title: Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation.
abstract: Results from two studies have implicated the interferon regulatory gene IRF5 as a susceptibility gene in systemic lupus erythematosus (SLE). In this study, we conducted a family-based association analysis in 380 UK SLE nuclear families. Using a higher density of markers than has hitherto been screened, we show that there is association with two SNPs in the first intron, rs2004640 (P = 3.4 x 10(-4)) and rs3807306 (P = 4.9 x 10(-4)), and the association extends into the 3'-untranslated region (UTR). There is a single haplotype block encompassing IRF5 and we show for the first time that the gene comprises two over-transmitted haplotypes and a single under-transmitted haplotype. The strongest association is with a TCTAACT haplotype (T:U = 1.92, P = 5.8 x 10(-5)), which carries all the over-transmitted alleles from this study. Haplotypes carrying the T alleles of rs2004640 and rs2280714 and the A allele of rs10954213 are over-transmitted in SLE families. The TAT haplotype shows a dose-dependent relationship with mRNA expression. A differential expression pattern was seen between two expression probes located each side of rs10954213 in the 3'-UTR. rs10954213 shows the strongest association with RNA expression levels (P = 1 x 10(-14)). The A allele of rs10954213 creates a functional polyadenylation site and the A genotype correlates with increased expression of a transcript variant containing a shorter 3'-UTR. Expression levels of transcript variants with the shorter or longer 3'-UTRs are inversely correlated. Our data support a new mechanism by which an IRF5 polymorphism controls the expression of alternate transcript variants which may have different effects on interferon signalling.
authors.affiliation: Imperial College, Faculty of Medicine, Molecular Genetics and Rheumatology Section, Hammersmith Hospital, London, UK.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Cunninghame Graham
authors.forename: Harinder
authors.initials: H
authors.lastname: Manku
authors.forename: Susanne
authors.initials: S
authors.lastname: Wagner
authors.forename: Julia
authors.initials: J
authors.lastname: Reid
authors.forename: Kirsten
authors.initials: K
authors.lastname: Timms
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Vyse
mesh_terms: D020413:3' Untranslated Regions; D005260:Female; D005786:Gene Expression Regulation; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D009679:Nuclear Family; D010290:Parents; D026723:Polyadenylation; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom
chemical_list: D020413:3' Untranslated Regions; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors