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. GGP= 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. CCP= 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 (adjustedP<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.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.

Gout is a common metabolic disorder characterized by hyperuricemia and chronic inflammation. Previous studies show that hyperuricemia accelerates the occurrence and worsening of cardiovascular disease due to LV remodeling. However, it is still unclear whether hyperuricemia is the sole contributor to organic heart remodeling in patients with gout. In addition, there is a paucity of data regarding the association between LV diastolic function and gout. The objective of this study was to investigate the effects of gout on LV diastolic function. A total of 173 patients were divided into tertiles based on the following serum uric acid (UA) levels: 1) serum UA ≤ 6.5 mg/dL (n = 54), 2) serum UA >6.5 to ≤8.5 mg/dL (n = 59), and 3) serum UA > 8.5 mg/dL (n = 60).Patients underwent a comprehensive Doppler-echocardiography examination to evaluate LV volume, systolic and diastolic function, and left atrial (LA) volume. LV diastolic parameters, including diastolic peak early transmitral flow velocity (E), late transmitral flow velocity (A), E/A, peak early diastolic mitral annular velocity (Em), late diastolic annular velocity (Am), Em/Am, E/Em, maximal LA volume index (LAVi) and prevalence of moderate to severe LV diastolic dysfunction were not significantly different between the three groups. Among the population being studied, 108 individuals received a gout diagnosis. Gout patients had greater LV end-systolic dimensions (27.08 ± 4.38 mm, p = 0.006), higher LV mass index (107.18 ± 29.51 g/m2, p < 0.001), higher E/Em (10.07 ± 2.91, p = 0.008), and larger maximal LAVi (16.96 ± 7.39 mL/m2, p < 0.001) than patients without gout. The prevalence of moderate to severe LV diastolic dysfunction was higher in patients with gout (23 %, p = 0.02). Gout, not hyperuricemia alone, is associated with LV diastolic dysfunction and LA volume enlargement.

MICA (major histocompatibility complex class I chain-related gene A) interacts with NKG2D on immune cells to regulate host immune responses. We aimed to determine whether MICA alleles are associated with AS susceptibility in Taiwanese. MICA alleles were determined through haplotype analyses of major MICA coding SNP (cSNP) data from 895 AS patients and 896 normal healthy controls in Taiwan. The distributions of MICA alleles were compared between AS patients and normal healthy controls and among AS patients, stratified by clinical characteristics. ELISA was used to determine soluble MICA (sMICA) levels in serum of AS patients and healthy controls. Stable cell lines expressing four major MICA alleles (MICA*002, MICA*008, MICA*010 and MICA*019) in Taiwanese were used for biological analyses. We found that MICA*019 is the only major MICA allele significantly associated with AS susceptibility (P_FDR = 2.25 × 10⁻¹¹⁵; OR, 14.90; 95% CI, 11.83–18.77) in Taiwanese. In addition, the MICA*019 allele is associated with syndesmophyte formation (P_FDR = 0.0017; OR, 1.69; 95% CI, 1.29–2.22) and HLA-B27 positivity (P_FDR = 1.45 × 10⁻³³; OR, 28.79; 95% CI, 16.83–49.26) in AS patients. Serum sMICA levels were significantly increased in AS patients as compared to healthy controls. Additionally, MICA*019 homozygous subjects produced the highest levels of sMICA, compared to donors with other genotypes. Furthermore, in vitro experiments revealed that cells expressing MICA*019 produced the highest level of sMICA, as compared to other major MICA alleles. In summary, the MICA*019 allele, producing the highest levels of sMICA, is a significant risk factor for AS and syndesmophyte formation in Taiwanese. Our data indicate that a high level of sMICA is a biomarker for AS.

Background/Purpose: The intergenic SNP rs10865331 at 2p15 was identified as a major risk factor for ankylosing spondylitis (AS) susceptibility in genome-wide association studies (GWAS). B3GNT2 gene regulates polylactosamine synthesis is potentially functionally relevant to AS disease development. We investigated whether SNP rs10865331 and two B3GNT2 SNPs (rs11900673 and rs1136151) are associated with AS susceptibility and disease severity in Taiwanese. Methods: Distributions of genotypes, alleles, and haplotypes of three SNPs were compared between 1,472 AS patients and 2,117 healthy blood donors and among AS patients stratified by clinical characteristics. Results: The intergenic SNP rs10865331 was significantly associated with AS (PFDR = 1.02E-05) in Taiwanese. In AS patients stratified by positivity of HLA-B27 and syndesmophyte formation, all three B3GNT2 locus SNPs (rs11900673, rs1136151, and rs10865331) were significantly associated with syndesmophyte formation among HLA-B27 positive AS patients. Haplotype analyses revealed that the "CTA " (rs11900673C/rs1136151T/rs10865331A) haplotype was significantly associated with AS susceptibility (Padj = 0.0177) and syndesmophyte formation (Padj = 0.016) in HLA-B27 positive patients. In contrast, "TCG " (rs11900673T/rs1136151C/ rs10865331G) haplotype showed protection against AS development (Padj = 0.0005 for HLAB27 positive and Padj = 0.004 for HLA-B27 negative, respectively) and syndesmophyte formation (Padj = 0.0017) in HLA-B27 positive patients. Furthermore, B3GNT2 mRNA expressions were negatively associated with erythrocyte sedimentation rate (ESR, P = 0.0103), C-reactive protein (CRP, P = 0.0353), Bath ankylosing spondylitis functional index (BASFI, P = 0.0171), and syndesmophyte formation (P = 0.0148). Conclusion: Our data suggest that B3GNT2 gene may contribute to AS development and affect AS severity by interacting with HLA-B27 in Taiwanese.Copyright (c) 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC.