Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Abstract

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Figure 1

Association findings for the ERAP1 SNP rs30187 stratified by the HLA-B27 tag SNP rs4349859. rs4349859 allele A tags HLA-B27. Error bars, 95% confidence intervals. Note that the ERAP1 risk allele T only increases risk in individuals carrying at least one copy of the HLA-B27 risk allele tag. The odds ratios for the genotype combinations were calculated using logistic regression in the R software package including covariates for ancestry (where appropriate). Genotypes with the low risk CC/GG genotype were set as the baseline, and the other genotype combinations were coded according to a series of dichotomous indicator variables. Odds ratios were derived by exponentiating the relevant coefficient from the logistic regression.

Figure 2

The mean rate of trimming of N-terminal tryptophan (mol, substrate/mol, enzyme/sec) from 10-mer peptide WRVYEKCALK by wild-type ERAP1 and variants associated with ankylosing spondylitis (rs30187 (p.Lys528Arg), rs17482078 (p.Arg725Gln) and rs10050860 (p.Asp575Asn)). WT, wild type. Circles represent results for wild-type genotype samples, squares represent results for rs30187, upright triangles represent results for rs17482078 and inverted triangles refer to results for rs10050860.