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Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

Genes & Immunity volume 13, pages 632–640 (2012)Cite this article

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Abstract

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10−5 and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.

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Acknowledgements

We thank Jana L Hoehna and Marta Janer for their contribution to this work. We acknowledge Professor Laura Fratiglioni and coworkers in the SNACK project for the SNACK controls and Dr Behnosh F Björk for the sample handling. This work was supported by grants from the Juvenile Diabetes Research Foundation International (2-2000-570) and (1-2001-873), the Swedish Research Council, Swedish Diabetes Foundation (Svenska Diabetes Fonden), Swedish Child Diabetes Foundation (Barndiabetes Fonden), Novo Nordisk Foundation, Magnus Bergvalls Foundation and Neuropromise (LSHM-CT-2005-018637). The Molecular and Genetics Core of the Diabetes Endocrinology Research Center is supported by NIH grant DK-17047. The project was also supported by the Swedish Brain Power initiative, Gun and Bertil Stohne’s Foundation, Foundation for Old Servants, Alzheimer Foundation and LIONS Foundation for Research of Age Related Disorders, the AFA foundation, the Söderberg Foundation, Knut and Alice Wallenbergs Foundation.

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Author notes

  1. , and: Members of the Swedish Childhood Diabetes Study Group, the Diabetes Incidence in Sweden Study Group and the Better Diabetes Diagnosis Study group are listed in Supplementary Material.

Authors and Affiliations

  1. Department of Clinical Neuroscience, Neuroimmunology Unit, Centre for Molecular Medicine, L8:05, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    A Gyllenberg, S Asad, F Piehl, T Olsson & I Kockum

  2. Department of Experimental Medical Science, Neurodegeneration and Inflammation Genetics Unit, Lund University, Lund, Sweden

    M Swanberg

  3. Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden

    L Padyukov

  4. Molecular and Genetics Core, Diabetes Endocrinology Research Center, University of Washington, Seattle, WA, USA

    B Van Yserloo

  5. Salish Kootenai College, Pablo, MT, USA

    E A Rutledge

  6. Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada

    B McNeney & J Graham

  7. Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Skåne University Hospital, Lund, Sweden

    M Orho-Melander & E Lindholm

  8. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

    C Graff & C Forsell

  9. Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden

    C Graff & C Forsell

  10. Department of Pediatrics, Ryhov County Hospital, Jönköping, Sweden

    K Åkesson

  11. Department of Medicine, Skåne University Hospital, Lund, Sweden

    M Landin-Olsson

  12. Department of Pediatrics, Skåne University Hospital, Lund, Sweden,

    A Carlsson

  13. Department of Pediatrics, The Queen Silvia Children’s Hospital, Sahlgrenska/Ostra University Hospital, Göteborg, Sweden

    G Forsander

  14. Department of Clinical Sciences, Skåne University Hospital, Malmö, Sweden

    S A Ivarsson, H Larsson & Å Lernmark

  15. Department of Pediatrics, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    B Lindblad

  16. Division of Pediatrics and Diabetes Research Center, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

    J Ludvigsson

  17. Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

    C Marcus

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

    Å Lernmark

  19. Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    L Alfredsson

  20. Department of Clinical Sciences, Clinical and Molecular Osteoporosis Research Unit, Lund University, Lund, Sweden

    K Åkesson

  21. Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden

    K Åkesson

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  1. A Gyllenberg
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the Swedish Childhood Diabetes Study Group

the Diabetes Incidence in Sweden Study Group

the Better Diabetes Diagnosis Study group

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Correspondence to A Gyllenberg.

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Gyllenberg, A., Asad, S., Piehl, F. et al. Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes. Genes Immun 13, 632–640 (2012). https://doi.org/10.1038/gene.2012.44

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