Free
Genetics  |   December 2014
FoxO1 Gene Confers Genetic Predisposition to Acute Anterior Uveitis With Ankylosing Spondylitis
Author Affiliations & Notes
  • Hongsong Yu
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Yunjia Liu
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Lijun Zhang
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Lili Wu
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Minming Zheng
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Ling Cheng
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Le Luo
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Aize Kijlstra
    University Eye Clinic Maastricht, Maastricht, The Netherlands
  • Peizeng Yang
    The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, Peoples Republic of China
  • Correspondence: Peizeng Yang, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P.R. China, 400016; peizengycmu@126.com 
Investigative Ophthalmology & Visual Science December 2014, Vol.55, 7970-7974. doi:10.1167/iovs.14-15460
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Hongsong Yu, Yunjia Liu, Lijun Zhang, Lili Wu, Minming Zheng, Ling Cheng, Le Luo, Aize Kijlstra, Peizeng Yang; FoxO1 Gene Confers Genetic Predisposition to Acute Anterior Uveitis With Ankylosing Spondylitis. Invest. Ophthalmol. Vis. Sci. 2014;55(12):7970-7974. doi: 10.1167/iovs.14-15460.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose.: Recent studies have shown that a decrease of regulatory T (Treg) cells may contribute to the activity of acute anterior uveitis (AAU) and ankylosing spondylitis (AS). A number of immunogenetic factors including IL2RA, miR-27a, miR-182, and FoxO1 are associated with Treg cell function. In this study, we investigated the association between polymorphisms of these genes and AAU with or without AS in a Chinese Han population.

Methods.: Using PCR-restricted fragment length polymorphism (RFLP) assay, a two-stage association study was performed in 680 AAU patients with or without AS and 1280 controls. Gene expression was quantified by real-time PCR.

Results.: In the first stage study, an association analysis of 10 single nucleotide polymorphisms (SNPs) was performed in 230 AAU patients with AS, 240 AAU patients without AS, and 650 controls. The results showed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU patients with AS (AA genotype: P = 6.23 × 10−5, odds ratio [OR] = 1.86; A allele: P = 2.17 × 10−4, OR = 1.53). No significant association of the other 9 SNPs with AAU with or without AS was observed. In the second stage study, an association analysis of FoxO1/rs2297626 was performed in 210 AAU patients with AS and 630 controls. The second stage and combined studies confirmed the association of FoxO1/rs2297626 with AAU with AS (AA genotype: P = 3.45 × 10−8, OR = 1.85; A allele: P = 1.55 × 10−7, OR = 1.55).

Conclusion.: This study suggests that FoxO1, but not miR-27a, miR-182, and IL2RA, contributes to the genetic susceptibility of AAU with AS, but none of the tested polymorphisms confer risk to AAU without AS.

Introduction
Acute anterior uveitis (AAU) is one of the most common uveitis entities in the world.1 The development of AAU may result in vision loss secondary to complicated cataract and glaucoma.2 Previous reports have shown that 52% to 88% of patients with AAU are HLA-B27–positive according to different racial groups.36 Besides, ankylosing spondylitis (AS) also is strongly associated with HLA-B27–positive AAU.7,8 Recent studies have revealed that the concentration of regulatory T (Treg) cells inversely correlates with disease activity in HLA-B27–positive AAU and AS.9,10 Moreover, recent surveys have shown that TLR2, TLR4, TNF, and TRAF5 confer risk of AAU,1113 and that IL-1A, ERAP1, IL-23R, ANTXR2, IL1R2, EDIL3, HAPLN1, and ANO6 polymorphisms are associated with AS.1418 These reports suggest that genetic factors besides the well-known HLA-B27 association may have an important role in both diseases. 
The Treg cells are critical to the maintenance of immune cell homeostasis by negatively controlling a variety of physiological and pathological immune responses. Recent studies showed that the transcription factor forkhead-box O1 (FoxO1) has a key role in Treg cell function and may be involved in Treg-cell–associated immunological disorders.19,20 The MiR-182, miR-27a, and miR-96 can reversely regulate FoxO1 expression by binding to its 3′ untranslated region.21,22 Meanwhile, IL-2 receptor-α (IL2RA) has been identified to be responsible to induce miR-182.2224 Recently, polymorphisms of the genes regulating Treg function, such as IL2RA, miR-182, and miR-27a, have been considered as genetic predisposing factors involved in various immune diseases.2530 To our knowledge, no reports have appeared concerning the role of FoxO1 gene polymorphisms and autoimmune-related diseases. 
In view of the fact that these genes mentioned above have an important role in Treg cell development and function, we investigated whether polymorphisms of these genes were possibly associated with AAU with or without AS. Our results showed that FoxO1, but not miR-27a, miR-182, and IL2RA, contribute to the genetic susceptibility of AAU with AS, but none of the tested polymorphisms confer risk to AAU without AS. 
Materials and Methods
Subjects
The study group consisted of 680 unselected, consecutive patients (440 AAU patients with AS and 240 AAU patients without AS) who were recruited from the department of ophthalmology in the First Affiliated Hospital of Chongqing Medical University (Chongqing, China) and the Zhongshan Ophthalmic Center of the Sun Yat-sen University (Guangzhou, China) between October 2006 and May 2014. A total of 1280 unselected, consecutive control subjects was matched geographically and ethnically with the patients. The AAU was diagnosed, as described by Jabs et al.,31 as the presence of inflammatory cells in the anterior chamber and dust-like keratic precipitates (KPs) with flare, iridocyclitis, or iritis with a duration of less than 3 months. The AAU patients with other HLA-B27–associated diseases, such as inflammatory bowel disease, Reiter's syndrome, and psoriatic arthritis, were excluded from this study. The diagnosis of AS was based strictly on the modified New York Criteria for radiological sacroiliitis.32 The study received the approval of the Local Ethics Research Committee (Permit Number 2009-201008), and all the tested subjects provided informed consent before blood collection. All procedures of this study followed the tenets of the Declaration of Helsinki. 
DNA Extraction and Genotyping
Genomic DNA extraction of AAU patients and healthy controls was conducted using the QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA). The target DNA sequence was amplified by the PCR using proper primers as described previously.33 The PCR products were digested with 3 units of restriction enzymes, such as PdiI, DraIII, AluI, Eco47I, BshNI, HindIII, TscAI, NdeI, BsmAI, BstNI (Fermentas, Shenzhen, China), and RsaI (Promega, Madison, WI, USA), in a 10 μL reaction volume for 14 hours. Digestion products were visualized on 3% or 4% agarose gels and stained with GoldView (SBS Genetech, Beijing, China). 
Cell Isolation and Culture
Peripheral blood mononuclear cells (PBMCs) were isolated from freshly drawn blood samples by Ficoll-Hypaque (TBDScience, Tianjin, China) density gradient centrifugation. Magnetic beads (Miltenyi Biotec, Palo Alto, CA, USA) were used to isolate CD4+ T cells according to the manufacturer's protocol. Purified CD4+ T cells were treated with anti-CD3/CD28 antibodies (5:1; Miltenyi Biotec) at 37°C for 72 hours.33 
Real-Time PCR
Total RNA was extracted from CD4+ T cells and anti-CD3/CD28 antibodies-stimulated CD4+ T cells obtained from normal controls using TRIzol Reagent (Invitrogen, Carlsbad, CA, USA), followed by reverse transcription using a transcriptase kit (Applied Biosystems, ABI, Foster City, CA, USA). Real-time PCR was performed on the 7500 System (Applied Biosystems, ABI) based on the SYBR-Green method. The expression of FoxO1 and β-actin (the internal reference) was examined using the primers as described previously.33 All tests were conducted in triplicate, and relative expression levels were calculated and quantified by the 2−ΔΔCt method. 
Statistical Analysis
The χ2 test was applied to analyze the Hardy-Weinberg equilibrium (HWE). Frequencies of genotype and allele were compared between patients and controls by the χ2 test using SPSS version 17.0 (SPSS, Inc., Chicago, IL, USA). Odds ratios (OR) and 95% confidence intervals (CI) also were calculated using SPSS version 17.0 (SPSS, Inc.) to evaluate disease risk. P values were corrected for multiple comparisons with the Bonferroni correction method by multiplying with the number (40) of analyses performed, thus a P value less than 1.25 × 10−3 (0.05/40) was considered to be statistically significant. The nonparametric Mann-Whitney U test or independent samples t-test was used for comparing FoxO1 expression levels among three genotype groups. A 2-tailed P value less than 0.05 was considered to be statistically significant. 
Results
Clinical Features of AAU Patients
The detailed clinical features and demographic characteristics of the enrolled AAU patients are shown in Table 1. The distribution of genotype and allele frequencies of all the 10 SNPs investigated did not deviate from the Hardy-Weinberg equilibrium in the controls. 
Table 1
 
Clinical Features of the Investigated AAU Patients
Table 1
 
Clinical Features of the Investigated AAU Patients
Clinical Features N, Total = 680 Percentage
Mean age ± SD 39.3 ± 11.7
Male 449 66.0
Female 231 34.0
Uveitis 680 100
AAU patients with AS 440 64.7
AAU patients without AS 240 35.3
HLA-B27+ AAU+ 451 (556 tested) 81.1
HLA-B27+ AAU+ AS+ 318 (355 tested) 89.6
HLA-B27+ AAU+ AS 133 (201 tested) 66.2
HLA-B27 AAU+ 105 (556 tested) 18.9
HLA-B27 AAU+ AS+ 37 (355 tested) 10.4
HLA-B27 AAU+ AS 68 (201 tested) 33.8
Genotype and Allele Frequencies of Tested SNPs in Controls and Patients in the First Stage Study
In total, 230 AAU patients with AS, 240 AAU patients without AS, and 650 controls were genotyped for 10 SNPs of IL2RA, miR-27a, miR-182, and FoxO1 genes in the first stage study. Our results showed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU with AS patients (AA genotype: P = 6.23 × 10−5, OR = 1.86; A allele: P = 2.17 × 10−4, OR = 1.53; Table 2). However, lack of association between FoxO1/rs2297626 and AAU without AS was found, and none of the other 9 SNPs showed a significant association with AAU with or without AS (Supplementary Tables S1 and S2). Moreover, there was no significant association between the tested SNPs and HLA-B27 (Supplementary Table S3). 
Table 2
 
Main Effects of FoxO1/rs2297626 SNPs on AAU With AS Risk
Table 2
 
Main Effects of FoxO1/rs2297626 SNPs on AAU With AS Risk
Genotype AAU With AS Controls P Value OR (95% CI)
N % N %
Stage 1 N = 230 N = 650
 AA 114 49.5 225 34.6 6.23 × 10−5* 1.86 (1.37–2.52)
 AG 92 40.2 328 50.5 6.33 × 10−3 0.65 (0.48–0.89)
 GG 24 10.3 97 14.9 0.09 0.66 (0.41–1.07)
 A allele 320 69.6 778 59.8 2.17 × 10−4* 1.53 (1.22–1.93)
Stage 2 N = 210 N = 630
 AA 105 50.0 222 35.3 1.45 × 10−4* 1.84 (1.34–2.52)
 AG 85 40.3 313 49.6 0.02 0.69 (0.50–0.95)
 GG 20 9.7 95 15.1 0.04 0.59 (0.36–0.99)
 A allele 295 70.2 757 60.1 1.94 × 10−4* 1.57 (1.24–1.99)
Combined N = 440 N = 1280
 AA 219 49.8 447 34.9 3.45 × 10−8* 1.85 (1.48–2.30)
 AG 177 40.2 641 50.1 3.58 × 10−4* 0.67 (0.54–0.84)
 GG 44 10.0 192 15.0 8.55 × 10−3 0.63 (0.45–0.89)
 A allele 615 69.9 1535 60.0 1.55 × 10−7* 1.55 (1.32–1.83)
Genotype and Allele Frequencies of Tested SNPs in Controls and Patients in the Second Stage and Combined Studies
To validate the significant association between FoxO1/rs2297626 and AAU with AS found in the first stage, another 210 AAU patients with AS and 630 controls were enrolled for the second stage study. The results again revealed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU with AS (AA genotype: P = 1.45 × 10−4, OR = 1.84; A allele: P = 1.94 × 10−4, OR = 1.57; Table 2). The combined data confirmed the association between rs2297626 and AAU with AS (AA genotype: P = 3.45 × 10−8, OR = 1.85; A allele: P = 1.55 × 10−7, OR = 1.55; Table 2). 
The Influence of rs2297626 on FoxO1 Expression
The aforementioned result showed a significant association between FoxO1/rs2297626 and AAU with AS. To investigate a possible function associated with this SNP, we performed real-time PCR analysis to evaluate its effect on the expression of FoxO1 using CD4+ T cells derived from 30 healthy individuals with known genotype. The results did not reveal an effect of the various rs2297626 genotypes on FoxO1 expression (see Fig., P > 0.05). We subsequently examined whether the expression of FoxO1 was affected by the various rs2297626 genotypes in anti-CD3/CD28 antibodies-stimulated CD4+ T cells. Although the results showed a lower FoxO1 expression in the rs2297626 AA genotype compared to the GG genotype in anti-CD3/CD28 antibodies-stimulated CD4+ T cells, no statistically significant differences were found between the two groups (see Fig., P > 0.05). 
Figure
 
The influence of various rs2297626 genotypes on expression of FoxO1. Purified CD4+ T cells and anti-CD3/CD28 antibodies-stimulated CD4+ T cells from genotyped healthy controls were used (10 AA genotypes, 10 AG genotypes, and 10 GG genotypes of rs2297626).
Figure
 
The influence of various rs2297626 genotypes on expression of FoxO1. Purified CD4+ T cells and anti-CD3/CD28 antibodies-stimulated CD4+ T cells from genotyped healthy controls were used (10 AA genotypes, 10 AG genotypes, and 10 GG genotypes of rs2297626).
Discussion
In the present study, we showed that a gene polymorphism in FoxO1 confers risk to AAU in combination with AS. Other polymorphisms in genes also affecting the function of Tregs, such as miR-27a, miR-182, and IL2RA, did not contribute to the genetic susceptibility of AAU with AS. None of the investigated gene polymorphisms was associated with AAU in the absence of AS. Up to now, to our knowledge no common SNP (minor allele frequency > 0.05) has been found in miR-96, which also is a pivotal regulator of FoxO1 function and this factor, therefore, was not included in our study. 
The IL2RA, also known as CD25, has a key role in the regulation of the immune system, and is responsible for the induction of miR-182 by activating STAT5. Previous studies suggested that polymorphisms of the IL2RA gene are associated with a variety of autoimmune-related diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes.28,34,35 A recent study did not detect association between several SNPs of IL2RA (rs2104286, rs11594656, and rs12722495) and endogenous nonanterior uveitis.36 In this study, we also did not find an association between IL2RA and AAU with or without AS. This finding is in agreement with our recent study that SNPs for IL2RA (rs706778, rs3118470, rs2104286, and rs7093069) were not associated with either Behçet's disease (BD) or Vogt-Koyanagi-Harada (VKH) syndrome.33 
The MiR-182 has a pivotal role in modulating adaptive immune responses by binding to a specific site of 3′ untranslated region of FoxO1 gene.23,37,38 Earlier polymorphism analysis identified a significant association between miR-182/rs76481776 and late insomnia in major depression patients.29 Our recent study also showed that the CC genotype of miR-182/rs76481776 had a significantly decreased frequency in BD and VKH patients, and a significantly increased expression of miR-182 in rs76481776 TT/CT cases compared to CC cases in anti-CD3/CD28 antibodies-stimulated CD4+ T cells.33 However, no significant association between miR-182/rs76481776 and AAU with or without AS was found in this study. 
Also, MiR-27a can bind to 3′ untranslated region of FoxO1 and negatively regulate its expression, resulting in abnormal differentiation and function of Treg cell.21,22 Recent surveys have shown that miR-27a/ rs895819 is associated with various cancers, such as gastric cancer, renal cell cancer, and breast cancer.26,39,40 In this study, we did not find an association between miR-27a/rs895819 and AAU with or without AS, which is in agreement with our recent study that miR-27a/rs895819 was not associated with BD or VKH.33 
The FoxO1 controls the development and function of Treg cells by binding to the promoter regions of Foxp3 and CTLA-4 genes.19,20 Previous surveys suggested that SNPs of FoxO1 were not associated with type 2 diabetes.41 Our recent study also didn't find a direct association between SNPs of FoxO1 with uveitis in either BD or VKH.33 To the best of our knowledge, the association between FoxO1/rs2297626 polymorphisms and autoimmune-related diseases has not yet been reported, and as yet there are no published genome-wide association studies (GWAS) for AAU. Although there are several published GWAS for AS,17,18 including Chinese datasets, no evidence of an association between FoxO1/rs2297626 and AS was reported. In this study, our result showed that the AA genotype of FoxO1/rs2297626 was significantly increased in frequency in AAU patients with AS, whereas there was no significant association between FoxO1/rs2297626 and AAU without AS. Whether FoxO1/rs2297626 is associated with AS alone or the combination of AAU and AS is not clear and is expected to be elucidated in the future. Although a trend for a lower expression of FoxO1 was observed in rs2297626 AA cases compared to GG cases in anti-CD3/CD28 antibodies-stimulated CD4+ T cells, data did not reach statistical significance. In view of the small sample size, further studies are needed to investigate whether polymorphisms of rs2297626 can influence the expression of the FoxO1 gene. The fact that FoxO1 is critical for Treg cell function may expand our knowledge concerning the role of these cells in the pathogenesis of AAU with AS. 
Our study has a number of limitations. Firstly, as our study only recruited patients visiting an ophthalmology department, only uveitis patients were included; thus, whether the same association exists between FoxO1 gene and AS patients without uveitis deserves further study. Furthermore only, a limited number of SNPs of IL2RA and FoxO1 genes were tested in our study and it is possible that other as yet unknown SNPs also might be involved. This survey was performed in Han Chinese, and future studies are needed in other ethnic populations to confirm the results. 
Conclusions
Our results suggested that FoxO1, but not miR-27a, miR-182, and IL2RA, contributes to the genetic susceptibility to AAU with AS. Further research concerning the role of FoxO1 and the biochemical pathways that control T cell homeostasis are needed to elucidate their role in the development of AAU with AS. 
Acknowledgments
The authors thank all donors enrolled in the present study. 
Supported by Natural Science Foundation Major International (Regional) Joint Research Project (81320108009), National Basic Research Program of China (973 Program, 2011CB510200), Key Project of Natural Science Foundation (81130019), National Natural Science Foundation Project (31370893, 81200678), Basic Research Program of Chongqing (cstc2013jcyjC10001), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), National Key Clinical Specialties Construction Program of China, Key Project of Health Bureau of Chongqing (2012-1-003), and Fund for PAR-EU Scholars Program. The authors alone are responsible for the content and writing of the paper. 
Disclosure: H. Yu, None; Y. Liu, None; L. Zhang, None; L. Wu, None; M. Zheng, None; L. Cheng, None; L. Luo, None; A. Kijlstra, None; P. Yang, None 
References
Chang JH Wakefield D. Uveitis: a global perspective. Ocul Immunol Inflamm. 2002; 10: 263–279. [CrossRef] [PubMed]
Nussenblatt RB Gery I. Experimental autoimmune uveitis and its relationship to clinical ocular inflammatory disease. J Autoimmun. 1996; 9: 575–585. [CrossRef] [PubMed]
Brewerton D Caftrey M Nicholls A. Acute anterior uveitis and HLA B27. Lancet. 1973; 2: 994–996. [CrossRef]
Saari R Lahti R Saari KM Frequency of rheumatic diseases in patients with acute anterior uveitis. Scand J Rheumatol. 1982; 11: 121–123. [CrossRef] [PubMed]
Torres S Borges S Artiles A. HLA-B27 and clinical features of acute anterior uveitis in Cuba. Ocul Immunol Inflamm. 2013; 21: 119–123. [CrossRef] [PubMed]
Yang P Zhang Z Zhou H Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005; 30: 943–948. [CrossRef] [PubMed]
Beckingsale A Davis J Gibson J Rosenthal A. Acute anterior uveitis, ankylosing spondylitis, back pain, and HLA B27. Br J Ophthalmol. 1984; 68: 741–745. [CrossRef] [PubMed]
Banares A Garcia H Fernandez GB. Eye involvement in the spondyloarthropathies. Rheum Dis Clin North Am. 1998; 24: 771–784. [CrossRef] [PubMed]
Zou W Wu Z Xiang X Sun S Zhang J. The expression and significance of T helper cell subsets and regulatory T cells CD(4)(+) CD(2)(5)(+) in peripheral blood of patients with human leukocyte antigen B27-positive acute anterior uveitis. Graefes Arch Clin Exp Ophthalmol. 2014; 252: 665–672. [CrossRef] [PubMed]
Zhao SS Hu JW Wang J Lou XJ Zhou LL. Inverse correlation between CD4+ CD25high CD127low/- regulatory T-cells and serum immunoglobulin A in patients with new-onset ankylosing spondylitis. J Int Med Res. 2011; 39: 1968–1974. [CrossRef] [PubMed]
Chang JH Hampartzoumian T Everett B Lloyd A McCluskey PJ Wakefield D. Changes in Toll-like receptor (TLR)-2 and TLR4 expression and function but not polymorphisms are associated with acute anterior uveitis. Invest Ophthalmol Vis Sci. 2007; 48: 1711–1717. [CrossRef] [PubMed]
Kuo NW Lympany PA Menezo V TNF-857T, a genetic risk marker for acute anterior uveitis. Invest Ophthalmol Vis Sci. 2005; 46: 1565–1571. [CrossRef] [PubMed]
Xiang Q Chen L Fang J TNF receptor-associated factor 5 gene confers genetic predisposition to acute anterior uveitis and pediatric uveitis. Arthritis Res Ther. 2013; 15: R113. [CrossRef] [PubMed]
Maksymowych WP Rahman P Reeve JP Gladman DD Peddle L Inman RD. Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: an analysis of three Canadian populations. Arthritis Rheum. 2006; 54: 974–985. [CrossRef] [PubMed]
Davidson SI Wu X Liu Y Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum. 2009; 60: 3263–3268. [CrossRef] [PubMed]
Rahman P Inman RD Gladman DD Reeve JP Peddle L Maksymowych WP. Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis Rheum. 2008; 58: 1020–1025. [CrossRef] [PubMed]
Lin Z Bei JX Shen M A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet. 2012; 44: 73–77. [CrossRef]
Australo-Anglo-American Spondyloarthritis Consortium (TASC) Reveille JD Sims AM . Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010; 42: 123–127. [CrossRef] [PubMed]
Kerdiles YM Stone EL Beisner DR Foxo transcription factors control regulatory T cell development and function. Immunity. 2010; 33: 890–904. [CrossRef] [PubMed]
Ouyang W Liao W Luo CT Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature. 2012; 491: 554–559. [CrossRef] [PubMed]
Guttilla IK White BA. Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J Biol Chem. 2009; 284: 23204–23216. [CrossRef] [PubMed]
O'Neill LA. Outfoxing Foxo1 with miR-182. Nat Immunol. 2010; 11: 983–984. [CrossRef] [PubMed]
Stittrich AB Haftmann C Sgouroudis E The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol. 2010; 11: 1057–1062. [CrossRef] [PubMed]
Kelada S Sethupathy P Okoye IS miR-182 and miR-10a are key regulators of Treg specialisation and stability during Schistosome and Leishmania-associated inflammation. PLoS Pathogens. 2013; 9: e1003451. [CrossRef] [PubMed]
Mussig K Staiger H Machicao F Association of common genetic variation in the FOXO1 gene with beta-cell dysfunction, impaired glucose tolerance, and type 2 diabetes. J Clin Endocrinol Metab. 2009; 94: 1353–1360. [CrossRef] [PubMed]
Sun Q Gu H Zeng Y Hsa-mir-27a genetic variant contributes to gastric cancer susceptibility through affecting miR-27a and target gene expression. Cancer Sci. 2010; 101: 2241–2247. [CrossRef] [PubMed]
Klinker MW Schiller JJ Magnuson VL Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects. Immunogenetics. 2010; 62: 101–107. [CrossRef] [PubMed]
Kawasaki E Awata T Ikegami H Genetic association between the interleukin-2 receptor-alpha gene and mode of onset of type 1 diabetes in the Japanese population. J Clin Endocrinol Metab. 2009; 94: 947–952. [CrossRef] [PubMed]
Saus E Soria V Escaramis G Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Hum Mol Genet. 2010; 19: 4017–4025. [CrossRef] [PubMed]
Hinks A Cobb J Sudman M Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap. Ann Rheum Dis. 2012; 71: 1117–1121. [CrossRef] [PubMed]
Jabs DA Nussenblatt RB Rosenbaum JT. The Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005; 140: 509–516. [CrossRef] [PubMed]
Van der Linden S Valkenburg H Cast A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum. 1984; 27: 361–368. [CrossRef] [PubMed]
Yu H Liu Y Bai L Kijlstra A Yang P. Predisposition to Behcet's disease and VKH syndrome by genetic variants of miR-182. J Mol Med (Berl). 2014; 92: 961–967. [CrossRef] [PubMed]
Knevel R de Rooy DP Zhernakova A Association of variants in IL2RA with progression of joint destruction in rheumatoid arthritis. Arthritis Rheum. 2013; 65: 1684–1693. [CrossRef] [PubMed]
Schmied MC Zehetmayer S Reindl M Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients. Neurogenetics. 2012; 13: 181–187. [CrossRef] [PubMed]
Cenit MC Marquez A Cordero-Coma M Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition. BMC Med Genet. 2013; 14: 52. [CrossRef] [PubMed]
Ceribelli A Satoh M Chan EK. MicroRNAs and autoimmunity. Curr Opin Immunol. 2012; 24: 686–691. [CrossRef] [PubMed]
Zhu S Pan W Qian Y. MicroRNA in immunity and autoimmunity. J Mol Med (Berl). 2013; 91: 1039–1050. [CrossRef] [PubMed]
Shi D Li P Ma L A genetic variant in pre-miR-27a is associated with a reduced renal cell cancer risk in a Chinese population. PLoS One. 2012; 7: e46566. [CrossRef] [PubMed]
Zhang N Huo Q Wang X A genetic variant in pre-miR-27a is associated with a reduced breast cancer risk in younger Chinese population. Gene. 2013; 529: 125–130. [CrossRef] [PubMed]
Li T Wu X Zhu X Association analyses between the genetic polymorphisms of HNF4A and FOXO1 genes and Chinese Han patients with type 2 diabetes. Mol Cell Biochem. 2011; 353: 259–265. [CrossRef] [PubMed]
Figure
 
The influence of various rs2297626 genotypes on expression of FoxO1. Purified CD4+ T cells and anti-CD3/CD28 antibodies-stimulated CD4+ T cells from genotyped healthy controls were used (10 AA genotypes, 10 AG genotypes, and 10 GG genotypes of rs2297626).
Figure
 
The influence of various rs2297626 genotypes on expression of FoxO1. Purified CD4+ T cells and anti-CD3/CD28 antibodies-stimulated CD4+ T cells from genotyped healthy controls were used (10 AA genotypes, 10 AG genotypes, and 10 GG genotypes of rs2297626).
Table 1
 
Clinical Features of the Investigated AAU Patients
Table 1
 
Clinical Features of the Investigated AAU Patients
Clinical Features N, Total = 680 Percentage
Mean age ± SD 39.3 ± 11.7
Male 449 66.0
Female 231 34.0
Uveitis 680 100
AAU patients with AS 440 64.7
AAU patients without AS 240 35.3
HLA-B27+ AAU+ 451 (556 tested) 81.1
HLA-B27+ AAU+ AS+ 318 (355 tested) 89.6
HLA-B27+ AAU+ AS 133 (201 tested) 66.2
HLA-B27 AAU+ 105 (556 tested) 18.9
HLA-B27 AAU+ AS+ 37 (355 tested) 10.4
HLA-B27 AAU+ AS 68 (201 tested) 33.8
Table 2
 
Main Effects of FoxO1/rs2297626 SNPs on AAU With AS Risk
Table 2
 
Main Effects of FoxO1/rs2297626 SNPs on AAU With AS Risk
Genotype AAU With AS Controls P Value OR (95% CI)
N % N %
Stage 1 N = 230 N = 650
 AA 114 49.5 225 34.6 6.23 × 10−5* 1.86 (1.37–2.52)
 AG 92 40.2 328 50.5 6.33 × 10−3 0.65 (0.48–0.89)
 GG 24 10.3 97 14.9 0.09 0.66 (0.41–1.07)
 A allele 320 69.6 778 59.8 2.17 × 10−4* 1.53 (1.22–1.93)
Stage 2 N = 210 N = 630
 AA 105 50.0 222 35.3 1.45 × 10−4* 1.84 (1.34–2.52)
 AG 85 40.3 313 49.6 0.02 0.69 (0.50–0.95)
 GG 20 9.7 95 15.1 0.04 0.59 (0.36–0.99)
 A allele 295 70.2 757 60.1 1.94 × 10−4* 1.57 (1.24–1.99)
Combined N = 440 N = 1280
 AA 219 49.8 447 34.9 3.45 × 10−8* 1.85 (1.48–2.30)
 AG 177 40.2 641 50.1 3.58 × 10−4* 0.67 (0.54–0.84)
 GG 44 10.0 192 15.0 8.55 × 10−3 0.63 (0.45–0.89)
 A allele 615 69.9 1535 60.0 1.55 × 10−7* 1.55 (1.32–1.83)
Supplementary Tables
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×