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Human Molecular Genetics Advance Access originally published online on December 22, 2006
Human Molecular Genetics 2007 16(6):579-591; doi:10.1093/hmg/ddl469
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation

Deborah S. Cunninghame Graham1, Harinder Manku1, Susanne Wagner2, Julia Reid2, Kirsten Timms2, Alexander Gutin2, Jerry S. Lanchbury2 and Tim J. Vyse1,*

1 Imperial College, Faculty of Medicine, Molecular Genetics and Rheumatology Section, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK and 2 Myriad Genetics Inc., 320 Wakara Way, Salt Lake City, UT 84108, USA

* To whom correspondence should be addressed. Tel: +44 2083832339; Fax: +44 2087433109; Email: t.vyse{at}imperial.ac.uk

Received September 20, 2006; Revised November 19, 2006; Accepted December 12, 2006

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.


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