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.
Arthritis Res Ther. 2012 May 25;14(3):R125. doi: 10.1186/ar3855.
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.
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.
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.
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.
强直性脊柱炎（AS）是一种家族遗传性疾病，其特征为骨桥形成导致脊柱强直。内质网氨肽酶 1（ERAP1）的遗传变异已被广泛证明与多个种族的 AS 相关。本研究旨在探讨 ERAP1 单核苷酸多态性（SNPs）是否与台湾地区 AS 的易感性和疾病严重程度相关。
对 797 例台湾地区 AS 患者和 1150 例健康对照者进行了 4 个 ERAP1 SNPs（rs27037、rs27980、rs27044 和 rs30187）的基因分型。比较了 AS 患者与健康对照组之间，以及 AS 患者按临床参数分层的基因型和等位基因分布。
SNP rs27037T 等位基因似乎是 AS 易感性的危险因素（P=5.5×10-5，OR 1.30，95%CI：1.15-1.48；GT+TT 与 GG 相比，P=9.3×10-5，OR 1.49，95%CI：1.22-1.82）。此外，编码 SNP（cSNP）rs27044G 等位基因（P=1.5×10-4，OR 1.28，95%CI：1.13-1.46；CG+GG 与 CC 相比，P=1.7×10-3，OR 1.44，95%CI：1.15-1.81）和 cSNP rs30187T 等位基因（P=1.7×10-3，OR 1.23，95%CI：1.08-1.40；CT+TT 与 CC 相比，P=6.1×10-3，OR 1.38，95%CI：1.10-1.74）是 AS 的易感因素。值得注意的是，rs27044G 等位基因携带者（CG+GG 与 CC 相比，P=0.015，OR 1.59，95%CI：1.33-2.30）和 rs30187T 等位基因携带者（CT+TT 与 CC 相比，P=0.011，OR 1.63，95%CI：1.12-2.38）易发生 AS 的骨桥形成。此外，两个 cSNP（rs27044 和 rs30187）与 AS 患者的 HLA-B27 阳性密切相关。最后，ERAP1 SNP 单体型 TCG（rs27037T/rs27980C/rs27044G）是台湾地区 AS 的主要危险因素（调整后 P<0.00001，OR 1.38，95%CI：1.12-1.58）。
本研究首次提供了 ERAP1 SNPs 参与骨桥形成的证据。ERAP1 SNPs 与 HLA-B27 的相互作用在 pMHC I 通路加工中起关键作用，导致多种人群中 AS 的发病机制。
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