Folate Metabolic Pathway Single Nucleotide Polymorphisms: A Predictive Pharmacogenetic Marker of Methotrexate Responsel in Indian (Asian) Patients with Rheumatoid Arthritis

Abstract

Aim: We evaluated the pharmacogenetic influence of genetic polymorphisms in folate pathway genes in Indian rheumatoid arthritis patients receiving methotrexate (MTX). Patients & methods: Twelve polymorphisms within nine folate pathway genes were analyzed for association with MTX response in 322 Indian rheumatoid arthritis (RA) patients and MTX pharmacokinetics in 94 RA patients. Results: Polymorphisms in GGH, SHMT1 and TS were associated with MTX-related adverse events while SNPs in MTHFR and RFC1/SLC19A1 were associated with MTX efficacy. TS5′UTR and SHMT1 polymorphisms were associated with higher plasma levels of MTX. Conclusion: Polymorphisms in folate-MTX pathway genes contribute to MTX response and affect MTX concentrations in Indian RA patients. A toxicogenetic index could identify patients who develop adverse events to MTX.

Keywords::

• folate metabolism
• homocysteine
• Indians
• methotrexate
• pharmacogenomics
• pharmacokinetics

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/PGS.15.145

Acknowledgements

The authors thank patients and management of ARCF_Center for Rheumatic Diseases for permission to carry out this clinical work in the center and the invaluable assistance for providing other connected logistic and infrastructure help (Ms V Anuradha and Ms S Manjit); Dr Anjali Radkar for providing valuable inputs during statistical analysis and Dr Anand Hardikar for providing Applied Biosystems 7500 real time PCR facility at National Center for Cell Sciences, Pune.

Financial & competing interests disclosure

Y Ghodke-Puranik is thankful to Council for Scientific and Industrial Research, New Delhi, India, for senior research fellowship and AS Puranik is thankful Lady Tata Memorial Trust, Mumbai, India for senior research fellowship. J Lamba is supported by NIH grants: R01CA132946 and R21CA155524. TB Niewold is supported by grants from: the NIH (AR060861, AR057781, AR065964, AI071651), Rheumatology Research Foundation, Cure JM Foundation, the Mayo Clinic Foundation, and the Foundation of Minnesota. 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

Y Ghodke-Puranik is thankful to Council for Scientific and Industrial Research, New Delhi, India, for senior research fellowship and AS Puranik is thankful Lady Tata Memorial Trust, Mumbai, India for senior research fellowship. J Lamba is supported by NIH grants: R01CA132946 and R21CA155524. TB Niewold is supported by grants from: the NIH (AR060861, AR057781, AR065964, AI071651), Rheumatology Research Foundation, Cure JM Foundation, the Mayo Clinic Foundation, and the Foundation of Minnesota. 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.