title: Tumor necrosis factor polymorphisms associated with tumor necrosis factor production influence the risk of idiopathic intermediate uveitis.
abstract: OBJECTIVE
  Idiopathic intermediate uveitis (IIU) is a potentially sight-threatening inflammatory disorder with well-defined anatomic diagnostic criteria. It is often associated with multiple sclerosis, and both conditions are linked to HLA-DRB1*15. Previously, we have shown that non-infectious uveitis (NIU) is associated with interleukin 10 (IL10) polymorphisms, IL10-2849A (rs6703630), IL10+434T (rs2222202), and IL10+504G (rs3024490), while a LTA+252AA/TNFA-238GG haplotype (rs909253/rs361525) is protective. In this study, we determined whether patients with IIU have a similar genetic profile as patients with NIU or multiple sclerosis.
  
  
  METHODS
  Twelve polymorphisms were genotyped, spanning the tumor necrosis factor (TNF) and IL10 genomic regions, in 44 patients with IIU and 92 population controls from the UK and the Republic of Ireland.
  
  
  RESULTS
  IIU was strongly associated with the TNFA-308A and TNFA-238A polymorphisms. We found the combination of TNFA-308 and -238 loci was more strongly associated with IIU than any other loci across the major histocompatibility complex, including HLA-DRB1.
  
  
  CONCLUSIONS
  TNF polymorphisms, associated with increased TNF production, are highly associated with IIU. These results offer the potential to ascribe therapeutic response and risk (i.e., the influence of HLA-DRB1*15 status and TNFR1 polymorphism) to anti-TNF therapy in IIU.
authors: School of Clinical Sciences, Bristol Eye Hospital, Lower Maudlin Street, Bristol, BS1 2LX, United Kingdom. Denize.Atan@bristol.ac.uk
authors: Denize
authors: D
authors: Atan
authors: Jarka
authors: J
authors: Heissigerova
authors: Lucia
authors: L
authors: Kuffová
authors: Aideen
authors: A
authors: Hogan
authors: Dara J
authors: DJ
authors: Kilmartin
authors: John V
authors: JV
authors: Forrester
authors: Jeff L
authors: JL
authors: Bidwell
authors: Andrew D
authors: AD
authors: Dick
authors: Amanda J
authors: AJ
authors: Churchill
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*; D015867:Uveitis, Intermediate / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
chemical_list: D059811:HLA-DRB1 Chains; C508609:IL10 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
references: Nervenarzt. 2011 Apr;82(4):509-10
references: 21153465
references: Ocul Immunol Inflamm. 2010 Dec;18(6):482-4
references: 20735341
references: J Exp Med. 1991 Nov 1;174(5):1209-20
references: 1940799
references: Genes Immun. 2002 Sep;3(6):313-30
references: 12209358
references: J Clin Invest. 1988 May;81(5):1506-10
references: 3366904
references: Nature. 2012 Aug 23;488(7412):508-511
references: 22801493
references: Genes Immun. 2003 Dec;4(8):547-58
references: 14647194
references: Am J Ophthalmol. 2005 Sep;140(3):509-16
references: 16196117
references: Neurology. 2001 Nov 27;57(10):1885-8
references: 11723281
references: J Exp Med. 1993 Feb 1;177(2):557-60
references: 8426126
references: J Clin Invest. 2001 Jun;107(12):1519-27
references: 11413159
references: Ophthalmology. 1999 Mar;106(3):594-9
references: 10080220
references: Nucleic Acids Res. 1992 Apr 25;20(8):1943-8
references: 1579496
references: Hum Immunol. 1989 Oct;26(2):91-7
references: 2573586
references: Tissue Antigens. 1995 Nov;46(5):355-67
references: 8838344
references: J Exp Med. 1989 Aug 1;170(2):607-12
references: 2754393
references: Eur J Immunol. 1996 Oct;26(10):2417-24
references: 8898955
references: Nature. 2003 Oct 23;425(6960):805-11
references: 14574404
references: Annu Rev Biochem. 1988;57:159-97
references: 3052270
references: J Exp Med. 1991 Dec 1;174(6):1549-55
references: 1744584
references: Ophthalmology. 2006 Apr;113(4):695-700
references: 16581430
references: Nat Genet. 2003 Apr;33(4):469-75
references: 12627232
references: Annu Rev Biochem. 1994;63:265-97
references: 7979240
references: Hum Hered. 2008;66(2):87-98
references: 18382088
references: J Immunol. 2003 Oct 1;171(7):3612-9
references: 14500658
references: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16850-5
references: 17940009
references: Arthritis Rheum. 2001 Dec;44(12):2862-9
references: 11762947
references: BioDrugs. 2006;20(1):67-70
references: 16573354
references: J Exp Med. 1991 Jan 1;173(1):209-19
references: 1670638
references: J Exp Med. 2002 Mar 4;195(5):603-16
references: 11877483
references: Ocul Immunol Inflamm. 1998 Dec;6(4):215-26
references: 9924918
references: Science. 2002 Jun 21;296(5576):2225-9
references: 12029063
references: Annu Rev Immunol. 2004;22:929-79
references: 15032600
references: Cytokine. 2006 Aug;35(3-4):200-6
references: 17005410
references: Semin Ophthalmol. 2005 Jul-Sep;20(3):147-54
references: 16282148
references: Ann Rheum Dis. 1999 Nov;58 Suppl 1:I32-9
references: 10577971
references: Cytokine. 2009 Feb;45(2):55-7
references: 19109035
references: Br J Ophthalmol. 1988 Jan;72(1):5-10
references: 3257703
references: Biochem Biophys Res Commun. 2006 Dec 22;351(3):777-83
references: 17084384
references: Genes Immun. 2004 Jan;5(1):76-9
references: 14735154
references: Genomics. 1993 Apr;16(1):180-6
references: 8486354
references: Chem Immunol Allergy. 2007;92:228-243
references: 17264499
references: J Biol Chem. 1998 Aug 14;273(33):21178-86
references: 9694874
references: Invest Ophthalmol Vis Sci. 2010 Aug;51(8):4133-42
references: 20335604
references: Ann Ophthalmol. 1981 May;13(5):553-7
references: 7258948
references: Nature. 2005 Oct 27;437(7063):1299-320
references: 16255080
references: Hum Mol Genet. 2009 Feb 15;18(4):767-78
references: 19010793
references: Ocul Immunol Inflamm. 1998 Jun;6(2):111-20
references: 9689641
references: PLoS One. 2008;3(10):e3490
references: 18941528
references: J Biol Chem. 1999 Jul 30;274(31):21714-8
references: 10419483
references: Clin Exp Immunol. 1993 Apr;92(1):14-8
references: 8096802
references: Ocul Immunol Inflamm. 2010 Dec;18(6):475-81
references: 20809867
references: Am J Hum Genet. 2005 Apr;76(4):634-46
references: 15747258
references: J Leukoc Biol. 1999 Oct;66(4):562-6
references: 10534109
references: Acta Ophthalmol Scand. 1997 Feb;75(1):76-81
references: 9088407
references: J Biol Chem. 1988 Dec 25;263(36):19259-62
references: 3198625
references: J Immunol. 1991 Sep 15;147(6):2047-54
references: 1909740
references: Hum Mol Genet. 1998 Aug;7(8):1229-34
references: 9668163
references: Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4245-50
references: 16249504
references: Int Ophthalmol. 1994;18(2):111-3
references: 7814201
references: Br J Ophthalmol. 1995 Sep;79(9):856-60
references: 7488606
references: Nat Med. 1999 Feb;5(2):170-5
references: 9930864
references: Br J Ophthalmol. 2005 Aug;89(8):1013-6
references: 16024856
references: J Exp Med. 2002 Jan 7;195(1):15-21
references: 11781361
references: N Engl J Med. 1991 Aug 15;325(7):467-72
references: 1852181
references: Invest Ophthalmol Vis Sci. 2005 May;46(5):1565-71
references: 15851552
references: Immunol Rev. 1999 Feb;167:257-74
references: 10319267
references: Ophthalmology. 2004 Feb;111(2):352-6
references: 15019389
references: Int Ophthalmol. 1998;22(5):275-7
references: 10826543
references: Eur J Immunol. 1996 May;26(5):1018-25
references: 8647162
references: Surv Ophthalmol. 2001 Nov-Dec;46(3):209-33
references: 11738429
references: Eur J Immunol. 1997 Mar;27(3):756-62
references: 9079819
references: Mult Scler. 2011 Jun;17(6):658-65
references: 21177755
references: J Exp Med. 1990 Jan 1;171(1):35-47
references: 2104921
references: PLoS Med. 2006 Aug;3(8):e297
references: 16942393
references: Ophthalmology. 1993 Jun;100(6):818-24; discussion 825
references: 8510893
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Eur J Immunol. 2009 Nov;39(11):3147-59
references: 19688742
references: N Engl J Med. 2007 Aug 30;357(9):851-62
references: 17660530
references: Invest Ophthalmol Vis Sci. 2011 Jun 01;52(6):3573-81
references: 21357402
references: Nucleic Acids Res. 2008 Sep;36(15):4845-62
references: 18653526
references: Cleve Clin J Med. 1993 Nov-Dec;60(6):460-5
references: 8287507
references: Mol Biol Rep. 2011 Aug;38(6):4137-44
references: 21136171
references: Arch Ophthalmol. 2004 Jun;122(6):845-51
references: 15197059
references: Eur J Immunol. 1997 Aug;27(8):1973-81
references: 9295034
references: Am J Epidemiol. 2007 May 15;165(10):1097-109
references: 17329717
references: Ophthalmic Paediatr Genet. 1990 Dec;11(4):305-8
references: 2096359
references: Am J Ophthalmol. 1997 Jan;123(1):70-5
references: 9186099
references: Int J Med Microbiol. 2010 Jan;300(1):19-24
references: 19781988
references: Am J Ophthalmol. 2004 Oct;138(4):648-50
references: 15488796
references: Retina. 1983;3(3):179-81
references: 6635352
references: J Immunother. 2006 Jul-Aug;29(4):407-15
references: 16799336
references: Immunogenetics. 1991;33(1):50-3
references: 1671667