title: Pharmacogenetics: can genes determine treatment efficacy and safety in JIA?
abstract: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood, with many children requiring immunomodulatory therapies for many years following diagnosis. A considerable proportion of children experience therapeutic inefficacy or substantial adverse effects, or both, but a lack of reliable clinical indicators and biomarkers to predict treatment response prevents optimization of existing therapies. The identification of valid candidate gene variants involved in the pathways of methotrexate and etanercept, the most commonly used medications in JIA, has seen little success to date. The limited success of these studies is possibly due to the presence of confounding variables in the study populations, the heterogeneity of outcome parameters used to determine treatment response and the small number of candidate gene variants analysed. The first genome-wide pharmacogenetic study in JIA has identified gene regions of particular biological interest, but these findings require validation. Moreover, epigenetic mechanisms as well as ontogeny processes might be additional factors influencing drug responses. Access to large, well-documented JIA cohorts and the rapid development of advanced genome analytics is ushering in a personalized approach to treatment. The discovery of new pharmacogenomic biomarkers and systems pathways can provide new drug targets and predictive tools for improved drug response and fewer adverse drug reactions in JIA.
authors.affiliation: Alberta Children's Hospital Research Institute, University of Calgary, Heritage Medical Research Building, Room 293, 3330 Hospital Drive, NW, Calgary, AB T2N 4N1, Canada.
authors.forename: Heinrike
authors.initials: H
authors.lastname: Schmeling
authors.affiliation: Centre of General Paediatrics and Neonatology, Department of Paediatrics, Asklepios Clinics, Arnold-Janssen Strasse 29, 537, Sankt Augustin D-53757, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Horneff
authors.affiliation: Alberta Children's Hospital Research Institute, University of Calgary, Heritage Medical Research Building, Room 293, 3330 Hospital Drive, NW, Calgary, AB T2N 4N1, Canada.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Benseler
authors.affiliation: Cumming School of Medicine, Health Sciences Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
mesh_terms: D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D044127:Epigenesis, Genetic; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008727:Methotrexate / Q000627:therapeutic use*; D010597:Pharmacogenetics; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept; D008727:Methotrexate
references.citation: Rheumatol Int. 2007 Feb;27(4):383-6
references.pmid: 16951943
references.citation: Clin Pharmacol Ther. 2007 Apr;81(4):477-9
references.pmid: 17375103
references.citation: J Rheumatol. 2013 Dec;40(12):2088-96
references.pmid: 24187099
references.citation: J Rheumatol. 2004 Feb;31(2):390-2
references.pmid: 14760812
references.citation: Rheumatology (Oxford). 2014 Dec;53(12):2155-66
references.pmid: 24987157
references.citation: Ann Rheum Dis. 2012 Sep;71(9):1484-9
references.pmid: 22473625
references.citation: Mt Sinai J Med. 1993 May;60(3):209-17
references.pmid: 8345848
references.citation: Ann Rheum Dis. 2008 Aug;67(8):1193-4
references.pmid: 18621970
references.citation: Arthritis Care Res (Hoboken). 2011 Jul;63(7):929-36
references.pmid: 21717596
references.citation: Am J Hum Genet. 2012 Apr 6;90(4):636-47
references.pmid: 22482804
references.citation: Pharmacogenomics J. 2013 Apr;13(2):137-47
references.pmid: 21931346
references.citation: Paediatr Drugs. 2010 Dec 1;12(6):367-77
references.pmid: 21028916
references.citation: N Engl J Med. 1992 Apr 16;326(16):1043-9
references.pmid: 1549149
references.citation: J Neurol Sci. 2006 Oct 25;248(1-2):56-61
references.pmid: 16774768
references.citation: J Inherit Metab Dis. 1996;19(5):589-94
references.pmid: 8892013
references.citation: Clin Pharmacokinet. 1996 Mar;30(3):194-210
references.pmid: 8882301
references.citation: Clin Pharmacokinet. 2002;41(12):959-98
references.pmid: 12222995
references.citation: J Physiol Biochem. 2010 Jun;66(2):173-80
references.pmid: 20596903
references.citation: Ann Rheum Dis. 2007 Jul;66(7):900-4
references.pmid: 17324969
references.citation: Rheumatology (Oxford). 2005 Aug;44(8):995-1001
references.pmid: 15827045
references.citation: Ann N Y Acad Sci. 2007 Jun;1108:127-36
references.pmid: 17893979
references.citation: Ann Rheum Dis. 2013 Jan;72(1):110-7
references.pmid: 22736089
references.citation: J Rheumatol. 2005 Sep;32(9):1832-6
references.pmid: 16142884
references.citation: Ann Rheum Dis. 2011 Aug;70(8):1395-400
references.pmid: 21515602
references.citation: Arthritis Care Res (Hoboken). 2011 Apr;63(4):465-82
references.pmid: 21452260
references.citation: J Clin Rheumatol. 2008 Apr;14(2):109-19
references.pmid: 18391684
references.citation: J Rheumatol. 2006 Apr;33(4):789-95
references.pmid: 16482643
references.citation: Rheumatology (Oxford). 2013 Nov;52(11):1941-51
references.pmid: 23630368
references.citation: Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S102-9
references.pmid: 21044441
references.citation: Blood. 2003 May 15;101(10):3862-7
references.pmid: 12531808
references.citation: Clin Cancer Res. 2002 Jul;8(7):2423-9
references.pmid: 12114448
references.citation: J Rheumatol. 2004 Nov;31(11):2290-4
references.pmid: 15517647
references.citation: Leukemia. 2007 Oct;21(10):2128-36
references.pmid: 17673902
references.citation: Pharmacol Ther. 2008 May;118(2):250-67
references.pmid: 18406467
references.citation: Pharmacol Ther. 2008 Feb;117(2):244-79
references.pmid: 18155297
references.citation: Pharmacogenomics. 2010 Nov;11(11):1591-602
references.pmid: 21121777
references.citation: Bull NYU Hosp Jt Dis. 2007;65(3):168-73
references.pmid: 17922664
references.citation: Arthritis Rheum. 2006 May;54(5):1366-77
references.pmid: 16645965
references.citation: Pharmacol Rev. 2005 Jun;57(2):163-72
references.pmid: 15914465
references.citation: Arthritis Rheum. 2001 Nov;44(11):2525-30
references.pmid: 11710708
references.citation: Clin Pharmacol Ther. 2010 Dec;88(6):757-9
references.pmid: 21081946
references.citation: Ann Rheum Dis. 2004 Dec;63(12):1638-44
references.pmid: 15115709
references.citation: Expert Rev Clin Pharmacol. 2009 Jan;2(1):55-65
references.pmid: 24422771
references.citation: Clin Immunol. 2012 Feb;142(2):176-93
references.pmid: 22154868
references.citation: Arch Dis Child. 2003 Mar;88(3):197-200
references.pmid: 12598376
references.citation: Pharmacogenet Genomics. 2005 Aug;15(8):523-33
references.pmid: 16006996
references.citation: Arthritis Rheum. 2011 Jul;63(7):2007-13
references.pmid: 21437879
references.citation: Pharmacogenomics J. 2014 Aug;14(4):356-64
references.pmid: 24709693
references.citation: Nat Clin Pract Rheumatol. 2007 Jan;3(1):26-34
references.pmid: 17203006
references.citation: Clin Chem. 2003 Oct;49(10):1632-41
references.pmid: 14500588
references.citation: Curr Opin Drug Discov Devel. 2003 May;6(3):297-303
references.pmid: 12833660
references.citation: Cell Mol Immunol. 2011 May;8(3):226-36
references.pmid: 21278766
references.citation: Clin Pharmacol Ther. 2011 Jun;89(6):902-7
references.pmid: 21508940
references.citation: Rheumatology (Oxford). 2013 Sep;52(9):1674-9
references.pmid: 23740187
references.citation: Ann Rheum Dis. 2004 Oct;63(10):1227-31
references.pmid: 15361376
references.citation: Arthritis Rheum. 1997 Jul;40(7):1202-9
references.pmid: 9214419
references.citation: J Rheumatol. 2011 May;38(5):938-53
references.pmid: 21362761
references.citation: J Clin Invest. 1993 Dec;92(6):2675-82
references.pmid: 8254024
references.citation: Adv Exp Med Biol. 1994;370:411-6
references.pmid: 7660940
references.citation: Pharmacogenet Genomics. 2009 Jun;19(6):403
references.pmid: 20161212
references.citation: Clin Pharmacokinet. 2002;41(13):1077-94
references.pmid: 12403644
references.citation: Ann Rheum Dis. 2011 Jan;70(1):4-7
references.pmid: 21068091
references.citation: Arthritis Res Ther. 2009;11(1):216
references.pmid: 19291269
references.citation: Curr Rheumatol Rep. 2006 Dec;8(6):450-8
references.pmid: 17092444
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19934-9
references.pmid: 19897727
references.citation: Pharmacogenet Genomics. 2011 Oct;21(10):679-86
references.pmid: 21317831
references.citation: Lupus. 2011 Feb;20(2):131-6
references.pmid: 21078759
references.citation: Purinergic Signal. 2007 Mar;3(1-2):145-52
references.pmid: 18404428
references.citation: Ann Rheum Dis. 2013 Feb;72(2):165-78
references.pmid: 23178294
references.citation: Pharmacogenet Genomics. 2007 Jun;17(6):383-90
references.pmid: 17502830
references.citation: Pharmacogenet Genomics. 2005 Oct;15(10):705-11
references.pmid: 16141796
references.citation: J Rheumatol. 2012 Oct;39(10):2032-40
references.pmid: 22859359
references.citation: Indian J Med Res. 2006 Nov;124(5):521-6
references.pmid: 17213520
references.citation: J Rheumatol. 2008 Apr;35(4):562-71
references.pmid: 18322994
references.citation: N Engl J Med. 2003 Sep 18;349(12):1157-67
references.pmid: 13679531
references.citation: Biomark Med. 2011 Dec;5(6):781-94
references.pmid: 22103612
references.citation: Ann Rheum Dis. 2014 Jun;73(6):1114-22
references.pmid: 23696632
references.citation: Curr Opin Rheumatol. 2007 Sep;19(5):471-6
references.pmid: 17762613
references.citation: Methods Mol Biol. 2013;1015:311-20
references.pmid: 23824865
references.citation: Am J Hum Genet. 1998 May;62(5):1044-51
references.pmid: 9545395
references.citation: Arthritis Rheum. 2013 Oct;65(10):2499-512
references.pmid: 24092554
references.citation: Pharmacogenet Genomics. 2010 Nov;20(11):665-76
references.pmid: 20827233
references.citation: Arthritis Res. 2002;4(4):266-73
references.pmid: 12106498
references.citation: J Biol Chem. 2006 Aug 18;281(33):23748-56
references.pmid: 16777850
references.citation: Reproduction. 2009 Sep;138(3):493-505
references.pmid: 19531609
references.citation: Arthritis Rheum. 2003 Jan;48(1):240-7
references.pmid: 12528125
references.citation: Genome Res. 2010 Feb;20(2):170-9
references.pmid: 20028698
references.citation: J Investig Dermatol Symp Proc. 2007 May;12(1):5-8
references.pmid: 17502862
references.citation: Arthritis Rheum. 2009 Jan 15;61(1):46-51
references.pmid: 19116975
references.citation: Clin Exp Rheumatol. 1999 May-Jun;17(3):367-74
references.pmid: 10410275
references.citation: Arthritis Res Ther. 2006;8(2):R53
references.pmid: 16519795
references.citation: Pharmacogenomics. 2004 Mar;5(2):139-41
references.pmid: 15016603
references.citation: Ann Rheum Dis. 1999 Feb;58(2):79-84
references.pmid: 10343521
references.citation: Clin Exp Rheumatol. 1999 May-Jun;17(3):313-20
references.pmid: 10410264
references.citation: Pediatr Rheumatol Online J. 2013 May 28;11(1):23
references.pmid: 23714105
references.citation: Ann Neurol. 2011 Dec;70(6):897-912
references.pmid: 22190364
references.citation: Nat Genet. 1995 May;10(1):111-3
references.pmid: 7647779
references.citation: Expert Opin Biol Ther. 2013 Mar;13(3):361-76
references.pmid: 23289865
references.citation: J Endocrinol. 2001 Jun;169(3):453-9
references.pmid: 11375115
references.citation: Int J Mol Med. 2003 May;11(5):593-600
references.pmid: 12684695
references.citation: Pharmacogenet Genomics. 2012 Feb;22(2):117-33
references.pmid: 22143415
references.citation: Pharmacogenetics. 2002 Apr;12(3):183-90
references.pmid: 11927833
references.citation: Nat Genet. 2010 Dec;42(12):1118-25
references.pmid: 21102463
references.citation: Inflammation. 1992 Oct;16(5):411-23
references.pmid: 1428120
references.citation: Arthritis Rheum. 2011 Jan;63(1):276-85
references.pmid: 20954192
references.citation: Clin Epigenetics. 2012 Nov 13;4(1):20
references.pmid: 23148518
references.citation: Mol Genet Metab. 1998 Jul;64(3):169-72
references.pmid: 9719624
references.citation: Clin Chim Acta. 2013 Nov 15;426:127-38
references.pmid: 24035970
references.citation: Hum Immunol. 1998 Sep;59(9):571-9
references.pmid: 9757913
references.citation: J Rheumatol. 2010 Oct;37(10):2180-6
references.pmid: 20595278
references.citation: Arthritis Rheum. 2007 May;56(5):1440-5
references.pmid: 17469101
references.citation: Mol Immunol. 1999 Oct-Nov;36(15-16):1017-27
references.pmid: 10698305
references.citation: Clin Rev Allergy Immunol. 2012 Feb;42(1):92-101
references.pmid: 22161696
references.citation: Curr Opin Pediatr. 2007 Feb;19(1):15-22
references.pmid: 17224657
references.citation: Br J Clin Pharmacol. 2011 Feb;71(2):237-43
references.pmid: 21219404
references.citation: Arthritis Rheum. 2008 May;58(5):1496-504
references.pmid: 18438876
references.citation: Pharmacogenomics. 2007 Oct;8(10):1403-11
references.pmid: 17979513
references.citation: Pharmacogenomics. 2007 Nov;8(11):1551-9
references.pmid: 18034620
references.citation: Arthritis Rheum. 2009 May 15;61(5):658-66
references.pmid: 19405003
references.citation: Arthritis Rheum. 2005 Nov;52(11):3554-62
references.pmid: 16255044
references.citation: Mutat Res. 2005 Jun 3;573(1-2):180-94
references.pmid: 15829247
references.citation: Ocul Immunol Inflamm. 2013 Jun;21(3):180-91
references.pmid: 23713827
references.citation: JAMA Intern Med. 2013 Aug 12;173(15):1416-28
references.pmid: 23797343
references.citation: N Engl J Med. 2002 Oct 31;347(18):1462-70
references.pmid: 12409558
references.citation: Arthritis Rheum. 2009 Sep;60(9):2794-804
references.pmid: 19714630