Subtype-specific inherited predisposition to pemphigus in the Chinese population

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.

To identify common and specific nongenetic and genetic factors associated with pemphigus and its subtypes in the Chinese population.

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.

A sex preference was observed only in PV (57·5% female) and not in PF (47·1% female). For male patients only, the mean age at diagnosis was significantly lower for PV than for PF (P < 0·001). The strongest associated single-nucleotide polymorphisms are in the human leucocyte antigen (HLA) region: rs70993900 (PV; P = 1·5 × 10^-45 ) and rs9469220 (PF; P = 1·1 × 10^-8 ). HLA-DQB1*05:03 ranks at the top (P = 4·7 × 10^-40 ; odds ratio 12·4) in both subtypes, with significantly different risk allele frequency (RAF_PV = 34·2% vs. RAF_PF = 18·8% vs. RAF_control = 4·4%), 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.

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.