ERAP1 genetic variations associated with HLA-B27 interaction and disease severity of syndesmophytes formation in Taiwanese ankylosing spondylitis

INTRODUCTION: Ankylosing spondylitis (AS) is a familial, heritable disease specified by syndesmophyte formation leading to an ankylosed spine. Endoplasmic reticulum aminopeptidase 1 (ERAP1) genetic variations have been widely proved to be associated with AS in several ethnic populations. The aim of this study was to investigate whether ERAP1 single nucleotide polymorphisms (SNPs) are associated with AS susceptibility and disease severity in Taiwanese. METHODS: Four ERAP1 SNPs (rs27037, rs27980, rs27044 and rs30187) were genotyped in 797 Taiwanese AS patients and 1,150 healthy controls. Distributions of genotype and alleles were compared between AS patients and healthy controls, and among AS patients stratified by clinical parameters. RESULTS: The SNP rs27037T allele appeared to be a risk factor for AS susceptibility (P = 5.5 × 10(-5), OR 1.30, 95% CI: 1.15 to 1.48; GT+TT vs. GG P = 9.3 × 10(-5), OR 1.49, 95% CI: 1.22 to 1.82). In addition, the coding SNP (cSNP) rs27044G allele (P = 1.5 × 10(-4), OR 1.28, 95% CI: 1.13 to 1.46; CG+GG vs. CC, P = 1.7 × 10(-3), OR 1.44, 95% CI: 1.15 to 1.81) and the cSNP rs30187T allele (P = 1.7 × 10(-3), OR 1.23, 95% CI: 1.08 to 1.40; CT+TT vs. CC P = 6.1 × 10(-3), OR 1.38, 95% CI: 1.10 to 1.74) were predisposing factors for AS. Notably, the rs27044G allele carriers (CG+GG vs. CC, P = 0.015, OR 1.59, 95% CI: 1.33 to 2.30) and rs30187T allele carriers (CT+TT vs. CC, P = 0.011, OR 1.63, 95% CI: 1.12 to 2.38) were susceptible to syndesmophyte formation in AS patients. Furthermore, two cSNPs (rs27044 and rs30187) strongly associated with HLA-B27 positivity in AS patients. Finally, the ERAP1 SNP haplotype TCG (rs27037T/rs27980C/rs27044G) is a major risk factor for AS (adjusted P <0.00001, OR 1.38, 95% CI: 1.12 to 1.58) in Taiwanese. CONCLUSIONS: This study provides the first evidence of ERAP1 SNPs involving syndesmophyte formation. The interactions between ERAP1 SNPs and HLA-B27 play critical roles in pMHC I pathway processing contributing to the pathogenesis of AS in multiple populations.