Low HERV-K(C4) Copy Number is Associated with Type 1 Diabetes

  1. Gerald T. Nepom1
  1. 1Benaroya Research Institute
  1. *Corresponding author: Mike J. Mason Email: mmason{at}


Complement component C4 (C4) is a highly variable complement pathway gene situated approximately 500kb from DRB1 and DQB1, the genes most strongly associated with many autoimmune diseases. Variations in C4 copy number, length, and isotype create a highly diverse gene cluster, in which insertion of an endogenous retrovirus in the 9th intron of C4, termed HERV-K(C4), is a notable component. Here we investigate the relationship between C4 variation/copy number and type 1 diabetes. We find that individuals with type 1 diabetes have significantly fewer copies of HERV-K(C4), and that this effect is not solely due to linkage with known MHC class II susceptibility alleles. We show that HERV-K(C4) is a novel type 1 diabetes marker that accounts for the disease association previously attributed to some key HLA-DQB1 alleles raising the possibility that this retroviral insertion element contributes to functional protection against type 1 diabetes.

  • Received September 6, 2013.
  • Accepted January 7, 2014.

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