Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis

Abstract

Objective. Alterations 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 singlenucleotide 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.Methods. The 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.Results. A 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.Conclusion. These 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.

Genetics in Ankylosing Spondylitis – Beyond HLA-B*27

“…The Wellcome Trust CaseControl consortium and Australo-Anglo-American Spondyloarthritis Consortium first described the association of five ERAP1 single nucleotide polymorphisms (SNPs) and AS (Consortium WTCCC/TASC, 2007), namely rs27044, rs17482078, rs10050860, rs30187 and rs2287987. Two of these SNPs, rs27044 and rs30187, gathered more consistent results in the subsequent reports and were the only markers that showed significant association both in Caucasian and in Han Chinese groups (Choi, et al, 2010;Harvey, et al, 2009a;Maksymowych, W. P., et al, 2009;Pazar, et al, 2010;Pimentel-Santos, et al, 2009). The significant relation between rs27044 and AS was not confirmed in Canadian, contrarily to all other replicates involving this SNP and Caucasian groups.…”

“…Since the confirmed association between ERAP1 and AS reported in 2007 (Consortium WTCCC/TASC, 2007), some replications occurred in studies involving Caucasian (Consortium TASC, 2010;Harvey, et al, 2009a;Maksymowych, W. P., et al, 2009;Pazar, et al, 2010;Pimentel-Santos, et al, 2009;Tsui, F. W., et al, 2010) and Han Chinese cohorts (Bang, et al, 2011;Choi, et al, 2010;Davidson, et al, 2009). The Wellcome Trust CaseControl consortium and Australo-Anglo-American Spondyloarthritis Consortium first described the association of five ERAP1 single nucleotide polymorphisms (SNPs) and AS (Consortium WTCCC/TASC, 2007), namely rs27044, rs17482078, rs10050860, rs30187 and rs2287987.…”

ERAP1 Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis

“…Such associations were subsequently confirmed in independent Caucasian and Asian cohorts of AS (6)(7)(8), as well as in the spondyloarthritides as a whole (9,10). Interestingly, the association between ERAP1 polymorphisms and SpA seems to be restricted to HLA-B27-positive disease (10)(11)(12).…”

Contribution of functional KIR3DL1 to ankylosing spondylitis

“…[7][8][9][10][11][12][13] Another group of genes with polymorphisms that likely contribute to AS and other HLA-B27-associated diseases is the killer immunoglobulin-like receptor (KIR) genes. 12,[14][15][16] These genes are located on chromosome region 19q13.…”