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Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies

Genes & Immunity volume 16, pages 541–551 (2015)Cite this article

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Abstract

The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1–34-year-old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P=0.049) and IA-2 autoantibody-negative (comparison P=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens.

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Acknowledgements

We thank Stephen Rich and Beena Alkolkar for facilitating the genotyping by the T1DGC. This research utilizes resources provided by the Type 1 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. The work in the authors’ laboratory was supported in part by the Swedish Child Diabetes Foundation, the National Institutes of Health (DK63861, DK26190), the Swedish Research Council, the Swedish Diabetes Association Research Fund, the Skåne County Council Foundation for Research and Development.

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  1. Jinko Graham, Brad MacNeney, Hans Arnqvist, Mona Landin-Olsson, Lennarth Nyström, Lars Olof Ohlson, Jan Östman, M Aili Halmstad, LE Bååth Östersund, E Carlsson Kalmar, H Edenwall Karlskrona, G Forsander Falun, BW Granström Gällivare, I Gustavsson Skellefteå, R Hanås Uddevalla, L Hellenberg Nyköping, H Hellgren Lidköping, E Holmberg Umeå, H Hörnell Hudiksvall, Sten-A Ivarsson Malmö, C Johansson Jönköping, G Jonsell Karlstad, B Lindblad Mölndal, A Lindh Borås, J Ludvigsson Linköping, U Myrdal Västerås, J Neiderud Helsingborg, K Segnestam Eskilstuna, L Skogsberg Boden, L Strömberg Norrköping, U Ståhle Ängelholm, B Thalme Huddinge, K Tullus Danderyd, T Tuvemo Uppsala, M Wallensteen Stockholm, O Westphal Göteborg and J Åman Örebro: Members of the Swedish Childhood Diabetes Register, the Diabetes Incidence in Sweden Study Group and the Type 1 Diabetes Genetics Consortium (T1DGC) are listed before references.

Authors and Affiliations

  1. Department of Biostatistics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    M Maziarz & N Breslow

  2. Pacific Northwest Diabetes Research Institute, Seattle, WA, USA

    W Hagopian

  3. Department of Medicine, University of Washington, Seattle, WA, USA

    J P Palmer

  4. Department of Medicine, Karolinska Institute, Solna, Sweden

    C B Sanjeevi

  5. Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden

    I Kockum

  6. Department of Clinical Sciences, Lund University, Malmö, Sweden

    Å Lernmark

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  1. M Maziarz
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The Swedish Childhood Diabetes Register, the Diabetes Incidence in Sweden Study Group and the Type 1 Diabetes Genetics Consortium

  • Jinko Graham
  • , Brad MacNeney
  • , Hans Arnqvist
  • , Mona Landin-Olsson
  • , Lennarth Nyström
  • , Lars Olof Ohlson
  • , Jan Östman
  • , M Aili Halmstad
  • , LE Bååth Östersund
  • , E Carlsson Kalmar
  • , H Edenwall Karlskrona
  • , G Forsander Falun
  • , BW Granström Gällivare
  • , I Gustavsson Skellefteå
  • , R Hanås Uddevalla
  • , L Hellenberg Nyköping
  • , H Hellgren Lidköping
  • , E Holmberg Umeå
  • , H Hörnell Hudiksvall
  • , Sten-A Ivarsson Malmö
  • , C Johansson Jönköping
  • , G Jonsell Karlstad
  • , B Lindblad Mölndal
  • , A Lindh Borås
  • , J Ludvigsson Linköping
  • , U Myrdal Västerås
  • , J Neiderud Helsingborg
  • , K Segnestam Eskilstuna
  • , L Skogsberg Boden
  • , L Strömberg Norrköping
  • , U Ståhle Ängelholm
  • , B Thalme Huddinge
  • , K Tullus Danderyd
  • , T Tuvemo Uppsala
  • , M Wallensteen Stockholm
  • , O Westphal Göteborg
  •  & J Åman Örebro

Corresponding author

Correspondence to M Maziarz.

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Competing interests

The authors declare no conflict of interest.

Additional information

The following authors are from the Diabetes Incidence in Sweden Study Group: Jinko Graham and Brad MacNeney, both at Simon Fraser University, Vancouver, British Columbia, Canada; Hans Arnqvist, Department of Internal Medicine, University of Linköping, Linköping; Mona Landin-Olsson, Department of Clinical Sciences, Lund University, Lund, Sweden; Lennarth Nyström, Department of Epidemiology and Public Health, University of Umeå, Umeå; Lars Olof Ohlson, Sahlgrenska Hospital, University of Göteborg, Göteborg; and Jan Östman, Center for Metabolism and Endocrinology, Huddinge University Hospital, Stockholm. The following authors are from the Swedish Childhood Diabetes Study Group, all from Departments of Pediatrics: M Aili, Halmstad; LE Bååth, Östersund; E Carlsson, Kalmar; H Edenwall, Karlskrona; G Forsander, Falun; BW Granström, Gällivare; I Gustavsson, Skellefteå; R Hanås, Uddevalla; L Hellenberg, Nyköping; H Hellgren, Lidköping; E Holmberg, Umeå; H Hörnell, Hudiksvall; Sten-A Ivarsson, Malmö; C Johansson, Jönköping; G Jonsell, Karlstad; B Lindblad, Mölndal; A Lindh, Borås; J Ludvigsson, Linköping; U Myrdal, Västerås; J Neiderud, Helsingborg; K Segnestam, Eskilstuna; L Skogsberg, Boden; L Strömberg, Norrköping; U Ståhle, Ängelholm; B Thalme, Huddinge; K Tullus, Danderyd; T Tuvemo, Uppsala; M Wallensteen, Stockholm; O Westphal, Göteborg; and J Åman, Örebro.

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Maziarz, M., Hagopian, W., Palmer, J. et al. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies. Genes Immun 16, 541–551 (2015). https://doi.org/10.1038/gene.2015.43

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