Genes in rheumatoid arthritis

A paper published this week in the open access journal PLoS Medicine provides strong evidence that one specific part of the genome is associated with rheumatoid arthritis. Rene Toes and colleagues from Leiden University Medical Center, the Karolinska Institute, and Celera studied four groups of patients and matched controls.

They found a consistent association with one specific region of the genome — a region on chromosome 9 that includes the two genes, complement component 5 (C5) of the complement system (a primitive system within the body that is involved in the defense against foreign molecules) and a gene involved in the inflammatory response, TNF receptor-associated factor 1(TRAF1) .

Rheumatoid arthritis is a very common chronic illness that affects around 1% of people in developed countries. It is caused by an abnormal immune reaction to various tissues within the body. As well as affecting joints and causing an inflammatory arthritis, it can also affect many other organs of the body. An association has been shown previously in humans with the part of the genome that contains the human leukocyte antigens (HLAs), which are involved in the immune response. In addition, previous work in mice that have a disease similar to human rheumatoid arthritis has identified a number of possible candidate genes including C5.

The researchers took 40 genetic markers, single-nucleotide polymorphisms (SNPs), from across the region that included the C5 and TRAF1 genes. They compared which of the alternate forms of the SNPs were present in 290 patients with rheumatoid arthritis and 254 unaffected participants of Dutch origin. They then repeated the study in three other groups of patients and controls of Dutch, Swedish, and US origin. They found a consistent association with rheumatoid arthritis of one region of 65 kilobases that included one end of the C5 gene as well as the TRAF1 gene and then refined the area of interest to a piece marked by one particular SNP that lay between the genes. They went on to show that the genetic region in which these genes are located may be involved in the binding of a protein that modifies the transcription of genes. Furthermore, they showed that one of the alternate versions of the marker in this region was associated with more aggressive disease.

This study adds to accumulating evidence that this region of the genome is associated with rheumatoid arthritis. The next steps will be to identify the precise genetic change involved.

Citation: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med

4(9): e278. doi:10.1371/journal.pmed.0040278

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