Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 16, Pages 6758-6763Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0701266104
Keywords
interferon pathway; systemic lupus erythematosus
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Funding
- NCRR NIH HHS [M01 RR000052, M01 RR000079, 5 M01 RR-00079, M01-RR-00052] Funding Source: Medline
- NIAID NIH HHS [K02 AI052170, R56 AI057484, R01 AI049494] Funding Source: Medline
- NIAMS NIH HHS [AR 43727, R01 AR043727] Funding Source: Medline
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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 inf luence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SUE illustrates how multiple common variants of the same gene can together influence risk of common disease.
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