title: Genetics and epigenetics of rheumatoid arthritis.
abstract: Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions.
authors: Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors: Sebastien
authors: S
authors: Viatte
authors: Darren
authors: D
authors: Plant
authors: Soumya
authors: S
authors: Raychaudhuri
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D019175:DNA Methylation; D057890:Epigenomics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006867:Hydrolases / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
chemical_list: D006867:Hydrolases; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
references: Nat Genet. 2009 Sep;41(9):1011-5
references: 19701192
references: Genome Med. 2012 Jan 20;4(1):2
references: 22264340
references: Cell. 2007 Feb 23;128(4):693-705
references: 17320507
references: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references: 22243964
references: Nat Immunol. 2012 Apr 18;13(5):439-47
references: 22513334
references: Am J Hum Genet. 2012 Mar 9;90(3):524-32
references: 22365150
references: Genome Res. 2003 May;13(5):868-74
references: 12727906
references: Curr Opin Rheumatol. 2010 May;22(3):293-8
references: 20061955
references: Arthritis Rheum. 2009 Jan;60(1):53-62
references: 19116923
references: Curr Opin Rheumatol. 2010 Mar;22(2):109-18
references: 20075733
references: Arthritis Rheum. 2011 Oct;63(10):2873-83
references: 21567378
references: Nat Genet. 2012 Jan 29;44(3):291-6
references: 22286218
references: Nat Rev Genet. 2009 May;10(5):295-304
references: 19308066
references: Epidemiology. 2009 Jul;20(4):508-11
references: 19525687
references: Am J Hum Genet. 2012 Jun 8;90(6):962-72
references: 22633398
references: Nat Genet. 2010 Jun;42(6):508-14
references: 20453842
references: PLoS One. 2011;6(10):e26277
references: 22046267
references: Arthritis Rheum. 1996 May;39(5):732-5
references: 8639169
references: Arthritis Rheum. 1987 Nov;30(11):1205-13
references: 2446635
references: Arthritis Rheum. 2000 Jan;43(1):30-7
references: 10643697
references: Nat Genet. 2012 Mar 25;44(5):483-9
references: 22446960
references: J Immunol. 2003 Jul 15;171(2):538-41
references: 12847215
references: Nat Genet. 2012 Dec;44(12):1336-40
references: 23143596
references: Ann Rheum Dis. 2012 Dec;71(12):1984-90
references: 22661644
references: Nat Genet. 2005 May;37(5):478-85
references: 15838509
references: Nat Rev Genet. 2010 Mar;11(3):191-203
references: 20125086
references: Nat Genet. 2010 Jun;42(6):515-9
references: 20453841
references: N Engl J Med. 2007 Sep 20;357(12):1199-209
references: 17804836
references: Arthritis Rheum. 2011 Feb;63(2):373-81
references: 21279994
references: Ann Rheum Dis. 2013 Jan;72(1):110-7
references: 22736089
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17372-7
references: 21987802
references: Mol Med. 2008 May-Jun;14(5-6):293-300
references: 18309376
references: Nat Genet. 2011 Oct 23;43(12):1232-6
references: 22019782
references: Nat Genet. 2005 Dec;37(12):1317-9
references: 16273109
references: Am J Hum Genet. 2008 Jan;82(1):48-56
references: 18179884
references: Nature. 2003 May 15;423(6937):356-61
references: 12748655
references: Nat Genet. 2011 Oct 09;43(11):1066-73
references: 21983784
references: Arthritis Rheum. 2005 Sep;52(9):2637-44
references: 16142711
references: Open Access Rheumatol. 2011 Jun 07;3:31-46
references: 27790002
references: Science. 1990 Oct 12;250(4978):223-8
references: 2218526
references: Nat Genet. 2009 Feb;41(2):178-186
references: 19151715
references: Nat Rev Genet. 2009 Jan;10(1):43-55
references: 19092835
references: Nat Rev Rheumatol. 2010 May;6(5):290-5
references: 20234359
references: PLoS Med. 2007 Sep;4(9):e278
references: 17880261
references: Nat Genet. 2007 Dec;39(12):1431-3
references: 17982455
references: Arthritis Rheum. 2009 Jan;60(1):30-8
references: 19116921
references: Nature. 2007 May 24;447(7143):425-32
references: 17522676
references: Mol Med. 2005 Jan-Dec;11(1-12):1-15
references: 16557334
references: Int Immunol. 1998 Dec;10(12):1891-5
references: 9885910
references: Nat Genet. 2003 Aug;34(4):395-402
references: 12833157
references: Nat Rev Rheumatol. 2011 May;7(5):263-71
references: 21343899
references: Nat Genet. 2009 Dec;41(12):1313-8
references: 19898481
references: Nat Genet. 2003 Jun;34(2):187-92
references: 12740577
references: Int J Epidemiol. 2006 Feb;35(1):34-41
references: 16155052
references: Arthritis Rheum. 2011 Apr;63(4):884-93
references: 21452313
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Crit Rev Immunol. 2011;31(2):99-114
references: 21542789
references: Autoimmunity. 2012 Aug;45(5):364-76
references: 22429183
references: Arthritis Rheum. 2005 Nov;52(11):3433-8
references: 16255021
references: Genomics. 2008 Nov;92(5):265-72
references: 18722519
references: Ann Rheum Dis. 1996 Feb;55(2):89-93
references: 8712872
references: Arthritis Rheum. 2008 May;58(5):1275-83
references: 18438843
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1412-7
references: 16432200
references: PLoS One. 2009 Nov 30;4(11):e8068
references: 19956648
references: PLoS One. 2011;6(9):e25389
references: 21980439
references: Sci Signal. 2012 Nov 27;5(252):ra87
references: 23193160
references: Arthritis Rheum. 2009 Mar;60(3):661-8
references: 19248111
references: Nat Rev Rheumatol. 2012 Jan 31;8(3):144-52
references: 22293763
references: Science. 2010 Dec 10;330(6010):1551-7
references: 21051598
references: Arthritis Rheum. 1990 Nov;33(11):1665-73
references: 2242063
references: Scand J Rheumatol. 2012 Aug;41(4):249-52
references: 22632125
references: Am J Epidemiol. 1984 May;119(5):813-29
references: 6609637
references: PLoS Genet. 2011 Jan 13;7(1):e1001273
references: 21249183
references: Nat Rev Genet. 2011 Jul 12;12(8):529-41
references: 21747404
references: Arthritis Rheum. 2011 Mar;63(3):645-53
references: 21061259
references: Ann Rheum Dis. 2011 Mar;70(3):463-8
references: 21068098
references: Am J Hum Genet. 2005 Dec;77(6):1044-60
references: 16380915
references: Genes Immun. 2012 Feb;13(2):120-8
references: 21881596
references: Am J Hum Genet. 2011 Oct 7;89(4):496-506
references: 21963258
references: Arthritis Rheum. 2003 Apr;48(4):906-16
references: 12687532
references: Nat Genet. 2012 Mar 25;44(5):511-6
references: 22446963
references: Ann Rheum Dis. 1970 Jul;29(4):357-79
references: 4916766
references: Biochem J. 2008 Jan 15;409(2):581-9
references: 17868033
references: Nat Rev Genet. 2007 Apr;8(4):253-62
references: 17363974
references: Arthritis Rheum. 2009 Dec;60(12):3613-22
references: 19950268
references: Arthritis Rheum. 2010 Jan;62(1):117-25
references: 20039411
references: Arthritis Rheum. 2010 May;62(5):1236-45
references: 20131291
references: Arthritis Rheum. 2011 Oct;63(10):2851-3
references: 21567373
references: Nucleic Acids Res. 2006 Aug 07;34(13):3687-97
references: 16893953
references: Arthritis Rheum. 2005 Apr;52(4):1063-8
references: 15818663
references: Eur Heart J. 2012 Nov;33(22):2841-8
references: 22511653
references: Am J Hum Genet. 2004 Aug;75(2):330-7
references: 15208781
references: Arthritis Rheum. 1988 Mar;31(3):315-24
references: 3358796
references: Nat Genet. 2008 Oct;40(10):1156-9
references: 18794857
references: Nat Genet. 2011 Mar;43(3):253-8
references: 21336280
references: Nat Rev Genet. 2010 Dec;11(12):843-54
references: 21085203
references: Ann Rheum Dis. 2010 Sep;69(9):1694-6
references: 20439292
references: Arthritis Rheum. 2009 Apr;60(4):916-23
references: 19333951
references: Nat Genet. 2003 Mar;33 Suppl:245-54
references: 12610534
references: Arthritis Res Ther. 2006;8(3):R79
references: 16646982
references: BMC Proc. 2009 Dec 15;3 Suppl 7:S128
references: 20017994
references: PLoS Genet. 2011 Feb;7(2):e1002004
references: 21383967
references: Nature. 2007 Jun 7;447(7145):661-78
references: 17554300
references: Nat Immunol. 2002 Jul;3(7):643-51
references: 12055628
references: Arthritis Rheum. 2002 Mar;46(3):632-9
references: 11920398
references: Immunogenetics. 2011 Aug;63(8):459-66
references: 21556860
references: PLoS Comput Biol. 2012;8(2):e1002375
references: 22383865
references: Arthritis Res Ther. 2012 May 17;14(3):R118
references: 22594821
references: Hum Mol Genet. 2008 Oct 15;17(R2):R122-8
references: 18852200
references: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10746-50
references: 9724775
references: Nat Genet. 2009 Jul;41(7):820-3
references: 19503088
references: Immunol Rev. 2008 Aug;224:124-40
references: 18759924
references: Nat Genet. 2007 Dec;39(12):1477-82
references: 17982456
references: Immunol Cell Biol. 2006 Jun;84(3):318-30
references: 16681829
references: Nat Genet. 2011 Aug 14;43(9):908-12
references: 21841782
references: Nat Rev Rheumatol. 2011 Apr;7(4):202-3
references: 21455249
references: J Mol Biol. 1987 Jul 20;196(2):261-82
references: 3656447
references: Arthritis Rheum. 2007 Jan;56(1):1-3
references: 17195190
references: Nature. 2001 Feb 15;409(6822):860-921
references: 11237011
references: Cancer Res. 2012 Aug 1;72(15):3775-85
references: 22710432
references: Hum Mol Genet. 2000 Oct;9(16):2395-402
references: 11005794
references: J Clin Invest. 1976 May;57(5):1148-57
references: 1262462
references: Hum Mol Genet. 2009 Jul 15;18(14):2693-9
references: 19417005
references: Nat Genet. 2011 Aug 14;43(9):902-7
references: 21841778
references: Am J Hum Genet. 2011 Apr 8;88(4):450-7
references: 21457905
references: Science. 2012 Jul 6;337(6090):64-9
references: 22604720
references: Immunity. 2011 Jul 22;35(1):82-96
references: 21723156
references: N Engl J Med. 1978 Apr 20;298(16):869-71
references: 147420
references: Clin Rev Allergy Immunol. 2012 Feb;42(1):92-101
references: 22161696
references: J Immunol. 2012 Jun 1;188(11):5267-75
references: 22539785
references: Nat Genet. 2008 Oct;40(10):1216-23
references: 18794853
references: Arthritis Rheum. 1969 Dec;12(6):547-54
references: 5363253
references: Nature. 2003 Dec 18;426(6968):789-96
references: 14685227
references: Arthritis Rheum. 2008 Sep;58(9):2686-93
references: 18759290
references: Science. 2009 Apr 17;324(5925):387-9
references: 19264985
references: Nature. 2005 Mar 17;434(7031):400-4
references: 15772666
references: Ann Rheum Dis. 2007 Nov;66(11):1497-502
references: 17491100
references: Curr Opin Rheumatol. 2011 May;23(3):227-32
references: 21427575
references: Arthritis Rheum. 2008 Apr;58(4):1001-9
references: 18383392
references: Curr Opin Immunol. 2012 Oct;24(5):530-7
references: 22889593
references: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2995-3000
references: 11867742
references: Nat Rev Rheumatol. 2012 Oct;8(10):573-86
references: 22907289
references: Am J Hum Genet. 2001 Apr;68(4):927-36
references: 11254450
references: Immunol Today. 1996 Dec;17(12):559-64
references: 8991287
references: Arthritis Rheum. 2010 Oct;62(10):2909-18
references: 20533291
references: Cell. 2011 Sep 30;147(1):57-69
references: 21962507