Abstract
Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.
Highlights
Systemic lupus erythematosus (SLE) is a complex disease with a multi-factorial etiology
Information collected in January 2009 from the NCBI single nucleotide polymorphisms (SNPs) database indicated that at least 301 SNPs are present in the human MAVS gene
Sequence alignments showed that only three SNPs affect amino acids that are conserved in all analyzed species, i.e. C79F, C79S, and T147S, whereas R218 and G396 residues were conserved from horse to human only
Summary
Systemic lupus erythematosus (SLE) is a complex disease with a multi-factorial etiology. It is of note that EBV-encoded small RNAs induce type I IFN via the viral sensor RIG-I, a component of the TLR-independent innate immune pathway (Samanta et al, 2006) Another recent study showed that MAVS, an adaptor transducing RIGI signaling, interacts with “Eyes absent 4” (EYA4) protein to induce type I IFN expression in response to self-DNA (Okabe et al, 2009), a candidate inducer of SLE (Deane & Bolland, 2006). This study supports the utility of a “function first, genetic epidemiology second” approach for studying candidate genes in which some knowledge of the candidate’s pathway function is already available This is important for rare variants, as standard unbiased techniques result in statistical correction for hundreds or thousands of comparisons, frequently abolishing the potential for rare variants to demonstrate independently significant associations
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