ERAP1 genetic variations associated with HLA-B27 interaction and disease severity of syndesmophytes formation in Taiwanese ankylosing spondylitis.
BACKGROUND
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.
Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, No, 5, Fu-Shin St, Kwei-Shan, Tao-Yuan, 33375 Taiwan.
Chin-Man
CM
Wang
Huei-Huang
HH
Ho
Su-Wei
SW
Chang
Yeong-Jian Jan
YJ
Wu
Jing-Chi
JC
Lin
Pi-Yueh
PY
Chang
Jianming
J
Wu
Ji-Yih
JY
Chen
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000626:Aminopeptidases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000473:pathology*; D013624:Taiwan; D055815:Young Adult
D015796:HLA-B27 Antigen; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human