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Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes

Genes & Immunity volume 5, pages 36–40 (2004)Cite this article

Abstract

Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-γ), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10*R2, IL-4*C, VDR*C and IGF-I*wt was found to be transmitted more frequently than expected (67%, Pc=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.

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Acknowledgements

This study was supported by grants from the Dutch Diabetes Research Foundation (97.137, 2001.10.004), The Netherlands Organisation for Health Research and Development (ZonMW) and The Juvenile Diabetes Research Foundation International (JDRF) (2001.10.004). We thank Prof. Dr FJ Claas and Prof. Dr RRP de Vries for carefully reading this manuscript.

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Authors and Affiliations

  1. Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    P Eerligh, B P C Koeleman, B O Roep & M J Giphart

  2. Division of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    B P C Koeleman

  3. MRC Human Genome Mapping Project Resource Centre, Cambridge, UK

    F Dudbridge

  4. Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands

    G Jan Bruining

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  1. P Eerligh
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  2. B P C Koeleman
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  4. G Jan Bruining
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Correspondence to B P C Koeleman.

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Eerligh, P., Koeleman, B., Dudbridge, F. et al. Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes. Genes Immun 5, 36–40 (2004). https://doi.org/10.1038/sj.gene.6364036

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