title: Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus.
abstract: Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Chieko
authors.initials: C
authors.lastname: Kyogoku
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Irina A
authors.initials: IA
authors.lastname: Vlasova
authors.forename: Leela R L
authors.initials: LR
authors.lastname: Davies
authors.forename: Emily C
authors.initials: EC
authors.lastname: Baechler
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Thearith
authors.initials: T
authors.lastname: Koeuth
authors.forename: Ward A
authors.initials: WA
authors.lastname: Ortmann
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hom
authors.forename: Jason W
authors.initials: JW
authors.lastname: Bauer
authors.forename: Clarence
authors.initials: C
authors.lastname: Gillett
authors.forename: Noel
authors.initials: N
authors.lastname: Burtt
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Cunninghame Graham
authors.forename: Robert
authors.initials: R
authors.lastname: Onofrio
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Kathy
authors.initials: K
authors.lastname: Moser
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Bohjanen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: D016022:Case-Control Studies; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012307:Risk Factors
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D020033:Protein Isoforms