13 Nov 2003

Some people are genetically predisposed to specific autoimmune diseases such as rheumatoid arthritis, though for the most part, the reason for their susceptibility is unclear. Now, in this month's Nature Genetics, two papers reveal that single nucleotide polymorphisms (SNPs) in the binding site for a single protein called Runt-related transcription factor 1 (RUNX1) can lead to either psoriasis or rheumatoid arthritis (RA). These findings, when coupled with a paper in the same journal last year showing that RUNX1-binding site polymorphisms are also responsible for some cases of systemic lupus erythematosus (SLE), suggest that the transcription factor may behave as an autoimmunity master switch.

Kazuhiko Yamamoto and colleagues at RIKEN, Yokohama, Japan, identified the rheumatoid arthritis-linked SNPs in the gene for SLC22A4, an organic cation transporter. First author Shinya Tokuhiro and colleagues used linkage disequilibrium mapping to home in on SNPs lying in the vicinity of chromosome 5q31, a cytokine cluster region that has been shown to be associated with RA. From over 170 SNPs in this region, Tokuhiro and colleagues compared RA-affected individuals with controls to identify polymorphisms linked to the disease. Haplotype analysis indicated that SNPs in the SLC22A4 gene are likely candidates for RA linkage. To pinpoint exactly which mutations are involved, the authors evaluated the sequence of the gene and its flanking DNA. SNPs 5' to the gene and missense mutations within the coding region could not be linked to RA cases, but one SNP in intron 1 was found to have a strong relation with RA and to be part of the binding site for RUNX1.

To test if this SNP, labeled SLC2F2, could provide a molecular explanation for RA susceptibility, the authors carried out RUNX1-binding assays using DNA containing either wild-type or mutant alleles. The SLC2F2 polymorphism resulted in a significant gain in affinity for the transcription factor, which was accompanied by suppression of a reporter gene. The data suggest that the polymorphism may result in reduced expression of the cation transporter.

In the second paper, Anne Bowcock and colleagues from the Washington University School of Medicine at St. Louis, Missouri, and elsewhere in the U.S. used similar analysis to home in on a region of chromosome 17q25 that has been linked to psoriasis. First author Cynthia Helms and colleagues narrowed down over 120 possible markers to just two regions where association with the disease was significant. From these regions, five SNPs that were consistently present or absent from affected individuals were identified.

None of these were found in coding DNA, but one, lying downstream of the gene for SLC9A3R1, was found to interrupt a RUNX1-binding site, and electrophoretic mobility shift assays showed that in contrast to the RA-associated SNP, this psoriasis-linked allele eliminated RUNX1-binding. In functional tests using RUNX1-binding sites containing the disease-linked allele, Helms found that addition of the transcription factor and its coactivator CBFβ resulted in much poorer expression of a reporter than was achieved using the wild-type allele.

Taken together with last year's findings by Marta Alarcon-Riquelme and colleagues at the University of Uppsala, Sweden, that an intronic SNP in the gene for the programmed cell death gene 1 (PDCD1) that is associated with SLE also alters a RUNX1 site, it suggests that the RUNX1 factor may be capable of switching different autoimmune responses on and off. In support of this, Tokuhiro and colleagues found that an SNP within the RUNX1 gene itself is associated with RA.—Tom Fagan

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