title: Reduced expression of IFIH1 is protective for type 1 diabetes.
abstract: IFIH1 (interferon induced with helicase C domain 1), also known as MDA5 (melanoma differentiation-associated protein 5), is one of a family of intracellular proteins known to recognise viral RNA and mediate the innate immune response. IFIH1 is causal in type 1 diabetes based on the protective associations of four rare variants, where the derived alleles are predicted to reduce gene expression or function. Originally, however, T1D protection was mapped to the common IFIH1 nsSNP, rs1990760 or Thr946Ala. This common amino acid substitution does not cause a loss of function and evidence suggests the protective allele, Ala(946), may mark a haplotype with reduced expression of IFIH1 in line with the protection conferred by the four rare loss of function alleles. We have performed allele specific expression analysis that supports this hypothesis: the T1D protective haplotype correlates with reduced IFIH1 transcription in interferon-β stimulated peripheral blood mononuclear cells (overall p = 0.012). In addition, we have used multiflow cytometry analysis and quantitative PCR assays to prove reduced expression of IFIH1 in individuals heterozygous for three of the T1D-associated rare alleles: a premature stop codon, rs35744605 (Glu627X) and predicted splice variants, rs35337543 (IVS8+1) and rs35732034 (IVS14+1). We also show that the nsSNP, Ile923V, does not alter pre-mRNA levels of IFIH1. These results confirm and extend the new autoimmune disease pathway of reduced IFIH1 expression and protein function protecting from T1D.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.forename: Marcin
authors.initials: M
authors.lastname: Pekalski
authors.forename: Karen L
authors.initials: KL
authors.lastname: Angus
authors.forename: Matthew
authors.initials: M
authors.lastname: Hardy
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D018389:Codon, Nonsense; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D015536:Down-Regulation; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; D020011:Protective Agents; D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1