Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting ∼1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for ∼30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33–34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA.
Methods and Findings
We performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (ncases/controls = 454/270), Sweden (ncases/controls = 1,500/1,000) and US (ncases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3′ end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located ∼10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17–1.39, pcombined = 1.40 × 10−8) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008).
Using a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.
Using a candidate-gene approach, Rene Toes and colleagues identified a novel genetic risk factor for rheumatoid arthritis in theTRAF1/C5 region.
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. Severe rheumatoid arthritis can be life-threatening, but even mild forms of the disease cause substantial illness and disability. Current treatments aim to give symptomatic relief with the use of simple analgesics, or anti-inflammatory drugs. In addition, most patients are also treated with what are known as disease-modifying agents, which aim to prevent joint damage. Rheumatoid arthritis is known to have a genetic component. For example, an association has been shown with the part of the genome that contains the human leukocyte antigens (HLAs), which are involved in the immune response. Information on other genes involved would be helpful both for understanding the underlying cause of the disease and possibly for the discovery of new treatments.
Why Was This Study Done?
Previous work in mice that have a disease similar to human rheumatoid arthritis has identified a number of possible candidate genes. One of these genes, complement component 5 (C5) is involved in the complement system—a primitive system within the body that is involved in the defense against foreign molecules. In humans the gene for C5 is located on Chromosome 9 close to another gene involved in the inflammatory response, TNF receptor-associated factor 1 (TRAF1). A preliminary study in humans of this region had shown some evidence, albeit weak, to suggest that this region might be associated with rheumatoid arthritis. The authors set out to look in more detail, and in a larger group of individuals, to see if they could prove this association.
What Did the Researchers Do and Find?
The researchers took 40 genetic markers, known as single-nucleotide polymorphisms (SNPs), from across the region that included the C5 and TRAF1 genes. SNPs have each been assigned a unique reference number that specifies a point in the human genome, and each is present in alternate forms so can be differentiated. They compared which of the alternate forms 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 (a small distance in genetic terms) that included one end of the C5 gene as well as the TRAF1 gene. They could refine 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, thus providing a possible explanation for the association. Furthermore, they showed that one of the alternate versions of the marker in this region was associated with more aggressive disease.
What Do These Findings Mean?
The finding of a genetic association is the first step in identifying a genetic component of a disease. The strength of this study is that a novel genetic susceptibility factor for RA has been identified and that the overall result is consistent in four different populations as well as being associated with disease severity. Further work will need to be done to confirm the association in other populations and then to identify the precise genetic change involved. Hopefully this work will lead to new avenues of investigation for therapy.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040278.
• Medline Plus, the health information site for patients from the US National Library of Medicine, has a page of resources on rheumatoid arthritis
• The UK's National Health Service online information site has information on rheumatoid arthritis
• The Arthritis Research Campaign, a UK charity that funds research on all types of arthritis, has a booklet with information for patients on rheumatoid arthritis
• Reumafonds, a Dutch arthritis foundation, gives information on rheumatoid arthritis (in Dutch)
• Autocure is an initiative whose objective is to transform knowledge obtained from molecular research into a cure for an increasing number of patients suffering from inflammatory rheumatic diseases
• The European league against Rheumatism, an organisation which represents the patient, health professionals, and scientific societies of rheumatology of all European nations