Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

被引:90
作者
Hermann, R
Lipponen, K
Kiviniemi, M
Kakko, T
Veijola, R
Simell, O
Knip, M
Ilonen, J
机构
[1] Univ Turku, Dept Virol, FIN-20520 Turku, Finland
[2] JDRF Ctr Prevent Type 1 Diabet Finland, Turku, Finland
[3] Semmelweis Univ, CellScreen Appl Biomed Res Ctr, Immunogenom Lab, H-1085 Budapest, Hungary
[4] Univ Oulu, Dept Paediat, Oulu, Finland
[5] Univ Turku, Dept Paediat, Turku, Finland
[6] Tampere Univ Hosp, Dept Paediat, Tampere, Finland
[7] Univ Helsinki, Hosp Children & Adolescents, Helsinki, Finland
基金
芬兰科学院;
关键词
autoantibodies; autoimmune disease; autoimmunity; CTLA4; DQB1; DRB1; HLA; insulin; insulin gene; PTPN22; type; 1; diabetes;
D O I
10.1007/s00125-006-0225-4
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims/hypothesis: We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cell-specific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset. Subjects and methods: A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n=574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case-control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms. Results: The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio=4.6, 95% CI 2.4-9.0; p=0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5-11.6; and 1.6, 95% CI 1.1-2.4, respectively; p=0.003). The strong effect of PTPN22 on disease susceptibility (p=2.1x10(-8)) was more pronounced in males (p=0.021) and in subjects with non-DR4-DQ8/low-risk HLA genotypes (p=0.0004). Conclusions/interpretation: In the pathogenesis of type 1 diabetes the underlying mechanism of the PTPN22 C1858T polymorphism appears to involve regulation of insulin-specific autoimmunity. Importantly, it strongly affects progression from prediabetes to clinical disease.
引用
收藏
页码:1198 / 1208
页数:11
相关论文
共 51 条
[1]  
Alberti KGMM, 1998, DIABETIC MED, V15, P539, DOI 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO
[2]  
2-S
[3]   Rentapping the insulin gene/IDDM2 locus in type 1 diabetes [J].
Barratt, BJ ;
Payne, F ;
Lowe, CE ;
Hermann, R ;
Healy, BC ;
Harold, D ;
Concannon, P ;
Gharani, N ;
McCarthy, MI ;
Olavesen, MG ;
McCormack, R ;
Guja, C ;
Ionescu-Tîrgoviste, C ;
Undlien, DE ;
Ronningen, KS ;
Gillespie, KM ;
Tuomilehto-Wolf, E ;
Tuomilehto, J ;
Bennett, ST ;
Clayton, DG ;
Cordell, HJ ;
Todd, JA .
DIABETES, 2004, 53 (07) :1884-1889
[4]   A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis [J].
Begovich, AB ;
Carlton, VEH ;
Honigberg, LA ;
Schrodi, SJ ;
Chokkalingam, AP ;
Alexander, HC ;
Ardlie, KG ;
Huang, QQ ;
Smith, AM ;
Spoerke, JM ;
Conn, MT ;
Chang, M ;
Chang, SYP ;
Saiki, RK ;
Catanese, JJ ;
Leong, DU ;
Garcia, VE ;
McAllister, LB ;
Jeffery, DA ;
Lee, AT ;
Batliwalla, F ;
Remmers, E ;
Criswell, LA ;
Seldin, MF ;
Kastner, DL ;
Amos, CI ;
Sninsky, JJ ;
Gregersen, PK .
AMERICAN JOURNAL OF HUMAN GENETICS, 2004, 75 (02) :330-337
[5]   A POLYMORPHIC LOCUS NEAR THE HUMAN INSULIN GENE IS ASSOCIATED WITH INSULIN-DEPENDENT DIABETES-MELLITUS [J].
BELL, GI ;
HORITA, S ;
KARAM, JH .
DIABETES, 1984, 33 (02) :176-183
[6]   A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes [J].
Bottini, N ;
Musumeci, L ;
Alonso, A ;
Rahmouni, S ;
Nika, K ;
Rostamkhani, M ;
MacMurray, J ;
Meloni, GF ;
Lucarelli, P ;
Pellecchia, M ;
Eisenbarth, GS ;
Comings, D ;
Mustelin, T .
NATURE GENETICS, 2004, 36 (04) :337-338
[7]   Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase [J].
Cloutier, JF ;
Veillette, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (01) :111-121
[8]   Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection:: the PTPN22 620W allele associates with multiple autoimmune phenotypes [J].
Criswell, LA ;
Pfeiffer, KA ;
Lum, RF ;
Gonzales, B ;
Novitzke, J ;
Moser, KL ;
Begovich, AB ;
Carlton, VEH ;
Li, W ;
Lee, AT ;
Ortmann, W ;
Behrens, TW ;
Gregersen, PK .
AMERICAN JOURNAL OF HUMAN GENETICS, 2005, 76 (04) :561-571
[9]   A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients [J].
Cucca, F ;
Goy, JV ;
Kawaguchi, Y ;
Esposito, L ;
Merriman, ME ;
Wilson, AT ;
Cordell, HJ ;
Bain, SC ;
Todd, JA .
NATURE GENETICS, 1998, 19 (03) :301-302
[10]   Pedigree disequilibrium tests for multilocus haplotypes [J].
Dudbridge, F .
GENETIC EPIDEMIOLOGY, 2003, 25 (02) :115-121