title: The association between the PTPN22 1858C>T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies.
abstract: The single nucleotide polymorphism 1858C>T in the PTPN22 gene is associated with type 1 diabetes (T1D) in several populations. Earlier reports have suggested that the association may be modified by human leukocyte antigen (HLA), as well as by islet autoantibodies. In a large case-control study of Swedish incident T1D patients and controls, 0-34 years of age, we tested whether the odds ratio (OR) measure of association was dependent on HLA or autoantibodies against the islet autoantigens glutamic acid decarboxylase 65 kDa autoantibodies (GADA), insulin, islet antigen-2, or islet cell. The association between the carrier status of 1858C>T allele in PTPN22 (PTPN22(CT+TT)) and T1D was modified by HLA. In addition, in GADA-positive T1D, the OR was 2.83 (2.00, 3.99), whereas in GADA-negative T1D, the OR was 1.41 (0.98, 2.04) (P for comparison=0.007). The OR of association between PTPN22(CT+TT) and GADA-positive T1D declined with increasing HLA-risk category from 6.12 to 1.54 (P=0.003); no such change was detected in GADA-negative T1D (P=0.722) (P for comparison=0.001). However, the absolute difference in risk between PTPN22(CC) and PTPN22(CT+TT) subjects with high-risk HLA was five times higher than that for subjects with low-risk HLA. We hypothesize that the altered T-cell function because of the PTPN22(1858C>T) polymorphism is exclusively associated with GADA-positive T1D at diagnosis.
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195-7232, USA. marlenam@u.washington.edu
authors.forename: M
authors.initials: M
authors.lastname: Maziarz
authors.forename: M
authors.initials: M
authors.lastname: Janer
authors.forename: J C
authors.initials: JC
authors.lastname: Roach
authors.forename: W
authors.initials: W
authors.lastname: Hagopian
authors.forename: J P
authors.initials: JP
authors.lastname: Palmer
authors.forename: K
authors.initials: K
authors.lastname: Deutsch
authors.forename: C B
authors.initials: CB
authors.lastname: Sanjeevi
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.forename: N
authors.initials: N
authors.lastname: Breslow
authors.forename: A
authors.initials: A
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D018570:Risk Assessment; D013548:Sweden
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
references.citation: Diabetologia. 2005 Aug;48(8):1484-91
references.pmid: 15991024
references.citation: Eur J Hum Genet. 2006 Mar;14(3):317-21
references.pmid: 16391555
references.citation: Diabetes Care. 2008 Mar;31(3):534-8
references.pmid: 18056891
references.citation: Autoimmunity. 1994;19(2):113-25
references.pmid: 7772701
references.citation: Int J Immunogenet. 2007 Dec;34(6):469-73
references.pmid: 18001305
references.citation: J Immunol Methods. 1988 Jan 21;106(1):83-8
references.pmid: 3123555
references.citation: Eur J Endocrinol. 2005 Dec;153(6):895-9
references.pmid: 16322396
references.citation: Diabetes. 1992 Aug;41(8):1022-7
references.pmid: 1628762
references.citation: Diabetes. 2002 May;51(5):1346-55
references.pmid: 11978629
references.citation: Epidemiology. 1992 Sep;3(5):449-52
references.pmid: 1391138
references.citation: Rheumatology (Oxford). 2008 Feb;47(2):138-41
references.pmid: 18156150
references.citation: Rheumatology (Oxford). 2007 Jan;46(1):49-56
references.pmid: 16760194
references.citation: Tissue Antigens. 2006 May;67(5):430-3
references.pmid: 16671953
references.citation: Eur J Immunogenet. 1999 Apr-Jun;26(2-3):117-27
references.pmid: 10331157
references.citation: Diabetes. 1996 Oct;45(10):1344-9
references.pmid: 8826969
references.citation: Autoimmunity. 2007 Sep;40(6):453-61
references.pmid: 17729039
references.citation: Diabetes. 2005 Dec;54 Suppl 2:S52-61
references.pmid: 16306341
references.citation: Diabetes. 2007 Feb;56(2):522-6
references.pmid: 17259401
references.citation: Diabetes Res Clin Pract. 2007 May;76(2):297-303
references.pmid: 17000021
references.citation: BMC Med Genet. 2007 Aug 13;8:54
references.pmid: 17697317
references.citation: Tissue Antigens. 2008 Nov;72(5):425-30
references.pmid: 18764813
references.citation: DNA Cell Biol. 1994 May;13(5):505-14
references.pmid: 8024693
references.citation: Hum Immunol. 2005 Jan;66(1):60-4
references.pmid: 15620463
references.citation: J Clin Invest. 1995 Apr;95(4):1505-11
references.pmid: 7706455
references.citation: Genes Immun. 2007 Sep;8(6):503-12
references.pmid: 17641683
references.citation: Diabetes. 2008 Jun;57(6):1730-7
references.pmid: 18305142
references.citation: Genes Immun. 2005 Oct;6(7):628-31
references.pmid: 16163373
references.citation: Pediatr Diabetes. 2006 Oct;7(5):274-8
references.pmid: 17054449
references.citation: Diabetologia. 2000 Oct;43(10):1282-92
references.pmid: 11079747
references.citation: Tissue Antigens. 2008 Mar;71(3):234-7
references.pmid: 18179648
references.citation: J Hum Genet. 2005;50(5):264-266
references.pmid: 15883854
references.citation: Ann N Y Acad Sci. 2006 Oct;1079:229-39
references.pmid: 17130560
references.citation: Am J Hum Genet. 2004 Aug;75(2):330-7
references.pmid: 15208781
references.citation: Int J Exp Diabetes Res. 2001;2(2):85-90
references.pmid: 12369720
references.citation: Diabetes. 2008 Jan;57(1):229-34
references.pmid: 17934143
references.citation: J Clin Invest. 1993 Jan;91(1):368-74
references.pmid: 8423232
references.citation: Science. 1983 Dec 23;222(4630):1337-9
references.pmid: 6362005
references.citation: Diabetes. 1995 Jan;44(1):125-31
references.pmid: 7813806
references.citation: Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S116-21
references.pmid: 17452059
references.citation: Eur J Immunogenet. 1999 Oct;26(5):361-72
references.pmid: 10553503
references.citation: J Intern Med. 2003 Apr;253(4):447-53
references.pmid: 12653874
references.citation: Curr Opin Rheumatol. 2009 May;21(3):272-8
references.pmid: 19365265
references.citation: Am J Hum Genet. 2005 Apr;76(4):561-71
references.pmid: 15719322
references.citation: Blood. 1999 Mar 15;93(6):2013-24
references.pmid: 10068674
references.citation: Diabetes. 2004 Nov;53(11):3020-3
references.pmid: 15504986
references.citation: Genes Immun. 2005 Sep;6(6):459-61
references.pmid: 15875058
references.citation: Autoimmun Rev. 2006 Jul;5(6):424-8
references.pmid: 16890898
references.citation: Diabetes. 1992 Feb;41(2):183-6
references.pmid: 1733807
references.citation: Diabetologia. 1994 Apr;37(4):344-50
references.pmid: 8063033
references.citation: Diabetologia. 2006 Jun;49(6):1198-208
references.pmid: 16614815
references.citation: Stat Methods Med Res. 2008 Dec;17(6):595-607
references.pmid: 18375456
references.citation: J Cell Mol Med. 2008 Jun;12(3):1061-2
references.pmid: 18194462
references.citation: Nat Genet. 2004 Apr;36(4):337-8
references.pmid: 15004560
references.citation: Am J Hum Genet. 2001 Apr;68(4):927-36
references.pmid: 11254450
references.citation: Diabetologia. 1987 May;30(5):327-32
references.pmid: 3301483