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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0701266104

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

Publication TypeJournal Article
Year of Publication2007
AuthorsGraham, RR, Kyogoku, C, Sigurdsson, S, Vlasova, IA, Davies, LRL, Baechler, EC, Plenge, RM, Koeuth, T, Ortmann, WA, Hom, G, Bauer, JW, Gillett, C, Burtt, N, Graham, DSCunningh, Onofrio, R, Petri, M, Gunnarsson, I, Svenungsson, E, Rönnblom, L, Nordmark, G, Gregersen, PK, Moser, K, Gaffney, PM, Criswell, LA, Vyse, TJ, Syvänen, A-C, Bohjanen, PR, Daly, MJ, Behrens, TW, Altshuler, D
JournalProc Natl Acad Sci U S A
Date Published2007 Apr 17
KeywordsCase-Control Studies, Cell Line, Transformed, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Interferon Regulatory Factors, Lupus Erythematosus, Systemic, Protein Isoforms, Risk Factors

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID17412832
PubMed Central IDPMC1847749
Grant ListM01 RR000079 / RR / NCRR NIH HHS / United States
5 M01 RR-00079 / RR / NCRR NIH HHS / United States
AR 43727 / AR / NIAMS NIH HHS / United States
R56 AI057484 / AI / NIAID NIH HHS / United States
K02 AI052170 / AI / NIAID NIH HHS / United States
R01 AI049494 / AI / NIAID NIH HHS / United States
M01-RR-00052 / RR / NCRR NIH HHS / United States
M01 RR000052 / RR / NCRR NIH HHS / United States
R01 AR043727 / AR / NIAMS NIH HHS / United States