AbstractObjectiveAlterations in antigen processing have been proposed to play a significant role in the pathogenesis of ankylosing spondylitis (AS). A non–major histocompatibility complex gene encoding an endoplasmic reticulum aminopeptidase, ERAP1, has been implicated recently. This study assessed 13 coding single‐nucleotide polymorphisms (SNPs) from 5 genes involved in antigen processing (ERAP1, TAP1, TAP2, LMP2, and LMP7) in 3 Canadian cohorts of patients with AS, to address the possibility of gene interactions in disease susceptibility.MethodsThe study involved 992 AS cases and 1,437 controls from 3 centers (472 cases and 451 controls from Alberta, 138 cases and 392 controls from Newfoundland, and 382 cases and 594 controls from Toronto). Most of the patients with AS and healthy, unrelated controls were Caucasians of northern European descent. Single‐marker and haplotype associations were determined using an allelic likelihood ratio test in UNPHASED, version 3.0.12, and the WHAP program, respectively. P values for significance of haplotype associations were calculated using a permutation test.ResultsA specific ERAP1 haplotype, rs27044/10050860/30187‐CCT, was strongly associated with increased risk of AS in all 3 case–control cohorts (pooled odds ratio [OR] 1.81, 95% confidence interval [95% CI] 1.46–2.24; P = 7 × 10−8), while a second specific ERAP1 haplotype, rs30187/26618/26653‐CTG, reduced the disease risk (pooled OR 0.77, 95% CI 0.67–0.88; P = 9 × 10−5). Significant associations were also noted for 3 ERAP1 SNP variants (rs10050860, rs30187, and rs26653), although no significant haplotype interaction between ERAP1 and TAP/LMP loci was evident.ConclusionThese data indicate that an AS disease locus may reside on a specific ERAP1 haplotype, and its effect is not multiplicative with contributions from TAP and LMP genes.