Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis

Shrikant S Kolan; Gaoyang Li; Franco Grimolizzi; Joe Sexton; Guro Goll; Tore K Kvien; Nina Paulshus Sundlisæter; Manuela Zucknick; Siri Lillegraven; Espen A Haavardsholm; Bjørn Steen Skålhegg

doi:10.3389/fphar.2022.1075603

Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis

Front Pharmacol. 2022 Nov 17:13:1075603. doi: 10.3389/fphar.2022.1075603. eCollection 2022.

Authors

Affiliations

¹ Department of Nutrition, Division of Molecular Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
² Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.
³ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Biostatistics, Oslo Centre for Biostatistics and Epidemiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
⁵ Department of Health Management and Health Economics, Institute of Health and Society, University of Oslo, Oslo, Norway.

Abstract

Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%-30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6 months, and failure to sustain MTX monotherapy from 12 to 24 months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12-24 months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA.

Keywords: association; clincal outcomes; methotexate; rheumatoid arthritis; single nucelotide polymorphisms.