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Multidrug resistance 1 (MDR1) 3435C>T gene polymorphism influences the clinical phenotype and methotrexate-induced adverse events in South Indian Tamil rheumatoid arthritis

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily targeting the synovial joints causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA, and approximately 10–30 % of the patients fail to attain remission because of inefficacy of the drug or due to development of adverse events. Multidrug resistance 1 (MDR1) gene encodes for permeable glycoprotein (P-gp) which is an integral membrane protein for the transport of chemotherapeutic agents, immunosuppressive drugs etc. MDR1 3435C>T results in a wobble mutation in exon 26 but is associated with altered P-gp expression and reduced P-gp function. The present study was carried out to find the role of MDR1 3435C>T gene polymorphism with clinical phenotype, treatment response, and MTX adverse events in 336 RA and 329 healthy controls of South Indian Tamil ethnicity.

Methods

MDR1 3435C>T gene polymorphism was analyzed by TaqMan 5′ nuclease assay.

Results

We found MDR1 3435T allele as a risk allele for contributing to high EULAR disease activity [p = 0.02, OR 1.50, 95 % CI (1.06–2.13)]. Also, MDR1 3435CT genotype was associated with deforming disease [p = 0.02, OR 1.79, 95 % CI (1.11–2.88)]. However, this SNP did not influence the MTX treatment response in these patients. MDR1 3435CT genotype was associated with MTX-induced adverse events [p = 0.01, OR 2.01, 95 % CI (1.15–3.52)], and the 3435 TT genotype remained protective for the development of adverse events [p = 0.009, OR 0.40, 95 % CI (0.21–0.78)]. Also, the heterozygous 3435 CT genotype was associated with gastrointestinal events [p = 0.02, OR 3.62, 95 % CI (1.25–10.47)], and CT genotype remained protective in patients developing infection [p = 0.002, OR 0.05, 95 % CI (0.006–0.460)].

Conclusion

MDR1 3435C>T gene polymorphism influences the clinical phenotype and adverse events to MTX in the South Indian cohort of patients with RA.

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Abbreviations

ACPA:

Anti-citrullinated peptide antibody

ACR:

American college of Rheumatology

DAS28 (ESR) score:

Disease Activity Score based on 28 joints and Erythrocyte Sedimentation Rate

DMARD:

Disease modifying antirheumatic drug

EULAR:

European League Against Rheumatism

JIA:

Juvenile idiopathic arthritis

MDR1:

Multidrug resistance

PCR:

Polymerase chain reaction

P-gp:

Permeable glycoprotein

PHA:

Phytohemagglutinin

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

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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.

Contributors

VSN conceived and planned the study. NM performed the laboratory work with the precious help of CMM. NM performed statistical analysis. VSN, PTA, and VKJ recruited the patients, collected, organized, and interpreted the clinical data. VSN and NM wrote the manuscript. VSN coordinated the research and critically reviewed the manuscript and takes the primary responsibility for the article.

Conflict of interest

All authors declare that they have no competing interest.

Ethical standards

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

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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, Paul T. Antony, Vikramraj K. Jain, Christina Mary Mariaselvam & Vir Singh Negi

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  1. Niveditha Muralidharan
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  2. Paul T. Antony
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  3. Vikramraj K. Jain
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Correspondence to Vir Singh Negi.

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Muralidharan, N., Antony, P.T., Jain, V.K. et al. Multidrug resistance 1 (MDR1) 3435C>T gene polymorphism influences the clinical phenotype and methotrexate-induced adverse events in South Indian Tamil rheumatoid arthritis. Eur J Clin Pharmacol 71, 959–965 (2015). https://doi.org/10.1007/s00228-015-1885-0

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