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

Robert R. Graham, 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 NordmarkPeter 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

Research output: Contribution to journalArticlepeer-review

337 Scopus citations


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 (IRFS), 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 IRFS mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRFS 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.

Original languageEnglish (US)
Pages (from-to)6758-6763
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
StatePublished - Apr 17 2007


  • Interferon pathway
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • General


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