Genetic Risk Markers Related to Diabetes-Associated Autoantibodies in Young Patients with Type 1 Diabetes in Berlin, Germany

Abstract

Aims: To determine the prevalence of genetic risk markers of type 1 diabetes (T1D) in children diagnosed at a single centre in Germany and to assess their relation to diabetes-associated autoantibodies.

Methods: Blood samples from 243 paediatric patients were genotyped for the high-risk HLA haplotypes DR3-DQ2 (DQA1*05-DQB1*02) and DR4-DQ8 (DRB1*0401/2/4/5-DQB1*0302) and PTPN22 C1858 T polymorphism. The patients (51.4% male) were diagnosed with T1D at a median age of 8.6 y. The T1D-related autoantibodies GADA, IAA and IA-2A were analysed at diagnosis.

Results: 166 patients (68.6%) carried the DR3-DQ2, 114 (47.1%) the DR4-DQ8 haplotype, while 41 (16.9%) patients were negative for both. The PTPN22 CC genotype was detected in 177 (72.8%), CT in 58 (23.9%) and TT in eight (3.3%) patients, respectively. The prevalence of T1D-related autoimmunity was 77.0% for IA-2A, 71.6% for GADA and 43.6% for IAA. There were no differences between patients with and without the 1858 T allele in terms of the frequency, levels or number of autoantibodies, but the former were younger at diagnosis than the latter (p=0.002), IA-2A were positively related to HLA DR4-DQ8 (p=0.004) and inversely associated with HLA DR3-DQ2 (p=0.002). GADA-positive patients were older than those without GADA (p=0.004). In multivariate logistic regression analysis including gender and age as confounding variables, DR4-DQ8 (OR 2.56, 95%CI 1.35–4.86) and DR3-DQ2 (OR 0.36, 95%CI 0.19-0.68) were the only independent predictors of IA-2A positivity.

Conclusion: The prevalence of genetic risk markers in Berlin children with T1D is found to be comparable to other Caucasian T1D populations. The presence of IA-2A at diagnosis is strongly associated with the HLA risk haplotypes, but not with PTPN22 polymorphism.

Key words

HLA - PTPN22 polymorphisms - autoantibodies - diabetes - children - GADA - IA-2A - IAA - age-differences

Literatur

• 1 Gillespie KM. Type 1 diabetes: pathogenesis and prevention.  CMAJ. 2006;  175 165-170
• 2 Devendra D, Eisenbarth GS. Immunologic endocrine disorders.  J Allergy Clin Immunol. 2003;  111 624-636
• 3 Bell GI, Horita S, Karam JH. A polymorphic locus near the insulin gene is associated with insulin-dependent diabetes mellitus.  Diabetes. 1984;  33 176-183
• 4 Ueda H, Howson JM, Esposito L. et al . Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.  Nature. 2003;  423 506-511
• 5 Bottini N, Musumeci L, Alonso A. et al . A functional variant of lymphoid tyrosine phosphatase is associated with type 1 diabetes.  Nature Genetics. 2004;  36 337-338
• 6 Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies.  Lancet. 1974;  30 1279-1283
• 7 Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2A and GADA in type 1 (insulin-dependent) diabetes.  Diabetologia. 1999;  42 3-14
• 8 Knip M, Vähäsalo P, Karjalainen J. et al . Natural history of preclinical IDDM in high-risk siblings. The Childhood Diabetes in Finland Study Group.  Diabetologia. 1994;  7 388-393
• 9 Bingley PJ, Bonifacio E, Williams AJ. et al . Predicition of IDDM in the general popluation: strategies based on combinations of autoantibody marker.  Diabetes. 1997;  46 1701-1710
• 10 Hermann R, Turpeinen H, Laine AP. et al . HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: An analysis of 622 nuclear families.  Tissue Antigens. 2003;  62 162-169
• 11 Hermann R, Lipponen K, Kiviniemi M. et al . Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes.  Diabetologia. 2006;  49 1198-1208
• 12 Sabbah E, Savola K, Ebeling T. et al . Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes.  Diabetes Care. 2000;  23 1326-1332
• 13 Kahles H, Ramos-Lopez E, Lange B. et al . Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto's thyroiditis or Addison's disease in the German population.  Eur J Endocrinol. 2005;  153 895-899
• 14 Santiago JL, Martinez A, de la Calle H. et al . Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population.  BMC Medical Genetics. 2007;  8 54-58
• 15 Van der Auwera, Vandewalle CL, Schuit FC. et al . CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers.  Clin Exp Immunol. 1997;  110 98-103
• 16 Cauchi S, Meyre D, Durand E. et al . Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value.  PLoS ONE. 2008;  3 e2031
• 17 Ferrari U, Gohlke H, Bonifacio E. et al . SLC30A8-Polymorphismen sind assoziiert mit frühem Diabetesbeginn von Typ 1.  Diabetologie & Stoffwechsel. 2008;  3 S25-S26
• 18 EURODIAB ACE Study Group. . Variation and trends in incidence of childhood diabetes in Europe.  Lancet. 2000;  356 1690
• 19 Sabbah E, Savola K, Kulmala P. et al . Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes.  J Clin Endocrinol Metab. 1999;  84 1534-1539
• 20 Graham J, Hagopian WA, Kockun I. et al . Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes.  Diabetes. 2002;  51 1346-1355
• 21 Decochez K, Truyen I, van der Auwera B. et al . Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes.  Diabetologia. 2005;  48 687-694
• 22 Lempainen J, Vaarala O, Mäkelä M. et al . Interplay between PTPN22 C1858T polymorphism and cow's milk formula exposure in type 1 diabetes.  J Autoimmun. 2009;  33 155-164
• 23 Achenbach P, Ziegler AG. Diabetes-related antibodies in euglycemic subjects.  Best Pract Res Clin Endocrinol Metab. 2005;  19 101-117
• 24 Ludvigsson J, Faresjö M, Hjorth M. et al . GAD treatment and insulin secretion in recent-onset type 1 diabetes.  N Engl J Med. 2008;  359 1909-1920

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