Low HERV-K(C4) Copy Number Is Associated With Type 1 Diabetes

  1. Gerald T. Nepom
  1. Systems Immunology, Benaroya Research Institute, Seattle, WA
  1. Corresponding author: Mike J. Mason, mmason{at}


Complement component C4 (C4) is a highly variable complement pathway gene situated ∼500 kb from DRB1 and DQB1, the genes most strongly associated with many autoimmune diseases. Variations in C4 copy number (CN), length, and isotype create a highly diverse gene cluster in which insertion of an endogenous retrovirus in the ninth intron of C4, termed HERV-K(C4), is a notable component. We investigated the relationship between C4 variation/CN and type 1 diabetes. We found 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 major histocompatibility complex class II susceptibility alleles. We show that HERV-K(C4) is a novel marker of type 1 diabetes 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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.

| Table of Contents