https://orcid.org/0000-0001-5419-9156
Abstract
Background
Rheumatoid arthritis (RA) is characterized by systemic synovitis with bone erosion and joint cartilage degradation. Although the analysis of polymorphisms in cytokine-encoding genes is important or understanding the pathophysiology of RA and selecting appropriate treatment for it, few studies have examined such single-nucleotide polymorphisms (SNPs) specifically in Japanese patients. This study was established to investigate the associations between polymorphisms in cytokine-encoding genes, autoantibodies and therapeutic responses in Japanese RA patients.
Methods
The subjects in this study consisted of 100 RA patients and 50 healthy controls. We extracted data on sex, age, disease duration, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and therapeutic responses, including to methotrexate (MTX) and biological disease-modifying antirheumatic drugs (DMARDs). Genomic DNA was isolated from peripheral blood, which was genotyped for IL-10, TNF-α, TGF-β1, and IFN-γ polymorphisms.
Results
Regarding IL-10 (−592 C/A and −819 C/T), significant decreases in the frequencies of the IL-10 (−592) CC genotype and (−819) CC genotype were found in RA patients compared with the levels in controls. For IFN-γ (+874 T/A), a significant decrease in the frequency of the TT genotype was found in RA patients compared with that in controls. Regarding TGF-β1 (+869 T/C), patients with positivity for anti-CCP antibody had a significantly lower frequency of the CC genotype than those with negativity for it. Furthermore, the IL-10 (−592) CC genotype and (−819) CC genotype might be related to the biological DMARD-response.
Conclusion
Our results suggest that the analysis of polymorphisms in cytokine-encoding genes may be useful when selecting treatment for Japanese RA patients.
Introduction
Rheumatoid arthritis (RA) is a common autoimmune disease, which afflicts 0.5–1% of the population worldwide.Citation1,Citation2 Although an increasing number of reports have indicated that certain pathogens might be linked to RA, its exact cause remains unknown.Citation3–Citation6 RA is characterized by systemic synovitis with bone erosion and joint cartilage degradation.Citation1 Specifically, osteoclast precursor cells in the inflamed synovium differentiate into osteoclasts in the presence of receptor activator of nuclear factor kappa-B ligand (RANKL) and inflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), which directly affect bone destruction.Citation7 Therefore, cytokines play crucial roles in the pathogenesis of RA, making them targets for treating this disease. For this reason, biological disease-modifying antirheumatic drugs (DMARDs) such as TNF and IL-6 receptor inhibitors have become popular.Citation8
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are used for the diagnosis of RA.Citation9 RF is an antibody directed against the Fc region of IgG and is found in 70–90% of RA patients. It can also be found in patients with other autoimmune or infectious diseases, as well as healthy people.Citation10 In contrast, anti-CCP antibody is an antibody against arginyl residue peptide citrullinated by peptidylarginine deiminase; it is more specific to RA than RF.Citation9 Studies have also shown that patients positive for anti-CCP antibody are more prone to radiographic progression than those negative for it.Citation11,Citation12 The production of autoantibodies is important for autoimmune diseases and cytokines play crucial roles in this process.Citation13
The assumption that genetic factors are important in autoimmune diseases has led to extensive molecular studies being performed. The analysis of polymorphisms in cytokine-encoding genes is important or understanding the pathophysiology and establishing appropriate treatment.Citation14 The distribution of single-nucleotide polymorphisms (SNPs) varies among different ethnic groups, which is also the case specifically for polymorphisms in cytokine-encoding genes related to RA.Citation15,Citation16 However, there have been few reports on cytokine-related polymorphisms in Japanese RA patients.Citation17 As such, this study was established to investigate the associations between polymorphisms in cytokine-encoding genes, autoantibodies, and therapeutic responses in Japanese RA patients.
Materials and Methods
Study Design and Subjects
This study was approved by the ethics committee of Kansai Medical University. All participants, or a parent or legal guardian for those under the age of 20 years, provided informed consent to participate in this study, which was conducted in accordance with the Declaration of Helsinki. The subjects in this study consisted of 100 RA patients and 50 healthy controls. The patients met the criteria for RA in the 1987 revised classification or the 2010 criteria. Therapeutic responses to MTX and biological DMARDs were determined using the DAS28 criteria after 6 months of therapy. Responders were defined as those having a DAS28 score <3.2 or an improvement in it of at least 1.2 points. Non-responders were defined as the rest. We extracted data on the patients’ sex, age, disease duration, RF, anti-CCP antibody, and therapeutic responses, including to methotrexate (MTX) and biological DMARDs such as anti-TNF-α blockers and anti-IL-6 blockers.
Genotyping
Genomic DNA was isolated from ethylene diamine-tetraacetic acid (EDTA) whole peripheral blood using QIAamp DNA Mini Kit (Qiagen, Hilden, Germany). TNF-α, TGF-β1, IL-10, and IFN-γ polymorphisms were analyzed the by polymerase chain reaction sequence-specific primer (PCR-SSP) method using Cytokine Genotyping Tray (One Lambda, Inc., Los Angeles, CA, USA). For TNF-α, the promoter region at position −308 G/A (rs1800629) was analyzed. For TGF-β1, two polymorphisms in the coding region, namely, codon 10 +869 T/C (rs1982073) and codon 25 +915 C/G (rs1800471), were analyzed. For IL-10, three polymorphisms in the promoter region, namely, −1082 G/A (rs1800896), −819 C/T (rs1800871), and −592 C/A (rs1800872), were analyzed. Finally, for IFN-γ, the coding region position +874 T/A (rs2430561) was analyzed. DNA fragments corresponding to each cytokine were amplified in accordance with the manufacturer’s instructions.
Statistical Analysis
Statistical analysis was performed using Fisher’s exact test and Pearson’s chi-squared test. The genotype distributions for the studied polymorphisms of the RA patients and control group individuals were statistically compared using Pearson’s chi-squared test and Fisher’s exact probability test with StatFlex v7 software. In addition, the genotype distribution was analyzed for the studied polymorphisms of two groups of RA patients divided by the presence or absence of anti-CCP antibody, as well as by whether treatment (with MTX and biological DMARD) had been undertaken. Results were considered statistically significant when the probability of findings occurring by chance was less than 5% (P<0.05). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for disease susceptibility, in groups with the presence or absence of anti-CCP antibody, and whether therapy such as MTX or biological DMARD had been undertaken.
Results
Patient Characteristics
The mean age of the RA patients was 61.1 ± 14.3 (range 17–85) years. A total of 85% of them were female. Data on the medical history revealed the treatment modalities of the patients to be MTX (56 patients) and biological DMARDs (66 patients; TNF blocker 42 and IL-6 blocker 24). Baseline characteristics of the RA patients and healthy controls are given in . Anti-CCP antibody was detected in 70% of the RA patients. There were no differences between antibody-positive and -negative patients, in terms of sex, age, and disease duration (positive vs negative; proportion of females, 84.3% vs 86.7%; age, 59.8 ± 15.1 vs 64.1 ± 11.6; disease duration, 111.1 ± 111.4 vs 85.5 ± 85.2).
Table 1 Baseline Characteristics of the RA Patients and Healthy Controls
Association of Polymorphisms in Cytokine-Encoding Genes with RA Susceptibility
The findings showed significant decreases in the frequencies of the IL-10 (−592) CC genotype and (−819) CC genotype in RA patients compared with those in controls (8% vs 24%, χ2=5.4162, p=0.01995, OR=0.333) (). Regarding IFN-γ (+874) a significant decrease in the frequency of the TT genotype was revealed in RA patients compared with that in controls (0% vs 6.0%, χ2=5.7736, p=0.01627). However, no significant differences in TNF-α and TGF-β1 genotypes were observed between the RA patients and controls.
Table 2 Frequencies of Cytokine Gene Polymorphisms in RA and Normal Controls
Association of Polymorphisms in Cytokine-Encoding Genes with Autoantibodies in RA Patients
Regarding TGF-β1 (+869), patients with positivity for anti-CCP antibody had a significant decrease in the frequency of the CC genotype compared with those negative for it (20% vs 47%, χ2=3.8788, p=0.04890, OR=0.429) (). No significant differences in IL-10, TNF-α, and IFN-γ genotype frequencies were observed between anti-CCP antibody-positive and -negative RA patients. Furthermore, no significant associations were found between RF and any polymorphism in cytokine-encoding genes (data not shown).
Table 3 Distribution of Cytokine Genotypes in ACPA-Positive and -Negative Patients with RA
Association of Polymorphisms in Cytokine-Encoding Genes with Therapeutic Responses in RA Patients
MTX
A total of 56 patients with RA initiated MTX treatment at our hospital. Thirty-three of these responded to it, while 23 did not. There were no significant differences between responders and nonresponders to MTX treatment in RA patients ().
Table 4 Distribution of Cytokine Genotypes in MTX-Responder and -Nonresponder Patients with RA
Biological DMARDs
A total of 66 patients were treated with biological DMARDs (anti-TNF blocker, 42 patients; anti-IL-6 blocker, 24 patients). Forty-eight of these responded to it, while 18 did not. The responders exhibited a significantly lower frequency of the IL-10-592 CC genotype and IL-10-819 CC genotype than the nonresponders (4% vs 20%, χ2=4.0225, p=0.04490, OR=0.188) ().
Table 5 Distribution of Cytokine Genotypes in BDM-Responder and -Nonresponder Patients with RA
Discussion
IL-10 is an anti-inflammatory cytokine mainly produced by Th2 cells and a variety of other cells, such as helper T (Th)1 cells, Th17 cells, B cells and macrophages.Citation18 This cytokine suppresses the secretion of Th1 cytokines, deactivates macrophages and natural killer cells, and is also involved in the differentiation of B cells and antibody production.Citation19 In the serum and synovial fluid of RA patients, IL-10 levels are elevated compared with those in healthy people.Citation20 Furthermore, it has been reported that IL-10 suppress joint swelling and deformation in an RA animal model.Citation21,Citation22 Therefore, IL-10 may be involved in the pathophysiology of RA. In this study, regarding IL-10 (−819 C/T and −592 C/A), significant decreases in the frequencies of the IL-10 (−592) CC genotype and (−819) CC genotype were found in RA patients compared with those in controls. Several studies have reported an association between IL-10 polymorphism and susceptibility to RA.Citation23,Citation24 Similar to these previous reports, our results indicated that IL-10 is strongly involved in the pathophysiology of RA.
IFN-γ is produced by Th1 and Th2 cells, and IFN-γ and IL-4 inhibit differentiation into osteoclasts.Citation25 IFN-γ is decreased in the synovium of RA patients, which leads to deterioration of the suppression of osteoclastogenesis and affects bone destruction.Citation26 In our study, there was a significant decrease in the frequency of the TT genotype of the IFN-γ (+874 A/T) polymorphisms in RA patients compared with that in controls. This suggests the possibility that IFN-γ polymorphism is involved in the pathophysiology of RA. Khani-Hanjani et alCitation27 reported the associations of IFN-γ (+874 A/T) polymorphism with susceptibility to, and severity of, RA. However, other studies have reported that IFN-γ polymorphisms are not associated with the susceptibility to RA.Citation28–Citation30 In addition, a recent meta-analysis by Lee et alCitation31 indicated that the IFN-γ (+874 A/T) polymorphism may play a significant role in modifying the risk of autoimmune diseases in Caucasian, Latin American, and Middle Eastern subjects, and in particular showed that this polymorphism is associated with increased susceptibility to idiopathic thrombocytopenic purpura and systemic lupus erythematosus (SLE). Furthermore, Teker et alCitation32 demonstrated that T/T genotype of the IFN-γ (+874 A/T) polymorphism is associated with both rheumatic heart disease and the severity of this disease. Similarly, the association between IFN-γ (+874 A/T) polymorphism and RA seems to be controversial. Therefore, our results concerning IFN-γ might be valid only in Japanese patients.
In the present study, we also investigated the association of polymorphisms in cytokine-encoding genes with autoantibodies in RA patients. Interestingly, regarding TGF-β1 (+869 T/C), we found that patients with positivity for anti-CCP antibody had a significantly lower frequency of the CC genotype than patients negative for it. TGF-β1 is produced by T cells, dendritic cells and macrophages, and plays essential roles in regulating immune function and controlling cell growth and differentiation.Citation33 Serum TGF-β1 level is elevated in diseases associated with fibrosis, while it is decreased in SLE.Citation34–Citation36 Moreover, TGF-β1-deficient mice have been shown to exhibit enhanced autoantibody production and inflammatory cell infiltration. This could be related to the pathology of SLE,Citation37 although TGF-β1 levels were reported not to differ significantly between RA patients and healthy controls.Citation38 Therefore, TGF-β1 can participate in the production of autoantibodies in RA patients. Actually, it was reported that the TGF-β1 (+869) T allele was significantly associated with RA in Asians,Citation38 which is consistent with our results. Additionally, Alayli et alCitation39 reported that Turkish RA patients with the TGF-β1 (+869) T allele may have an increased risk of RF positivity, although little has been reported on anti-CCP antibody and TGF-β1 polymorphisms. As we mentioned earlier, TGF-β1 is produced by T cells, dendritic cells, and macrophages, and plays essential roles in regulating immune function and controlling cell growth and differentiation.Citation33 Given that patients positive for anti-CCP antibody are more prone to radiographic progression than those negative for it, we may be able to use TGF-β1 polymorphism as a predictor of radiographic progression. However, there is a need for further investigation of the feasibility of this.
Several studies have reported that polymorphisms in cytokine-encoding genes are associated with therapeutic responses in RA patients.Citation40–Citation43 In the present study, we investigated the relationship between such polymorphisms and the therapeutic responses to MTX and biological DMARDs in RA patients. There were no significant differences between responders and nonresponders to MTX treatment in RA patients. Furthermore, those who responded to biological DMARDs exhibited a significantly lower frequency of the IL-10 (-592) CC genotype and IL-10 (-819) CC genotype than those who did not. Other reports also described the existence of a relationship between TNF-α −308 G/A and anti-TNF-α blocker.Citation40–Citation42 However, our results did not show such relationships. It was previously reported that the effect of anti-TNF blocker may be related to polymorphisms in cytokine-encoding genes other than TNF-α.Citation44 The mechanisms behind the differences in therapeutic responses depending on such polymorphisms remain incompletely understood.Citation45 One factor o influencing this could be ethnic differences. Further studies are needed to clarify the association between polymorphisms in cytokine-encoding gene and therapeutic responses.
This study had some limitations. First, the sample size of this study was too small to draw any robust conclusions. Second, the samples were probably not representative of the Japanese RA population, because data were obtained from only a single facility. Finally, we did not completely define the relationship between polymorphisms in cytokine-encoding genes and biological DMARDs other than anti-TNF and -IL-6 blockers in this study. Therefore, it remains unknown whether all biological DMARDs in RA patients are directly linked to such polymorphisms. Future prospective studies will be needed to confirm the observations from this study.
Conclusions
This study showed that the IL-10 (−592 CC, −819 CC) and IFN-γ (+874 TT) genotypes might be related to RA in the Japanese. Additionally, the TGF-β1 (+869 CC) genotype may be associated with the production of anti-CCP antibody. Furthermore, the IL-10 (−592 CC, −819 CC) genotype might be linked to the biological DMARD response. These results suggest that analyzing polymorphisms in cytokine-encoding genes could be useful when selecting treatment for Japanese RA patients.
Abbreviations
RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; DMARD, disease-modifying antirheumatic drugs; RF, rheumatoid factor; CCP, cyclic citrullinated peptide; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor; IL-10, interleukin-10; SNP, single-nucleotide polymorphism; MTX, methotrexate; PCR-SSP, polymerase chain reaction sequence-specific primer; OR, odds ratio; CI, confidence interval.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all of these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Acknowledgments
This study was supported in part by a grant from the Advanced Medical Care from the Ministry of Health, Labour and Welfare of Japan, and a grant (19K07948 to S.N.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. We thank Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript. The abstract of this paper was presented at EULAR 2020 E-congress (Frankfurt, Germany) as a poster presentation (FRI0550) with interim findings.
Disclosure
The authors report no conflicts of interest for this work.
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