84 x 10(-17), OR = 5.64). In addition, DRB1*14 was demonstrated to be a second independent variants (P = 4.2 x 10(-63), OR = 35.47) for PV, while DRB1*04:06 was demonstrated to be the second independent signal (P = 7.44 x 10(-13), OR = 5.58) for PF. Conclusions These findings advance our understanding of the genetic basis of pemphigus susceptibility and may offer opportunities for risk prediction and preventive treatment for pemphigus, in particular for PV.