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SM Journal of Pharmacology and Therapeutics

Influence of Genetic Polymorphisms of MDR1, RFC1, FPGS, GGH, and MTHFR on Methotrexate Efficacy and Toxicity in Chinese Patients with Rheumatoid Arthritis

[ ISSN : 2574-2396 ]

Abstract
Details

Received: 28-Apr-2015

Accepted: 25-May-2015

Published: 20-Jun-2015

Research Article | Volume 1 - Issue 1 | Article DOI :

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Xiao-lan MO¹²#, Jia-li LI³#, Jie CHEN¹, Xiu-yan YANG⁴, Min HUANG³, Moses SS Chow⁵, Yan-ling HE², Ye-chun YANG⁶, and Xiao CHEN¹*

¹ Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, China

² Department of Pharmacy, Guangzhou Women and Children’s Medical Center, China
³ Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, China
? Department of Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, China
? College of Pharmacy, Western University of Health Sciences, USA
? Statistics Room, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, China

Corresponding Author:

Xiao Chen, Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, China, Email: frankwychen@yahoo.com

Keywords

Methotrexate; Rheumatoid arthritis; Reduced folate carrier; Multidrug resistant transporter; Folylpolyglutamyl synthase; Methylenetetrahydrofolate reductase; Gamma glutamyl hydrolase; Single nucleotide polymorphisms; Chinese population

Abstract

Aim: To investigate the influence of genetic polymorphisms of Multidrug Resistant Gene (MDR1), Reduced Folate Carrier (RFC1), Folylpolyglutamyl Synthase (FPGS), Gamma Glutamyl Hydrolase (GGH), and Methylenetetrahydrofolate Reductase (MTHFR) on Methotrexate (MTX) efficacy and toxicity in Chinese patients with Rheumatoid Arthritis (RA).

Methods: One hundred and thirteen Rheumatoid Arthritis (RA) patients defined by the American College of Rheumatology (ACR) 1987 classification criteria were recruited in this study. All patients were treated with low-dose MTX (10-20 mg/week) without concomitant uses of other DMARDs for at least six months. RFC1 80G>A, MDR1 3435C>T, FPGS rs1544105 G>A, GGH - 401C>T, MTHFR 677C>T and MTHFR 1298A>C were genotyped by Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR–RFLP) methods. The MTX toxicity assessment was categorized according to the common toxicity criteria of the National Cancer Institute.

Result: The remission of RA symptoms was achieved in all the MDR1 3435TT genotype carriers (16/16), in 73.1% of subjects with 3435CT genotype (38/52), and in 75.6% of patients with 3435CC genotype (34/45) (P=0.046), respectively. Interaction between SNPs in RFC1 80 and MTHFR 1298 seemed to affect the efficacy of MTX with the best overall performances (accuracy of 0.67) and a CVC of 10/10 (P=0.002). MTHFR 677T allele carriers were more susceptible to MTX toxicity (P=0.007, OR:1.897, 95%CI: 1.725-2.087), compared to those with CC genotype. Of four diplotypes, patients with MTHFR CA-TA diplotype were more easy to experience toxicity (P=0.007, OR: 2.273, 95%CI: 1.303-3.964) when compared to patients without CA-TA diplotype.

Conclusion: MDR1 3435C>T might influence efficacy of RA therapy with MTX. Interaction between RFC1 80 and MTHFR 1298 seemed to impact MTX efficacy. Polymorphisms in the MTHFR gene were associated with toxicity of MTX. Further studies are warranted.

Citation

Mo X, Li J, Chen J, Yang X, Huang M, Chow MSS, et al. Influence of Genetic Polymorphisms of MDR1, RFC1, FPGS, GGH, and MTHFR on Methotrexate Efficacy and Toxicity in Chinese Patients with Rheumatoid Arthritis. SM J Pharmac Ther. 2015; 1(1): 1003.