GENETIC POLYMORPHISMS INFLUENCING EFFICACY AND SAFETY OF METHOTREXATE IN RHEUMATOID ARTHRITIS
Objective: This review will summarize pharmacogenetic studies of single nucleotide polymorphisms in genes coding enzymes of methotrexate (MTX) pathway, related to its response and toxicity in rheumatoid arthritis (RA). In addition, this review focuses on the racial and ethnic differences in distribution of the polymorphisms in genes related to efficacy and toxicity of MTX in RA.
Methods: Articles were searched using Pubmed database using the search term â€œpharmacogenetics and MTX and arthritis.â€ The search revealed 72 articles, of which 27 were given special importance, due to open-access.
Results: Many genes and single nucleotide polymorphisms are investigated in this context, and the highlighting genes are ATP-binding cassette proteins (ABCB1) reduced folate carrier (RFC), methylenetetrahydrofolatereductase (MTHFR), gamma-glutamyl hydrolase (GGH), serine hydroxyl methyltransferase (SHMT), 5-aminoimidazole-4-carboxamide ribonucleotidetransformylase (ATIC), methionine synthase reductase (MTRR), methionine synthase (MS), adenosine monophosphate deaminase1 (AMPD1), inosine triphosphate pyrophosphatase (ITPA). The study highlighted RFC-1 80AA, ITPA 94CC, and AMPD1 347CC as responders. The allelic types prone to toxicity were MTHFR 677TT, MTRR 2756AA, MS 66GG, SHMT 1420CC, ATIC 347GG, and thymidylate synthase *3/*2. The genotypes reported as non-responders were ABCB1 3434TT, MTHFR 1298AA, DHFR A317G, GGH 16CC, and GGH 401TT.
Conclusion: Although these studies highlight inconsistency in results, due to the difference in sample size and assessment parameters and racial and ethnic differences, larger prospective studies are essential to reach the cornerstone of the concept of personalized medicine.
2. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004;50:2766-74.
3. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: Implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007;65:168-73.
4. Subhani S, Jamil K, Nirni SS. Association of MDR1 gene (C3435T) polymorphism and gene expression profiling in lung cancer patients treated with platinum-based chemotherapy. Mol Diagn Ther 2015;19:289-97.
5. Taur SR, Kulkarni NB, Gandhe PP, Thelma BK, Ravat SH, Gogtay NJ, et al. Association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and activity of P-glycoprotein with response to anti-epileptic drugs. J Postgrad Med 2014;60:265-9.
6. Rao DN, Anuradha C, Vishnupriya S, Sailaja K, Surekha D, Raghunadharao D, et al. Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev 2010;11:1063-6.
7. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I, Gawronska- Szklarz B. The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther 2004;42:496-503.
8. 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;24:546-54.
9. Kato T, Hamada A, Mori S, Saito H. Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet 2012;27:192-9.
10. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, et al. Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genomics 2008;18:1041-9.
11. Grabar PB, 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 Clin Pharmacol 2008;64:1057-68.
12. Baslund B, Gregers J, Nielsen CH. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells. Rheumatology (Oxford) 2008;47:451-3.
13. Mirgal D, Ghosh K, Mahanta J, Dutta P, Shetty S. Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India. Trans R Soc Trop Med Hyg 2016;110:294-8.
14. Dorababu P, Naushad SM, Linga VG, Gundeti S, Nagesh N, Kutala VK, et al. Genetic variants of thiopurine and folate metabolic pathways determine 6-MP-mediated hematological toxicity in childhood ALL. Pharmacogenomics 2012;13:1001-8.
15. Naushad SM, Pavani A, Rupasree Y, Divyya S, Deepti S, Digumarti RR, et al. Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer. Mol Carcinog 2012;51 Suppl 1:E32-41.
16. Hashiguchi M, Shimizu M, Hakamata J, Tsuru T, Tanaka T, Suzaki M, et al. Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population. J Pharm Health Care Sci 2016;2:35.
17. Drozdzik M, Rudas T, Pawlik A, Kurzawski M, Czerny B, Gornik W, et al. The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur J Clin Pharmacol 2006;62:933-7.
18. Hayashi H, Tazoe Y, Tsuboi S, Horino M, Morishita M, Arai T, et al. A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet 2013;28:164-8.
19. 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;16:2019-34.
20. 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 Clin Pharmacol 2008;64:1057-68.
21. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111-3.
22. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998;64:169-72.
23. van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: A genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001;44:2525-30.
24. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics 2002;12:183-90.
25. 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;17:383-90.
26. Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ, et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 2006;54:607-12.
27. Brambila-Tapia AJ, DurÃ¡n-GonzÃ¡lez J, Sandoval-RamÃrez L, Mena JP, Salazar-PÃ¡ramo M, GÃ¡mez-Nava JI, et al. MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis. Dis Markers 2012;32:109-14.
28. Aggarwal P, Naik S, Mishra KP, Aggarwal A, Misra R. Correlation between methotrexate efficacy and toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J Med Res 2006;124:521-6.
29. Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, 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;54:1087-95.
30. Hughes LB, Beasley TM, Patel H, Tiwari HK, Morgan SL, Baggott JE, et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 2006;65:1213-8.
31. Davis LA, Polk B, Mann A, Wolff RK, Kerr GS, Reimold AM, et al. Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis. Clin Exp Rheumatol 2014;32:324-32.
32. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, et al. Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 2004;63:1227-31
33. Choe JY, Lee H, Jung HY, Park SH, Bae SC, Kim SK. Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int 2012;32:1837-42.
34. Naushad SM, Pavani A, Rupasree Y, Sripurna D, Gottumukkala SR, Digumarti RR, et al. Modulatory effect of plasma folate and polymorphisms in one-carbon metabolism on catecholamine methyltransferase (COMT) H108L associated oxidative DNA damage and breast cancer risk. Indian J Biochem Biophys 2011;48:283-9.
35. Mohammad NS, Jain JM, Chintakindi KP, Singh RP, Naik U, Akella RR. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet 2009;19:171-6.
36. 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. Pharmacogenet J 2013;13:227-34.
37. Milic V, Jekic B, Lukovic L, Bunjevacki V, Milasin J, Novakovic I, et al. Association of dihydrofolate reductase (DHFR)-317AA genotype with poor response to methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol 2012;30:178-83.
38. Chave KJ, Ryan TJ, Chmura SE, Galivan J. Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Gene 2003;319:167-75.
39. Oppeneer SJ, Ross JA, Koh WP, Yuan JM, Robien K. Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese health study. Mol Genet Metab 2012;105:73-8.
40. 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;19:823-8.
41. Kumagai K, Hiyama K, Oyama T, Maeda H, 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;11:593-600.
42. Stamp LK, Hazlett J, Roberts RL, Frampton C, Highton J, Hessian PA. Adenosine receptor expression in rheumatoid synovium: a basis for methotrexate action. Arthritis Res Ther 2012;14:R138.
43. Hider SL, Bruce IN, Thomson W. The pharmacogenetics of methotrexate. Rheumatology (Oxford) 2007;46:1520-4.
44. Wessels JA, Kooloos WM, De Jonge R, De Vries-Bouwstra JK, Allaart CF, Linssen A, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2006;54:2830-9.
45. Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW. Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. Rheumatology (Oxford) 2009;48:613-7.
46. Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 2006;54:3095-103.
47. Singh K, Singh SK, Raman R. MTHFR A1298C polymorphism and idiopathic male infertility. J Postgrad Med 2010;56:267-9.
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