Usefulness of Cytokine Gene Polymorphisms for the Therapeutic Choice in Japanese Patients with Rheumatoid Arthritis

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.

Keywords:

• RA
• SNP
• cytokine gene polymorphism
• anti-CCP antibody
• biological DMARD

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.

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.

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.

Disclosure

The authors report no conflicts of interest for this work.