title: Low HERV-K(C4) copy number is associated with type 1 diabetes.
abstract: 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.
authors.affiliation: Systems Immunology, Benaroya Research Institute, Seattle, WA.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Mason
authors.forename: Cate
authors.initials: C
authors.lastname: Speake
authors.forename: Vivian H
authors.initials: VH
authors.lastname: Gersuk
authors.forename: Quynh-Anh
authors.initials: QA
authors.lastname: Nguyen
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: O'Brien
authors.forename: Jared M
authors.initials: JM
authors.lastname: Odegard
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D003181:Complement C4 / Q000235:genetics*; D056915:DNA Copy Number Variations; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D011110:Polymorphism, Genetic
chemical_list: D003181:Complement C4