A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients.
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.
Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France; Inserm U874, Paris, France.
Julien
J
Pothlichet
Timothy B
TB
Niewold
Damien
D
Vitour
Brigitte
B
Solhonne
Mary K
MK
Crow
Mustapha
M
Si-Tahar
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001741:Black or African American; D019943:Amino Acid Substitution / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; C505371:MAVS protein, human
J Biomed Biotechnol. 2010;2010:826434
20671926
PLoS Pathog. 2009 Nov;5(11):e1000650
19893624
J Intern Med. 2009 Jun;265(6):680-8
19493061
Medicine (Baltimore). 2008 Nov;87(6):311-318
19011502
BMC Struct Biol. 2008 Feb 28;8:11
18307765
Nat Genet. 2008 Feb;40(2):204-10
18204446
Trends Mol Med. 2006 Feb;12(2):53-6
16406812
Nat Immunol. 2007 Jun;8(6):592-600
17468758
Arthritis Rheum. 1982 Nov;25(11):1271-7
7138600
Autoimmunity. 2003 Dec;36(8):481-90
14984025
J Immunol. 2007 Mar 15;178(6):3368-72
17339430
Curr Opin Investig Drugs. 2008 May;9(5):505-14
18465661
Lupus. 2009 Sep;18(10):878-83
19671786
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2610-5
12604793
Nature. 2008 Jan 31;451(7178):573-7
18200010
Arthritis Rheum. 2010 Feb;62(2):553-61
20112359
Genes Immun. 2007 Sep;8(6):492-502
17581626
Arthritis Rheum. 2008 Feb;58(2):541-6
18240214
Nat Genet. 1998 May;19(1):56-9
9590289
Genes Immun. 2009 Jul;10(5):470-7
19387456
Science. 2008 Aug 1;321(5889):691-6
18669862
Cell. 2005 Sep 9;122(5):669-82
16125763
N Engl J Med. 1979 Jul 5;301(1):5-8
449915
J Immunol. 2009 Jan 1;182(1):34-8
19109131
Science. 2005 Feb 18;307(5712):1072-9
15718463
Autoimmunity. 2006 Feb;39(1):63-70
16455583
EMBO J. 2006 Jul 26;25(14):3257-63
16858409
J Immunol. 2006 Nov 15;177(10):6573-8
17082566
Am J Hum Genet. 1998 Dec;63(6):1839-51
9837836
Nat Immunol. 2005 Oct;6(10):981-8
16127453
Arthritis Rheum. 2005 May;52(5):1491-503
15880830
Eur J Immunol. 2008 Dec;38(12):3487-98
19009528
Arthritis Res Ther. 2009;11(5):245
19849817
Nat Immunol. 2004 Jul;5(7):730-7
15208624
PLoS One. 2009 Oct 27;4(10):e7582
19859543
Cell Death Differ. 2006 May;13(5):798-815
16528382
Arthritis Rheum. 2008 Aug;58(8):2481-7
18668568
Nature. 2009 Jul 23;460(7254):520-4
19561593
J Immunol. 2008 Feb 15;180(4):2034-8
18250407
Arthritis Rheum. 2004 Dec;50(12):3958-67
15593221
EMBO J. 2006 Sep 20;25(18):4207-14
16946700