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Pharmacogenomics of Autoimmune Diseases

  • Melvin George
  • Sandhiya Selvarajan
  • Suresh Kumar Srinivasamurthy
Chapter

Abstract

Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis cause a considerable degree of morbidity worldwide. Although the treatment of these conditions has shown progress over the last decade with the steady trickle of new drug molecules, drug therapy is far from satisfactory due to the reduced efficacy and maximal toxicity in certain patients. Several factors are known to influence the efficacy and toxicity of these drugs such as age, gender, liver and kidney function, and concomitant drug therapy. Another crucial factor influencing drug response of the patient is the genetic constitution of the patient. For example, polymorphisms in the gene MTHFR such as 677T>C can increase methotrexate serum levels and lead to toxicity in a patient with RA. Similarly polymorphisms in the drug transporter ABCB1 are associated with decreased efficacy to methotrexate. Polymorphisms within the TNF promoter region have been shown to modify the clinical efficacy and toxicity of anti-TNF therapy in RA patients. SLE patients with polymorphic TPMT gene may require a reduced dose of azathioprine to circumvent the catastrophe of fatal bone marrow suppression. Polymorphisms in the TYMS gene could lead to reduced efficacy with methotrexate in psoriatic arthritis patients. Although our understanding of autoimmune diseases has improved considerably over the last decade and several studies in pharmacogenomics of autoimmune diseases have been carried out, the only clinical application is TPMT testing for azathioprine. Yet with improved methodology adopted in pharmacogenomics studies coupled with novel technologies, the field of pharmacogenomics does appear to offer significant promise in the coming years towards the dream of personalized medicine in autoimmune diseases.

Keywords

Systemic Lupus Erythematosus Rheumatoid Arthritis Patient Systemic Lupus Erythematosus Patient Psoriatic Arthritis Certolizumab Pegol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Acikbas I, Sanli B, Tepeli E, Ergin S, Aktan S, Bagci H (2012) Vitamin D receptor gene polymorphisms and haplotypes (Apa I, Bsm I, Fok I, Taq I) in Turkish psoriasis patients. Med Sci Monit 18:CR661–CR666PubMedCentralPubMedGoogle Scholar
  2. Aggarwal P, Naik S, Mishra KP, Aggarwal A, Misra R (2006) Correlation between methotrexate efficacy & toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J Med Res 124:521–526PubMedGoogle Scholar
  3. Bluett J, Barton A (2012) What have genome-wide studies told us about psoriatic arthritis? Curr Rheumatol Rep 14:364–368PubMedCrossRefGoogle Scholar
  4. Cargill M, Schrodi SJ, Chang M et al (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–290PubMedCentralPubMedCrossRefGoogle Scholar
  5. Chen H, Poon A, Yeung C et al (2011) A genetic risk score combining ten psoriasis risk loci improves disease prediction. PLoS One 6:e19454PubMedCentralPubMedCrossRefGoogle Scholar
  6. Chouchana L, Narjoz C, Beaune P, Loriot MA, Roblin X (2012) Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 35:15–36PubMedCrossRefGoogle Scholar
  7. Cobos A, Sanchez P, Aguado J, Carrasco JL (2011) Methodological quality in pharmacogenetic studies with binary assessment of treatment response: a review. Pharmacogenet Genomics 21:243–250PubMedCrossRefGoogle Scholar
  8. Cooper GS, Stroehla BC (2003) The epidemiology of autoimmune diseases. Autoimmun Rev 2:119–125PubMedCrossRefGoogle Scholar
  9. Coulthard LR, Taylor JC, Eyre S et al (2011) Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis 70:98–103PubMedCrossRefGoogle Scholar
  10. Criswell LA, Lum RF, Turner KN et al (2004) The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 50:2750–2756PubMedCrossRefGoogle Scholar
  11. Cuchacovich M, Ferreira L, Aliste M et al (2004) Tumour necrosis factor-alpha (TNF-alpha) levels and influence of −308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 33:228–232PubMedCrossRefGoogle Scholar
  12. Cui J, Saevarsdottir S, Thomson B et al (2010) Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. Arthritis Rheum 62:1849–1861PubMedCentralPubMedGoogle Scholar
  13. Davila L, Ranganathan P (2011) Pharmacogenetics: implications for therapy in rheumatic diseases. Nat Rev Rheumatol 7:537–550PubMedCrossRefGoogle Scholar
  14. Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland RA (1996) The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry 35:1270–1273PubMedCrossRefGoogle Scholar
  15. de Rotte MC, Luime JJ, Bulatovic M, Hazes JM, Wulffraat NM, de Jonge R (2010) Do snapshot statistics fool us in MTX pharmacogenetic studies in arthritis research? Rheumatology (Oxford) 49:1200–1201CrossRefGoogle Scholar
  16. De IS, Stocco G, Martelossi S et al (2011) Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases. J Clin Gastroenterol 45:e1–e7CrossRefGoogle Scholar
  17. Duerr RH, Taylor KD, Brant SR et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–1463PubMedCrossRefGoogle Scholar
  18. Dziedziejko V, Kurzawski M, Safranow K, Chlubek D, Pawlik A (2011) The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 12:41–47PubMedCrossRefGoogle Scholar
  19. Fisher MC, Cronstein BN (2009) Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 36:539–545PubMedCentralPubMedCrossRefGoogle Scholar
  20. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64(Suppl 2):ii14–ii17PubMedCentralPubMedGoogle Scholar
  21. Grabar PB, Rozman B, Logar D, Praprotnik S, Dolzan V (2009) Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis. Ann Rheum Dis 68:1367–1368PubMedCrossRefGoogle Scholar
  22. Haider AS, Lowes MA, Suarez-Farinas M et al (2008) Identification of cellular pathways of “type 1,” Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol 180:1913–1920PubMedGoogle Scholar
  23. Halsall JA, Osborne JE, Pringle JH, Hutchinson PE (2005) Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet Genomics 15:349–355PubMedCrossRefGoogle Scholar
  24. Haritunians T, Taylor KD, Targan SR et al (2010) Genetic predictors of medically refractory ulcerative colitis. Inflamm Bowel Dis 16:1830–1840PubMedCentralPubMedCrossRefGoogle Scholar
  25. Hebert HL, Ali FR, Bowes J, Griffiths CE, Barton A, Warren RB (2012) Genetic susceptibility to psoriasis and psoriatic arthritis: implications for therapy. Br J Dermatol 166:474–482PubMedCrossRefGoogle Scholar
  26. Hoebert JM, Mantel-Teeuwisse AK, van Dijk L, Bijlsma JW, Leufkens HG (2012) Do rheumatoid arthritis patients have equal access to treatment with new medicines?: tumour necrosis factor-alpha inhibitors use in four European countries. Health Policy 104:76–83PubMedCrossRefGoogle Scholar
  27. Hughes LB, Beasley TM, Patel H et al (2006) 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 65:1213–1218PubMedCentralPubMedCrossRefGoogle Scholar
  28. Ishihara S, Aziz MM, Yuki T, Kazumori H, Kinoshita Y (2009) Inflammatory bowel disease: review from the aspect of genetics. J Gastroenterol 44:1097–1108PubMedCrossRefGoogle Scholar
  29. Jankovic S, Raznatovic M, Marinkovic J et al (2011) Health-related quality of life in patients with psoriasis. J Cutan Med Surg 15:29–36PubMedGoogle Scholar
  30. Jorgensen AL, Williamson PR (2008) Methodological quality of pharmacogenetic studies: issues of concern. Stat Med 27:6547–6569PubMedCrossRefGoogle Scholar
  31. Jurgens M, Laubender RP, Hartl F et al (2010) Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. Am J Gastroenterol 105:1811–1819PubMedCrossRefGoogle Scholar
  32. Kelly PJ, Stallard N, Whittaker JC (2005) Statistical design and analysis of pharmacogenetic trials. Stat Med 24:1495–1508PubMedCrossRefGoogle Scholar
  33. Langley RG, Krueger GG, Griffiths CE (2005) Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 64(Suppl 2):ii18–ii23; discussion ii24–ii5PubMedCentralPubMedGoogle Scholar
  34. Lee YH, Song GG (2010) Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin Drug Investig 30:101–108PubMedCrossRefGoogle Scholar
  35. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG (2006) Association of TNF-alpha −308 G/A polymorphism with responsiveness to TNF-alpha-blockers in rheumatoid arthritis: a meta-analysis. Rheumatol Int 27:157–161PubMedCrossRefGoogle Scholar
  36. Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW (2009) Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. Rheumatology (Oxford) 48:613–617CrossRefGoogle Scholar
  37. Lee YH, Ji JD, Bae SC, Song GG (2010) Associations between tumor necrosis factor-alpha (TNF-alpha) −308 and −238 G/A polymorphisms and shared epitope status and responsiveness to TNF-alpha blockers in rheumatoid arthritis: a metaanalysis update. J Rheumatol 37:740–746PubMedCrossRefGoogle Scholar
  38. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2012) Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis: a meta-analysis. Inflamm Res 61:635–641PubMedCrossRefGoogle Scholar
  39. Leonardi CL, Kimball AB, Papp KA et al (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665–1674PubMedCrossRefGoogle Scholar
  40. Liu Y, Helms C, Liao W et al (2008) A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 4:e1000041PubMedCentralPubMedCrossRefGoogle Scholar
  41. Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517PubMedCrossRefGoogle Scholar
  42. Louis E, Franchimont D, Piron A et al (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113:401–406PubMedCentralPubMedGoogle Scholar
  43. Mak RK, Hundhausen C, Nestle FO (2009) Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr 100(Suppl 2):2–13PubMedCentralPubMedCrossRefGoogle Scholar
  44. Milic V, Jekic B, Lukovic L et al (2012) Association of dihydrofolate reductase (DHFR) -317AA genotype with poor response to methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol 30:178–183PubMedGoogle Scholar
  45. Mittal N, Mittal R, Sharma A, Jose V, Wanchu A, Singh S (2012) Treatment failure with disease-modifying antirheumatic drugs in rheumatoid arthritis patients. Singap Med J 53:532–536Google Scholar
  46. Molodecky NA, Soon IS, Rabi DM et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46–54PubMedCrossRefGoogle Scholar
  47. Montrone M, Martorelli D, Rosato A, Dolcetti R (2009) Retinoids as critical modulators of immune functions: new therapeutic perspectives for old compounds. Endocr Metab Immune Disord Drug Targets 9:113–131PubMedCrossRefGoogle Scholar
  48. Nair RP, Duffin KC, Helms C et al (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41:199–204PubMedCentralPubMedCrossRefGoogle Scholar
  49. Ngamjanyaporn P, Thakkinstian A, Verasertniyom O et al (2011) Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus. Rheumatol Int 31:1215–1218PubMedCrossRefGoogle Scholar
  50. Niriella MA, De Silva AP, Dayaratne AH et al (2010) Prevalence of inflammatory bowel disease in two districts of Sri Lanka: a hospital based survey. BMC Gastroenterol 10:32PubMedCentralPubMedCrossRefGoogle Scholar
  51. Owlia MB, Mostafavi Pour Manshadi SM, Naderi N (2012) Cardiac manifestations of rheumatological conditions: a narrative review. ISRN Rheumatol 2012:463620. doi: 10.5402/2012/463620, Epub 2012 Oct 17PubMedCentralPubMedGoogle Scholar
  52. Pawlik A, Herczynska M, Kurzawski M, Safranow K, Dziedziejko V, Drozdzik M (2009) The effect of exon (19C > A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 10:303–309PubMedCrossRefGoogle Scholar
  53. Potter C, Cordell HJ, Barton A et al (2010) Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis 69:1315–1320PubMedCrossRefGoogle Scholar
  54. Press RR, de Fijter JW, Guchelaar HJ (2010) Individualizing calcineurin inhibitor therapy in renal transplantation–current limitations and perspectives. Curr Pharm Des 16:176–186PubMedCrossRefGoogle Scholar
  55. Ranganathan P, Culverhouse R, Marsh S et al (2008) Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 35:572–579PubMedGoogle Scholar
  56. Reichert JM (2012) Marketed therapeutic antibodies compendium. MAbs 4:413–415PubMedCentralPubMedCrossRefGoogle Scholar
  57. Schmeling H, Biber D, Heins S, Horneff G (2005) Influence of methylenetetrahydrofolate reductase polymorphisms on efficacy and toxicity of methotrexate in patients with juvenile idiopathic arthritis. J Rheumatol 32:1832–1836PubMedGoogle Scholar
  58. Smits KM, Schouten JS, Smits LJ, Stelma FF, Nelemans P, Prins MH (2005) A review on the design and reporting of studies on drug-gene interaction. J Clin Epidemiol 58:651–654PubMedCrossRefGoogle Scholar
  59. Tan RJ, Gibbons LJ, Potter C et al (2010) Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment. Ann Rheum Dis 69:1029–1035PubMedCentralPubMedCrossRefGoogle Scholar
  60. Taniguchi A, Urano W, Tanaka E et al (2007) 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 17:383–390PubMedCrossRefGoogle Scholar
  61. Taraborelli M, Andreoli L, Archetti S, Ferrari M, Cattaneo R, Tincani A (2009a) Methylenetetrahydrofolate reductase polymorphisms in methotrexate treatment of rheumatoid arthritis patients. Review of the literature and personal experience. Reumatismo 61:98–106PubMedGoogle Scholar
  62. Taraborelli M, Andreoli L, Archetti S, Ferrari M, Cattaneo R, Tincani A (2009b) Methylenetetrahydrofolate reductase polymorphisms and methotrexate: no association with response to therapy nor with drug-related adverse events in an Italian population of rheumatic patients. Clin Exp Rheumatol 27:499–502PubMedGoogle Scholar
  63. Vasku V, Bienertova VJ, Pavkova GM, Vasku A (2007) Three retinoid X receptor gene polymorphisms in plaque psoriasis and psoriasis guttata. Dermatology 214:118–124PubMedGoogle Scholar
  64. Wahie S, Daly AK, Cordell HJ et al (2011) Clinical and pharmacogenetic influences on response to hydroxychloroquine in discoid lupus erythematosus: a retrospective cohort study. J Investig Dermatol 131:1981–1986PubMedCrossRefGoogle Scholar
  65. Warren RB, Smith RL, Campalani E et al (2009) Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol 160:438–441PubMedCentralPubMedCrossRefGoogle Scholar
  66. Weizman AV, Silverberg MS (2012) Have genomic discoveries in inflammatory bowel disease translated into clinical progress? Curr Gastroenterol Rep 14:139–145PubMedCrossRefGoogle Scholar
  67. Wessels JA, de Vries-Bouwstra JK, Heijmans BT et al (2006) Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 54:1087–1095PubMedCrossRefGoogle Scholar
  68. Yanagimachi M, Naruto T, Hara T et al (2011) 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 71:237–243PubMedCentralPubMedCrossRefGoogle Scholar
  69. Young HS, Summers AM, Read IR et al (2006) Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis. J Investig Dermatol 126:453–459PubMedCrossRefGoogle Scholar
  70. Zaba LC, Suarez-Farinas M, Fuentes-Duculan J et al (2009) Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol 124:1022–1030PubMedCentralPubMedCrossRefGoogle Scholar
  71. Zhong S, Huang M, Yang X et al (2006) Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br J Clin Pharmacol 62:457–472PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2013

Authors and Affiliations

  • Melvin George
    • 1
  • Sandhiya Selvarajan
    • 2
  • Suresh Kumar Srinivasamurthy
    • 2
  1. 1.Department of CardiologySRM Medical College and Hospital Research CentreKattankulathur, Kancheepuram DistrictIndia
  2. 2.Division of Clinical PharmacologyJIPMERPondicherryIndia

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