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

Arthritis Rheum. 2009 May;60(5):1317-23. doi: 10.1002/art.24467.

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 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.

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=7x10(-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=9x10(-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ATP Binding Cassette Transporter, Subfamily B, Member 3
  • ATP-Binding Cassette Transporters / genetics
  • Aminopeptidases / genetics*
  • Canada
  • Genetic Predisposition to Disease / genetics*
  • Haplotypes
  • Humans
  • Minor Histocompatibility Antigens
  • Multienzyme Complexes / genetics
  • Polymorphism, Single Nucleotide
  • Proteasome Endopeptidase Complex
  • Spondylitis, Ankylosing / genetics*
  • White People

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ATP Binding Cassette Transporter, Subfamily B, Member 3
  • ATP-Binding Cassette Transporters
  • Minor Histocompatibility Antigens
  • Multienzyme Complexes
  • TAP1 protein, human
  • TAP2 protein, human
  • Aminopeptidases
  • ERAP1 protein, human
  • LMP7 protein
  • Proteasome Endopeptidase Complex