ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 S3.3

Gene environment interactions in type 1 diabetes

George Eisenbarth


University of Colorado Denver, Aurora, Colorado, USA.


The incidence of type 1A diabetes has been doubling approximately every two decades in multiple developed countries. This implies important environmental determinants that are either increasing or decreasing and influencing overall incidence. Recent studies indicate that extreme genetic risk can be defined for major defined genetic subsets. For instance, siblings of a patient with type 1A diabetes who have the highest risk HLA alleles DR3/4-DQ2/8 and in addition have inherited identical by descent the same two HLA haplotypes as their proband sibling have a risk of islet autoimmunity by age 10 of 80%, and 60% for diabetes (Aly et al. PNAS 2006). The risk for siblings with DR3/4-DQ2/8 but sharing only a single haplotype identical by descent is 20%. For the general population combining HLA DR, DQ typing with exclusion of protective DP alleles can identify a risk as high as 20% (Baschal et al. Diabetes 2007). Such a high risk indicates that triggering environmental factors are likely to be ubiquitous. In animal models activation of the innate immune system by a virus such as KRV or by viral mimics such as poly-IC can trigger diabetes in genetically susceptible animals. Specifically poly-IC combined with what may be a primary autoantigen of diabetes of the NOD mouse, namely insulin peptide B: 9–23, induces insulitis in normal mouse strains. In addition to triggering, environmental factors may influence overall risk as illustrated by a recent report of omega-3-fatty acid decreasing risk of activating anti-islet autoimmunity in young children (Norris et al. JAMA 2007). A series of newly discovered genes associated with type 1 diabetes, apparently acting at the level of the immune system, will help define immunopathogenesis of type 1 diabetes, with fewer loci contributing to genetic prediction.

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