Genetic variations in methotrexate metabolic pathway genes influence methotrexate responses in rheumatoid arthritis patients in Malaysia

Hong Xi Sha; Kumar Veerapen; Sook Khuan Chow; Suk Chyn Gun; Ing Soo Lau; Renee Lay Hong Lim; Zaliha Zulkifli; Yoon-Yen Yow; Suat Cheng Peh; Jung Shan Hwang

doi:10.1038/s41598-022-15991-0

Genetic variations in methotrexate metabolic pathway genes influence methotrexate responses in rheumatoid arthritis patients in Malaysia

Sci Rep. 2022 Jul 13;12(1):11844. doi: 10.1038/s41598-022-15991-0.

Authors

Hong Xi Sha¹, Kumar Veerapen^{2

3}, Sook Khuan Chow^{4

5}, Suk Chyn Gun⁶, Ing Soo Lau⁷, Renee Lay Hong Lim⁸, Zaliha Zulkifli⁵, Yoon-Yen Yow¹, Suat Cheng Peh⁵, Jung Shan Hwang⁹

Affiliations

¹ Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Sunway Medical Centre, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
⁵ Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
⁶ Department of Medicine, Hospital Tuanku Ja'afar Seremban, Seremban, Negeri Sembilan, Malaysia.
⁷ Department of Medicine, Hospital Selayang, Batu Caves, Selangor Darul Ehsan, Malaysia.
⁸ Department of Biotechnology, Faculty of Applied Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia.
⁹ Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia. hwangjs@sunway.edu.my.

Abstract

Methotrexate (MTX) is the most widely used disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA). Many studies have attempted to understand the genetic risk factors that affect the therapeutic outcomes in RA patients treated with MTX. Unlike other studies that focus on the populations of Caucasians, Indian and east Asian countries, this study investigated the impacts of six single nucleotide polymorphisms (SNPs) that are hypothesized to affect the outcomes of MTX treatment in Malaysian RA patients. A total of 647 RA patients from three ethnicities (N_Malay = 153; N_Chinese = 326; N_Indian = 168) who received MTX monotherapy (minimum 15 mg per week) were sampled from three hospitals in Malaysia. SNPs were genotyped in patients using TaqMan real-time PCR assay. Data obtained were statistically analysed for the association between SNPs and MTX efficacy and toxicity. Analysis of all 647 RA patients indicated that none of the SNPs has influence on either MTX efficacy or MTX toxicity according to the Chi-square test and binary logistic regression. However, stratification by self-identified ancestries revealed that two out of six SNPs, ATIC C347G (rs2372536) (OR 0.5478, 95% CI 0.3396-0.8835, p = 0.01321) and ATIC T675C (rs4673993) (OR 0.5247, 95% CI 0.3248-0.8478, p = 0.008111), were significantly associated with MTX adequate response in RA patients with Malay ancestry (p < 0.05). As for the MTX toxicity, no significant association was identified for any SNPs selected in this study. Taken all together, ATIC C347G and ATIC T675C can be further evaluated on their impact in MTX efficacy using larger ancestry-specific cohort, and also incorporating high-order gene-gene and gene-environment interactions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antirheumatic Agents* / therapeutic use
Arthritis, Rheumatoid* / chemically induced
Arthritis, Rheumatoid* / drug therapy
Arthritis, Rheumatoid* / genetics
Humans
Malaysia
Metabolic Networks and Pathways
Methotrexate
Polymorphism, Single Nucleotide

Substances

Antirheumatic Agents
Methotrexate