title: Opposed independent effects and epistasis in the complex association of IRF5 to SLE.
abstract: Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, P<10(-17)) and protection (rs729302, P<10(-6)). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5' side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.
authors.affiliation: Laboratorio Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ferreiro-Neira
authors.forename: M
authors.initials: M
authors.lastname: Calaza
authors.forename: E
authors.initials: E
authors.lastname: Alonso-Perez
authors.forename: M
authors.initials: M
authors.lastname: Marchini
authors.forename: R
authors.initials: R
authors.lastname: Scorza
authors.forename: G D
authors.initials: GD
authors.lastname: Sebastiani
authors.forename: F J
authors.initials: FJ
authors.lastname: Blanco
authors.forename: I
authors.initials: I
authors.lastname: Rego
authors.forename: R
authors.initials: R
authors.lastname: Pullmann
authors.forename: R
authors.initials: R
authors.lastname: Pullmann
authors.forename: C G
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: M
authors.initials: M
authors.lastname: Bijl
authors.forename: F N
authors.initials: FN
authors.lastname: Skopouli
authors.forename: M
authors.initials: M
authors.lastname: Mavromati
authors.forename: S
authors.initials: S
authors.lastname: Migliaresi
authors.forename: N
authors.initials: N
authors.lastname: Barizzone
authors.forename: S
authors.initials: S
authors.lastname: Ruzickova
authors.forename: C
authors.initials: C
authors.lastname: Dostal
authors.forename: R E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: T
authors.initials: T
authors.lastname: Witte
authors.forename: C
authors.initials: C
authors.lastname: Papasteriades
authors.forename: I
authors.initials: I
authors.lastname: Kappou-Rigatou
authors.forename: E
authors.initials: E
authors.lastname: Endreffy
authors.forename: A
authors.initials: A
authors.lastname: Kovacs
authors.forename: J
authors.initials: J
authors.lastname: Ordi-Ros
authors.forename: E
authors.initials: E
authors.lastname: Balada
authors.forename: P
authors.initials: P
authors.lastname: Carreira
authors.forename: J J
authors.initials: JJ
authors.lastname: Gomez-Reino
authors.forename: A
authors.initials: A
authors.lastname: Gonzalez
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors