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rs2476601 T allele (R620W) defines high-risk PTPN22 type I diabetes-associated haplotypes with preliminary evidence for an additional protective haplotype

Genes & Immunity volume 10, pages S21–S26 (2009)Cite this article

Abstract

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is the third major locus affecting risk of type I diabetes (T1D), after HLA-DR/DQ and INS. The most associated single-nucleotide polymorphism (SNP), rs2476601, has a C->T variant and results in an arginine (R) to tryptophan (W) amino acid change at position 620. To assess whether this, or other specific variants, are responsible for T1D risk, the Type I Diabetes Genetics Consortium analyzed 28 PTPN22 SNPs in 2295 affected sib-pair (ASP) families. Transmission Disequilibrium Test analyses of haplotypes revealed that all three haplotypes with a T allele at rs2476601 were overtransmitted to affected children, and two of these three haplotypes showed statistically significant overtransmission (P=0.003 to P=5.9E-12). Another haplotype had decreased transmission to affected children (P=3.5E-05). All haplotypes containing the rs2476601 T allele were identical for all SNPs across PTPN22 and only varied at centromeric SNPs. When considering rs2476601 ‘C’ founder chromosomes, a second haplotype (AGGGGC) centromeric of PTPN22 in the C1orf178 region was associated with protection from T1D (odds ratio=0.81, P=0.0005). This novel finding requires replication in independent populations. We conclude the major association of PTPN22 with T1D is likely due to the recognized non-synonymous SNP rs2476601 (R620W).

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Acknowledgements

This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. BOB was support by the German Research Foundation (DFG: SFB 518 & GrK 1041).

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Authors and Affiliations

  1. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA

    A K Steck, E E Baschal, J M Jasinski & G S Eisenbarth

  2. Department of Internal Medicine, Ulm University, Ulm, Germany

    B O Boehm

  3. Institute for Genetic Medicine,

    N Bottini

  4. , University of Southern California, Los Angeles, CA, USA

    N Bottini

  5. Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA

    P Concannon

  6. Génétique des Maladies Infectieuses et Autoimmunes, Institut Pasteur, Paris, France

    C Julier

  7. Western Australian Institute for Medical Research,

    G Morahan

  8. , The University of Western Australia, Perth, Australia

    G Morahan

  9. Children's Hospital Oakland Research Institute, Oakland, CA, USA

    J A Noble

  10. Department of Human Genetics, The McGill University Health Center, Montreal, Quebec, Canada

    C Polychronakos

  11. Center for Biotechnology and Genomic Medicine,

    J X She

  12. , Medical College of Georgia, Augusta, GA, USA

    J X She

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Correspondence to G S Eisenbarth.

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Steck, A., Baschal, E., Jasinski, J. et al. rs2476601 T allele (R620W) defines high-risk PTPN22 type I diabetes-associated haplotypes with preliminary evidence for an additional protective haplotype. Genes Immun 10 (Suppl 1), S21–S26 (2009). https://doi.org/10.1038/gene.2009.87

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