Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus - PubMed (original) (raw)

Comparative Study

. 2007 Apr 17;104(16):6758-63.

doi: 10.1073/pnas.0701266104. Epub 2007 Apr 5.

Chieko Kyogoku, Snaevar Sigurdsson, Irina A Vlasova, Leela R L Davies, Emily C Baechler, Robert M Plenge, Thearith Koeuth, Ward A Ortmann, Geoffrey Hom, Jason W Bauer, Clarence Gillett, Noel Burtt, Deborah S Cunninghame Graham, Robert Onofrio, Michelle Petri, Iva Gunnarsson, Elisabet Svenungsson, Lars Rönnblom, Gunnel Nordmark, Peter K Gregersen, Kathy Moser, Patrick M Gaffney, Lindsey A Criswell, Timothy J Vyse, Ann-Christine Syvänen, Paul R Bohjanen, Mark J Daly, Timothy W Behrens, David Altshuler

Affiliations

Comparative Study

Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus

Robert R Graham et al. Proc Natl Acad Sci U S A. 2007.

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Expression levels of IRF5 mRNA are influenced by a polymorphism in a proximal 3′ UTR polyA+ signal sequence. (a) Microarray data from 233 CEU cell lines carrying various genotypes for rs2004640 and rs10954213 were examined for expression levels of IRF5. (b) Schematic of the 3′ UTR region of IRF5. (c) Northern blot of 500 ng of polyA+ RNA from cell lines carrying the indicated genotypes at rs10954213 (three cell lines from unrelated individuals for each genotype) using a common proximal 3′ UTR probe. Blots were stripped and reprobed for GAPDH. (d) Quantitative _Taq_Man RT-PCR in EBV cell lines (n = 9) and in control peripheral blood mononuclear cells (n = 14) for levels of IRF5 isoforms carrying the short or long 3′ UTR. (e) Northern blot using β-globin and GFP cDNA probes in Tet-off 293 cells transfected with chimeric β-globin:IRF5 3′ UTR expression plasmids for either the A or G allele of rs10954213. GFP expression plasmids were cotransfected as a control. (f) Graph shows the decay of β-globin:3′ IRF5 UTR mRNAs after suppression of new transcription with doxycycline. Results represent four independent experiments. ∗, P < 0.05; ∗∗, P < 0.01. (g) Western blot for IRF5 in two cell lines for each of the indicated genotypes at rs10954213 by using monoclonal anti-IRF5 antibodies that recognize a C-terminal peptide sequence of IRF5. Blots were stripped and reprobed with antibodies to GAPDH. Representative of five independent experiments.

Fig. 2.

Fig. 2.

Three functional variants in IRF5 define risk and protective haplotypes for SLE. (a) Diagram showing the location of the three common functional alleles identified in IRF5. (b) Summary of IRF5 haplotypes and their association to SLE.

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