Genetic Association with ERAP1 in Psoriasis Is Confined to Disease Onset after Puberty and Not Dependent on HLA-C*06

HLA-C remains the strongest susceptibility candidate gene in psoriasis. Evidence for interaction between HLA-C and endoplasmic reticulum aminopeptidase 1 (ERAP1) confined to individuals carrying the HLA-C risk allele was recently reported. Psoriasis displays wide variation, and genetic heterogeneity is likely to contribute to clinical diversity. Age at disease onset is a putative discriminator, and separating psoriasis into early- (<40 years) and late-onset disease has been useful. To sharpen the age-dependent phenotype, we compared genotypes for ERAP1 (rs26653, rs30187, and rs27524) and HLA-C*06:02 in healthy controls and cases stratified for onset of psoriasis at <10, 10–20, 20–40, and >40 years of age. This approach revealed that association with ERAP1 was confined to cases with onset between 10 and 20 years (odds ratio 1.59, 95% confidence interval: 1.28–1.98, P=0.00008) and no association was detected in cases with onset below 10 years, reflecting genetic heterogeneity within the childhood psoriasis population. In contrast to earlier findings, association with ERAP1 was neither dependent on nor interacting with HLA-C*06:02. ERAP1 single-nucleotide polymorphism rs26653, which, to our knowledge, has not previously been reported in psoriasis, is nonsynonymous, has suggestive functional consequences, and herein displays strong association with disease.