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Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis

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Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA. MTX inhibits several enzymes of the folate and nucleotide pathways. Thymidylate synthase (TYMS) is an important enzyme in the de novo pyrimidine pathway responsible for DNA replication. The two common gene polymorphisms analyzed in TYMS are 28-bp tandem repeat polymorphism and a 6-bp insertion/deletion polymorphism. The present study was carried out to find the role of these TYMS gene polymorphisms with clinical phenotype, treatment response, and MTX adverse events in 254 patients with RA of south Indian Tamil ethnicity. TYMS gene polymorphisms were analyzed by PCR. The allele frequencies of TYMS gene polymorphisms did not differ between good and non-responders. However, the TYMS 28-bp tandem repeat 3R allele was higher in non-responders than in patients undergoing remission [64 vs 51.11%, p = 0.06, OR 0.58, 95% CI (0.34–1.00)]. The TYMS 6-bp deletion allele was higher in non-responders than good responders [78.20 vs 64.92%, p = 0.06, OR 0.51 95% CI (0.27–0.98)]. TYMS 3R allele and TYMS 6-bp deletion allele may favor non-response to MTX in south Indian Tamils. TYMS gene polymorphisms did not influence MTX adverse events.

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Abbreviations

ACPA:

Anti-citrullinated peptide antibody

ACR:

American College of Rheumatology

bp:

Base pairs

DAS28 (ESR) score:

Disease Activity Score based on 28 joints and Erythrocyte Sedimentation Rate

D/Del:

Deletion

DMARD:

Disease-modifying antirheumatic drug

EULAR:

European League Against Rheumatism

I/Ins:

Insertion

HWE:

Hardy-Weinberg equilibrium

PCR:

Polymerase chain reaction

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

TYMS:

Thymidylate synthase

UTR:

Untranslated region

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Acknowledgments

The study was supported by an intramural research grant by JIPMER, Puducherry, India. In addition, the infrastructure and other support provided by DST-FIST and ICMR-INSERM programs are also acknowledged.

Author’s contribution

VSN conceived and planned the study. VSN, VKJ, and DPM enrolled the patients and evaluated treatment response. NM carried out genotyping and relevant immunological assays. NM and DPM carried out the statistical analysis. NM wrote the manuscript with the help of VSN, VKJ, and DPM. VSN is the lead author and takes the primary responsibility for the data presented.

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Authors and Affiliations

  1. Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India

    Niveditha Muralidharan, Durga P. Misra, Vikramraj K. Jain & Vir Singh Negi

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  1. Niveditha Muralidharan
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  2. Durga P. Misra
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  3. Vikramraj K. Jain
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  4. Vir Singh Negi
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Corresponding author

Correspondence to Vir Singh Negi.

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Ethical standards

The study was carried out in compliance with international, national, and institutional regulations. Institute Ethics committee approved the study. All participants gave informed consent prior to the inclusion in the study.

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Muralidharan, N., Misra, D.P., Jain, V.K. et al. Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis. Clin Rheumatol 36, 1253–1259 (2017). https://doi.org/10.1007/s10067-017-3608-7

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  • DOI: https://doi.org/10.1007/s10067-017-3608-7

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