Subtype-Specific Inherited Predisposition To Pemphigus In The Chinese Population

Background Pemphigus is a group of rare life-threatening mucocutaneous autoimmune diseases, presenting mainly as two subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited predispositions to pemphigus have long been speculated but they remain poorly understood. Objectives To identify common and specific nongenetic and genetic factors associated with pemphigus and its subtypes in the Chinese population. Methods A genome-wide association study (GWAS) was performed in 496 unrelated patients with pemphigus (including 365 with PV and 104 with PF) and 1105 controls without pemphigus. Results A sex preference was observed only in PV (57 center dot 5% female) and not in PF (47 center dot 1% female). For male patients only, the mean age at diagnosis was significantly lower for PV than for PF (P < 0 center dot 001). The strongest associated single-nucleotide polymorphisms are in the human leucocyte antigen (HLA) region: rs70993900 (PV; P = 1 center dot 5 x 10(-45)) and rs9469220 (PF; P = 1 center dot 1 x 10(-8)). HLA-DQB1*05:03 ranks at the top (P = 4 center dot 7 x 10(-40); odds ratio 12 center dot 4) in both subtypes, with significantly different risk allele frequency (RAF(PV) = 34 center dot 2% vs. RAF(PF) = 18 center dot 8% vs. RAF(control) = 4 center dot 4%), whereas HLA-DRB1*14:01 and HLA-DRB1*04:06 are PV specific. HLA-DQB1*03:03 and HLA-DQB1*03:02 show significant subtype specificity in opposite directions. All of these associations were validated in the replication series with 147 cases of pemphigus and 604 controls. Multiple novel non-HLA susceptibility loci were also identified in the GWAS. Conclusions This study represents the largest GWAS on pemphigus in the Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus.