title: Association of IRF5 polymorphisms with increased risk for systemic lupus erythematosus in population of Crete, a southern-eastern European Greek island.
abstract: Interferon regulatory factor 5 (IRF5) regulates type I interferon (IFN)-responsive genes, and has been one of the most consistently associated genes with systemic lupus erythematosus (SLE). We sought to investigate whether IRF5 haplotypes are associated with risk for SLE in the genetically homogeneous Greek population of the island of Crete, as well as whether these haplotypes are associated with increased type I IFN. 322 SLE patients and 247 healthy controls from Crete were genotyped for rs2004640, rs3807306, rs10488631 and rs2280714 SNPs of IRF5 gene by using Taqman primer-probe sets. Type I IFN levels were measured using a functional reporter cell assay. All IRF5 SNPs examined were found to be associated with SLE in univariate case-control analysis. The 4 SNPs formed 5 major haplotypes and the Neanderthal-derived TACA risk haplotype was present in Crete and enriched in the SLE cases (OR=2.01, P=0.0003). Serum IFN levels were measured in a subset of the SLE patients, and carriage of the TACA haplotype was associated with higher circulating type I IFN levels (P=0.037). This study demonstrates the association of IRF5 with an increased susceptibility for SLE in the population of Crete and emphasizes the association of the Neanderthal-derived IRF5 haplotype with SLE susceptibility. Patients carrying allele the Neanderthal allele C had greater type I IFN, supporting a functional consequence of this polymorphism.
authors.affiliation: Section of Molecular Pathology and Human Genetics, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: M I
authors.initials: MI
authors.lastname: Zervou
authors.affiliation: Division of Rheumatology, Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Dorschner
authors.affiliation: Division of Rheumatology, Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ghodke-Puranik
authors.affiliation: Institute of Molecular Biology and Biotechnology, FORTH-Hellas, Voutes, Heraklion, Greece; Biomedical Research Foundation, Academy of Athens, Greece; Faculty of Medicine, National and Kapodestrian University of Athens, Athens, Greece.
authors.forename: D T
authors.initials: DT
authors.lastname: Boumpas
authors.affiliation: Division of Rheumatology, Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Niewold
authors.affiliation: Section of Molecular Pathology and Human Genetics, School of Medicine, University of Crete, Heraklion, Greece. Electronic address: goulielmos@med.uoc.gr.
authors.forename: G N
authors.initials: GN
authors.lastname: Goulielmos
mesh_terms: D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006115:Greece; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007370:Interferon Type I / Q000097:blood / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D059125:Neanderthals / Q000235:genetics
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007370:Interferon Type I
keywords: Gene polymorphism; Genetic association; Haplotype; Interferon regulatory factor 5 (IRF5) gene; Systemic lupus erythematosus (SLE)