The Prevalence of SNP rs12517451 in Gene Transcribing Dihydrofolate Reductase and Drug Adverse Effects among MTX- treated Rheumatoid Arthritis Patients in Kelantan, Malaysia
Main Article Content
Abstract
Introduction: Disease-modifying anti rheumatic drugs (DMARDs) provide the mainstay for the treatment of rheu- matoid arthritis (RA). Adverse effects (AEs) in DMARDs among RA patients are usually related with methotrexate (MTX) use, the common conventional DMARDs. Genetic variant such as single nucleotide polymorphism (SNP) in gene transcribing dihydrofolate reductase (DHFR) (i.e, 829C>T, rs12517451) has been correlated with drug AEs in MTX-treated RA. The prevalence of the DHFR rs12517451 SNP has been reported in other populations, but not in Malaysian. The aim of this study was to determine the prevalence of the DHFR rs12517451 SNP and its association with drug AEs among MTX-treated RA patients from Kelantan, Malaysia. Methods: A total of 78 RA patients receiving MTX (alone or in combination) were included in this study. Based on evidence of clinically perceived drug AEs in MTX-treated RA patients, 33 and 45 samples were assigned as cases and controls, respectively. The genotype of the patients was determined using the polymerase chain reaction-restriction fragment length polymorphism method and validated by sequencing analysis. Results: Minor allele frequency (MAF) for DHFR rs12517451 in cases and controls were 28.8% and 32.2% but there was no significant difference (p=0.727) for the possession of the minor allele T be- tween the two groups. The most reported AEs among cases were haematological effects, gastrointestinal toxicity, and skin problems resulting in 21% withdrawal of MTX. Conclusion: We did not find significant association of the DHFR rs12517451 with drug AEs in MTX-treated RA patients. Our findings warrant replication in a larger patient cohort.
Downloads
Article Details
References
Muralidharan N, Mariaselvam CM, Jain VK, Gulati R, Negi VS. ATIC 347C>G gene polymorphism may be associated with methotrexate-induced adverse events in south Indian Tamil rheumatoid arthritis. Pharmacogenomics. 2016;17(3):241–8.
Deane KD, Kristen Demoruelle M, Kelmenson LB, Kuhn KA, Norris JM, Michael Holers V. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3-18.
Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492-509.
Owen SA, Hider SL, Martin P, Bruce IN, Barton A, Thomson W. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharmacogenomics. 2013;13(3):227–34.
Allegra CJ, Fine RL, Drake JC, Chabner BA. The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells. Evidence for direct inhibition of purine synthesis. J Biol Chem. 1986;261(14):6478-85.
Swierkot J and Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 2006;58(4):473-92.
Sramek M, Neradil J, Veselska R. Much more than you expected: the non-DHFR-mediated effects of methotrexate. Biochim Biophys Acta Gen Subj. 2017;1861:499-503.
Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997;350:309-18.
Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, et al. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020;172(6):369-80.
Romão VC, Lima A, Bernardes M, Canhão H and Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: Can we predict toxicity? Immunol Res. 2014;60(2-3):289– 310.
Jekic B, Vejnovic, D, Milic V, Maksimovic N, Damnjanovic T, Bunjevacki V, et al. Association of 63/91 length polymorphism in the DHFR gene major promoter with toxicity of methotrexate in patients with rheumatoid arthritis. Pharmacogenomics. 2016;17(15):1687-91.
Askari BS, Krajinovic N. Dihydrofolate Reductase Gene Variations in Susceptibility to Disease and Treatment Outcomes, Current Genomics. Curr Genomics. 2010;11(8): 78–83.
Mishra PJ, Humeniuk R, Mishra, PJ, Longo-Sorbello GSA, Banerjee D, Bertino JRA. A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Nat Acad Sci. 2007;104:13513-18.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-24.
Wang H, Shao J, Chow SC. Sample size calculations in clinical research. 2nd ed., New York: Chapman & Hall/CRC; 2007.
Dupont WD,Plummer WD. Power and sample size program available for free on the internet. Control Clin Trials. 1997;18(3):274.
Hannessy S, Bilker WB, Berlin JA, Strom BL. Factors Influencing the Optimal Control-to-Case Ratio in Matched Case-Control Studies. Am J Epid. 1999;149(2):195-7).
Daly AK, Day CP. Candidate gene case-control association studies: advantages and potential pitfalls. Br J Clin Pharmacol. 2001;52(5):489-99.
Zhu H, Deng FY, Mo XB, Qiu YH, Lei SF. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014;15(4):551-66.
Serra M, Reverter-Branchat G, Maurici D, Benini S, Shen JN, Chano T, et al. Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells. Ann Oncol. 2004;15(1):151-60.
Koomdee N, Hongeng S, Apibal S, Pakakasama S. Association between polymorphisms of dihydrofolate reductase and gamma glutamyl hydrolase genes and toxicity of high dose methotrexate in children with acute lymphoblastic leukemia. Asian Pac J Cancer Prev. 2012;13(7):3461–4.
Wessels JAM, De Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YPM, Allaart CF, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006;54(4):1087–95.
Bohanec Grabar P, Logar D, Lestan B, Dolzan V. Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients : a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur J Pharmacol. 2008;64(11):1057–68.
Wessels JAM, De Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YPM, Allaart CF, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006;54(4):1087–95.
Kodidela S, Pradhan SC, Dubashi B, Basu D. Influence of dihydrofolate reductase gene polymorphisms rs408626 (-317A>G) and rs442767 (-680C>A) on the outcome of methotrexate-based maintenance therapy in South Indian patients with acute lymphoblastic leukemia. Eur J Clin Pharmacol. 2015;71(11):1349-58.
Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Singh P, et al. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among North Indians. Pharmacogenet Genomics. 2009;19(10):823-8.
Goto Y, Yue L, Yokoi A, Nishimura R, Uehara T, Koizumi S, et al. A novel single-nucleotide polymorphism in the 3’-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res. 2001;7(7):1952–6.
Salanti G, Amountza G, Ntzani EE, Ioannidis JPA. Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet. 2005;13:840-8.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos- Ioannidis DG. Replication validity of genetic association studies. Nat Genet. 2001;29(3):306-9.
Kumagai K, Hiyama K, Oyama T, Maeda H and Kohno N. Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med. 2003;11(5):593–600.
Taniguchi A, Urano W, Tanaka E, Furihata S, Kamitsuji S, Inoue E, et al. Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet Genomics. 2007;17(6):383–90.
Zeng Q-Y, Wang Y-K, Xiao Z-Y, Chen S-B. Pharmacogenetic study of 5,10-methylenetetrahydrofolate reductase C677T and thymidylate synthase 3R/2R gene polymorphisms and methotrexate-related toxicity in Chinese Han patients with inflammatory arthritis. Ann Rheum Dis. 2008;67(8):1193–4.
Ghodke-Puranik Y, Puranik AS, Shintre P, Joshi K, Patwardhan B, Lamba J, et al. Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis. Pharmacogenomics. 2015;16(18):2019–34.
Yanagimachi M, Naruto T, Hara T, Kikuchi M, Hara R, Miyamae T, et al. Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis. Br J Clin Pharmacol. 2011;71(2):237–43.
Takatori R, Takahashi KA, Tokunaga D, Hojo T, Fujioka M, Asano T, et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol. 2006;24(5):546–54.
Sakthiswary R, Chan GYL, Koh ET, Leong KP and Thong BYH. Methotrexate-Associated Nonalcoholic Fatty Liver Disease with Transaminitis in Rheumatoid Arthritis. The Scientific World Journal. 2014;823763.Epub 2014/5/28.
Hayashi H, Fujimaki C, Daimon T, Tsuboi S, Matsuyama T and Itoh K. Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J Clin Pharm Ther. 2009;34(3):355–61.
Premkumar B. Genetic polymorphisms influencing efficacy and safety of methotrexate in rheumatoid arthritis. Asian J Pharm Clin Res. 2018;11(8):395.
Muralidharan N, Antony PT, Jain VK, Mariaselvam CM and Negi VS. Multidrug resistance 1 (MDR1) 3435C>T gene polymorphism influences the clinical phenotype and methotrexate-induced adverse events in South Indian Tamil rheumatoid arthritis. Eur J Clin Pharmacol. 2015;71(8):959–65.
Bologna C, Viu P, Jorgensen C, Sany J. Effect of Age on the Efficacy and Tolerance of Methotrexate in Rheumatoid Arthritis. Br J Rheumatol. 1996;35(5):453–7.
Ede van AE, Laan RF, Rood MJ, Huizinga, TW, van de Laar MA, van Denderen CJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double- blind, placebo-controlled study. Arthritis Rheum. 2001;44(7):1515–24.
Aggarwal P, Sita N, Mishra KP, Amita A, Ramnath M. Correlation between methotrexate efficacy & toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J Med. 2006;124(5):521–6.
Fhlliquin P, Renoux M, Perrot S, Puechal X, Menkes CJ. Occurrence of pulmonary complications during methotrexate therapy in rheumatoid arthritis. Rheumatol. 1996;35(1):441-5.
Swierkot J, Szechiński J. Side effects of methotrexate treatment in patients with rheumatoid arthritis. Adv Clin Exp Med. 2008;17(4):387–94.
Buhroo AM, Ortho MS. Adverse effects of low-dose methotrexate in patients with rheumatoid arthritis. Indian J Physic Med Rehab. 2006;17(2):21–5.
Hong EP, Park JW. Sample size and statistical power calculation in genetic association studies. Genomic Inform. 2012;10(2):117-22.