Moving Toward Personalized Medicine in Rheumatoid Arthritis: Snps in Methotrexate Intracellular Pathways are Associated with Methotrexate Therapeutic Outcome

Abstract

Aim: Evaluate the potential of selected SNPs as predictors of methotrexate (MTX) therapeutic outcome. Patients & methods: In total, 35 SNPs in 14 genes involved in MTX intracellular pathways and Phase II reactions were genotyped in 233 rheumatoid arthritis (RA) patients treated with MTX. Binary logistic regressions were performed by genotype/haplotype-based approaches. Non-Response- and Toxicity-Genetic Risk Indexes (Non-RespGRI and ToxGRI) were created. Results: MTX nonresponse was associated to eight genotypes and three haplotypes: MTHFR rs1801131 AA and rs1801133 TT; MS rs1805087 AA; MTRR rs1801394 A carriers; ATIC rs2372536 C carriers, rs4673993 T carriers, rs7563206 T carriers and rs12995526 T carriers; CC for GGH rs3758149 and rs12681874; CGTTT for ATIC combination 1; and CTTTC for ATIC combination 2. From overall Non-RespGRI patients with indexes 6–8 had more than sixfold increased risk for MTX nonresponse than those patients with indexes 0–5. MTX-related toxicity was associated to five genotypes and two haplotypes: ATIC rs2372536 G carriers, rs3821353 T carriers, rs7563206 CC and rs12995526 CC; ADORA2A rs2267076 T; CTTCC for ATIC combination 1; and TC for ADORA2A rs2267076 and rs2298383. From overall ToxGRI, patients with indexes 3–4 had more than sevenfold increased risk for MTX-related toxicity than those patients with indexes 1–2. Conclusion: Genotyping may be helpful to identify which RA patients will not benefit from MTX treatment and, consequently, important to personalized medicine in RA. Nevertheless, further studies are required to validate these findings.

Keywords::

• genetic risk index
• methotrexate
• personalized medicine
• pharmacogenomics
• polymorphisms
• response
• rheumatoid arthritis
• therapeutic outcome
• toxicity

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Acknowledgements

The authors thank the Nursing Service of Rheumatology Day Hospital and to the Physicians from Rheumatology Department of São João Hospital Center for the support in patients’ recruitment and, to Genomics Unit-Genotyping Service of Instituto Gulbenkian de Ciência for genotyping service.

Financial & competing interests disclosure

The authors wish to acknowledge Fundação para a Ciência e Tecnologia (FCT) for Aurea Lima’s Doctoral Grant (SFRH/BD/64441/2009). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The authors wish to acknowledge Fundação para a Ciência e Tecnologia (FCT) for Aurea Lima’s Doctoral Grant (SFRH/BD/64441/2009). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript