A Large-Scale, Stratified Genetic Analysis of the Major Histocompatibility Complex Region in Early- and Late-Onset Psoriasis in China

BACKGROUND: Psoriasis vulgaris is a chronic inflammatory skin disease which occur at any age. It can be clinically classified into two age-onset subtypes: early-onset psoriasis (EOP; <40 years) and late-onset psoriasis (LOP; ≥40 years). More evidence showed EOP and LOP have different genetic architecture, notably the risk allele human leukocyte antigen (HLA)-C(*)06:02 located within the major histocompatibility complex (MHC) region, which was reported to be the outstanding variant associated with EOP. However, genetic structure of EOP and LOP have not been fully elucidated. OBJECTIVE: To investigated HLA genetic heterogeneity between EOP and LOP in China. METHODS: We first calculated the MHC-based heritability of EOP and LOP respectively. Then, we conducted a large-scale, stratified analysis including 7,097 EOP, 1,337 LOP patients, and 9,906 healthy controls by using MHC target sequencing data from a previous study. RESULTS: We observed that HLA alleles collectively explained a larger heritability of EOP (27.4%) than LOP (11.3%). Further association analysis identified three independent loci (HLA-C(*)01:02, p=6.70×10(−8); HLA-A amino acid position 9, p=3.27×10(−17); and HLA-A amino acid position 161, p=5.75×10(−10)) that confer specific susceptibility to EOP. Our data also confirmed HLA-C(*)06:02 as an independent psoriasis-associated variant, contributing a higher degree of risk to EOP than LOP. Moreover, case-case analysis confirmed that HLA-C(*)06:02-positive psoriasis patients have earlier onset. CONCLUSION: Our analysis indicating that different genetic background underlie the EOP and LOP. We believe these findings will serve to predict psoriasis risk in the future and facilitate clinical decision.