Scientific Publications

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

Publication TypeJournal Article
AuthorsGraham, RR, Kyogoku C., Sigurdsson S., Vlasova IA, Davies LR, Baechler EC, Plenge RM, Koeuth T., Ortmann WA, Hom G., Bauer JW, Gillett C., Burtt N., Cunninghame Graham DS, Onofrio R., Petri M., Gunnarsson I., Svenungsson E., Rönnblom L., Nordmark G., Gregersen PK, Moser K., Gaffney PM, Criswell LA, Vyse TJ, Syvänen AC, Bohjanen PR, Daly M. J., Behrens TW, and Altshuler D.
AbstractSystematic 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.
Year of Publication2007
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue16
Pages6758-63
Date Published (YYYY/MM/DD)2007/04/17
ISSN Number0027-8424
DOI10.1073/pnas.0701266104
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/17412832?dopt=Abstract