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Association of the ABCB1 C3435T polymorphism with responsiveness to and toxicity of DMARDs in rheumatoid arthritis

A meta-analysis

Assoziation des ABCB1-C3435T-Polymorphismus mit dem Ansprechen auf DMARDs sowie deren Toxizität bei rheumatoider Arthritis

Eine Metaanalyse

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Abstract

Objective

The aim of this study was to investigate whether the C3435T polymorphism in the gene encoding multidrug resistance protein 1 (ABCB1) can predict responsiveness to or toxicity of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA).

Methods

We conducted a meta-analysis of studies on the association between the ABCB1 C3435T polymorphism and nonresponsiveness to or toxicity of DMARDs in RA patients, using the PUBMED and EMBASE electronic citation databases. Subsequent inclusion/exclusion procedures were performed and then data were extracted for association analysis.

Results

A total of 14 comparison studies from 9 articles met our inclusion criteria. This final group comprised 4 studies containing data on associations between the ABCB1 C3435T polymorphism and RA susceptibility, 5 studies on the response to DMARDs, and 5 on toxicity of DMARDs in RA patients according to ABCB1 polymorphism status. Meta-analysis revealed no association between RA susceptibility and the ABCB1 C3435T polymorphism [odds ratio (OR) for the T allele = 0.948, 95 % confidence interval (CI) 0.756–1.189, p = 0.645]. Meta-analysis showed no association between the ABCB1 C3435T T allele and a nonresponse to DMARD therapy (OR 0.952, 95 % CI 0.516–1.685, p = 0.817). Stratification by DMARD type indicated no association between the ABCB1 C3435T T allele and nonresponse to methotrexate (MTX) treatment (OR 1.201, 95 % CI  0.456–3.164, p = 0.711). However, the analysis did indicate that MTX toxicity was associated with the ABCB1 C3435T polymorphism in RA under an overdominant model (TC vs. TT + CC; OR 0.483, 95 % CI 0.259–0.900, p = 0.022), evidencing a lower risk of MTX toxicity for heterozygotes (TC) than homozygotes (TT and CC).

Conclusion

This meta-analysis demonstrated that the ABCB1 C3435T polymorphism may be not associated with responsiveness to DMARD therapy, but may be associated with MTX toxicity in RA.

Zusammenfassung

Ziel

Das Ziel dieser Studie war es, zu untersuchen, ob der C3435T-Polymorphismus in dem Gen, welches das Multidrug-Resistenz-Protein 1 kodiert (ABCB1), das Ansprechen auf krankheitsverändernde antirheumatische Medikamente (DMARDs) oder deren Toxizität bei Patienten mit rheumatoider Arthritis (RA) vorhersagen kann.

Methoden

Wir führten eine Metaanalyse von Studien zur Assoziation zwischen dem ABCB1-C3435T-Polymorphismus und dem Nichtansprechen auf DMARDs oder deren Toxizität bei RA-Patienten unter Verwendung der Datenbanken PubMed und Embase durch. Im Anschluss wurden Einschluss-/Ausschlussverfahren angewendet, und die Daten für die Assoziationsanalyse wurden extrahiert.

Ergebnisse

Insgesamt 14 Studien aus 9 Artikeln erfüllten unsere Einschlusskriterien. Diese finale Gruppe umfasste 4 Studien mit Daten zu Assoziationen zwischen dem ABCB1-C3435T-Polymorphismus und RA-Suszeptibilität, 5 Studien zum Ansprechen auf DMARDs sowie 5 Studien zur Toxizität von DMARDs bei RA-Patienten, abhängig vom Status des ABCB1-Polymorphismus. Die Metaanalyse zeigte keine Assoziation zwischen RA-Suszeptibilität und dem ABCB1-C3435T-Polymorphismus [Odds-Ratio (OR) für das T-Allel = 0,948; 95 % Konfidenzintervall (CI) 0,756–1,189; p = 0,645]. Die Metaanalyse zeigte keine Assoziation zwischen dem ABCB1-C3435T-T-Allel und einem Nichtansprechen auf die DMARD-Therapie (OR 0,952; 95 % CI 0,516–1,685; p = 0,817). Bei der Stratifizierung nach DMARD-Typ gab es keine Hinweis auf eine Assoziation zwischen dem ABCB1-C3435T-T-Allel und dem Nichtansprechen auf die Behandlung mit Methotrexat (MTX; OR 1,201; 95 % CI  0,456–3,164; p = 0,711). Jedoch zeigte die Analyse, dass in einem überdominanten Modell die MTX-Toxizität mit dem ABCB1-C3435T-Polymorphismus bei RA assoziiert war (TC vs. TT + CC; OR 0,483; 95 % CI 0,259–0,900; p = 0,022), was ein geringeres Risiko der MTX-Toxizität für Heterozygote (TC) als für Homozygote (TT und CC) belegt.

Schlussfolgerung

Diese Metaanalyse hat gezeigt, dass der ABCB1-C3435T-Polymorphismus möglicherweise nicht mit dem Ansprechen auf eine DMARD-Therapie assoziiert ist, jedoch mit einer MTX-Toxizität bei RA assoziiert sein könnte.

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Acknowledgments

This study was supported in part by a grant of the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI13C2124).

Compliance with ethical guidelines

Conflict of interest. Y.H. Lee, S.-C. Bae, and G.G. Song state that there are no conflicts of interest.

The accompanying manuscript does not include studies on humans or animals.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, 136–705, Seoul, Korea

    Y.H. Lee MD, PhD & G.G. Song

  2. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea

    S.-C. Bae

Authors
  1. Y.H. Lee MD, PhD
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  2. S.-C. Bae
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  3. G.G. Song
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Correspondence to Y.H. Lee MD, PhD.

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Lee, Y., Bae, SC. & Song, G. Association of the ABCB1 C3435T polymorphism with responsiveness to and toxicity of DMARDs in rheumatoid arthritis. Z Rheumatol 75, 707–715 (2016). https://doi.org/10.1007/s00393-015-1618-x

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  • DOI: https://doi.org/10.1007/s00393-015-1618-x

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