Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes
Author: Gyllenberg, Alexandra; Asad, Samina; Piehl, Fredrik; Swanberg, Maria; Padyukov, Leonid; van Yserloo, Brian; Graham, Jinko; Rutledge, Elizabeth; Orho-Melander, Marju; Lindholm, Eero; Graff, Caroline; Forsell, Charlotte; Åkesson, Karin; Landin-Olsson, Mona; Carlsson, Annelie; Forsander, Gun; Ivarsson, Sten; Larsson, Helena; Alfredsson, Lars; Åkesson, Kristina; Olsson, Tomas; Kockum, Ingrid; Lindblad, Bengt; Ludvigsson, Johnny; Marcus, Claude; Lernmark, Åke; McNeney, Brad; Swedish Childhood Diabetes Study Group; Diabetes Incidence in Sweden Study Group; Better Diabetes Diagnosis Study Group
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
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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.
Institution:
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Neuroimmunology Unit, Centre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Experimental Medical Science, Neurodegeneration and Inflammation Genetics Unit, Lund University, Lund, Sweden
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Molecular and Genetics Core, Diabetes Endocrinology Research Center, University of Washington, Seattle, WA, USA
- Salish Kootenai College, Pablo, MT, USA
- Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada
- Genetic Epidemiology, Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Skåne University Hospital, Lund, Sweden
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Department of Pediatrics, Ryhov County Hospital, Jönköping, Sweden
- Department of Medicine, Skåne University Hospital, Lund, Sweden
- Department of Pediatrics, Skåne University Hospital, Lund, Sweden
- Department of Pediatrics, Queen Silvia Children’s Hospital, Sahlgrenska/Östra University Hospital, Gothenburg, Sweden
- Department of Clinical Sciences, Skåne University Hospital, Malmö, Sweden
- Department of Pediatrics, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Division of Pediatrics and Diabetes Research Center, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
- Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Sciences, Clinical and Molecular Osteoporosis Research Unit, Lund University, Lund, Sweden
- Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden
Citation: Genes Immun. 2012 Dec;13(8):632-40.
Citation DOI: 10.1038/gene.2012.44
Citation PMID: 23052709
Citation ISI: 000312000700004
Publishing journal: Genes and Immunity
Eprint status: Peer Reviewed
Version: Accepted
Issue date: 2013-03-25
Sponsorship:
- Juvenile Diabetes Research Foundation International, 2-2000-570, 1-2001-873
- Swedish Research Council
- Swedish Diabetes Foundation
- Swedish Child Diabetes Foundation
- Novo Nordisk Foundation
- Magnus Bergvalls Foundation
- Neuropromise, LSHM-CT-2005-018637
- National Institute of Diabetes & Digestive & Kidney Diseases, DK17047
- Swedish Brain Power initiative
- Gun and Bertil Stohne's Foundation
- Foundation for Old Servants
- Alzheimer Foundation
- LIONS Foundation for Research of Age Related Disorders
- AFA Foundation
- Söderberg Foundation
- Knut and Alice Wallenbergs Foundation
Rights:
Article is made available in accordance with the publisher's policy and may be subject to copyright law. Please refer to the publisher's site for terms of use.
Publication year: 2012
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