The Genetics of Rheumatoid Arthritis

Dr Sophia Steer
Original article: 11/09/2003
Reviewed: 19/03/2009
Next review due: 19/03/2012

Despite much research, the reasons for which an individual develops rheumatoid arthritis remain unknown. The possibilities can broadly be divided into:

1. Those factors which are inherited
2. Those factors which are encountered in our environment

Recent technological advances have made it possible to examine our inherited material, that is DNA (deoxyribonucleic acid) which makes up our genes, in great detail. However, this requires considerable investment from patients, their families, physicians, researchers and their funding institutions.

The paragraphs below outline the evidence that supports such investment in the investigation of the genetics of rheumatoid arthritis, the progress that has been made so far and the potential benefits of this work in the long term.

Evidence for the role of genes in rheumatoid arthritis family studies

Isolated reports of rheumatoid arthritis affecting several generations in families all published in the early 20 ^th century prompted further studies in the 50s, 60s and 70s. These compared the number of cases of rheumatoid arthritis in relatives of patients with the disease with the number of cases in relatives of patients without the disease or with the number of cases in the general population. These studies confirmed that relatives of individuals with the disease had an increased risk of getting the disease themselves compared to other relatives or the general population. The estimates of the degree of this risk vary quite widely between the studies, reflecting the different methods used. However, in first degree relatives the increase in risk was in general between two to four times that of the general population and for those with very severe disease, it could be as great as seven times.

Twin studies

Twin studies also suggest that genes contribute to the risk of rheumatoid arthritis. Monozygotic twins (twins that share 100% of their genes) are more likely to be concordant for rheumatoid arthritis (ie both suffer from disease) than dizygotic twins (twins that share 50% of their genes). In a recent study involving twins in the United Kingdom, 15% of monozygotic twin pairs were concordant for disease compared with 4% of dizygotic twin pairs.

How much of disease risk is determined by genes?

Although the work outlined above clearly supports the role of genes in determining risk of rheumatoid arthritis, it is also clear that they do not account for all of an individual’s susceptibility to the disease. Many patients may not have a family history of disease and in families with more than one individual affected, the disease is not clearly transmitted from one generation to another. These observations suggest that both genes, the environment and the interaction between the two, may determine who develops disease.

The relative importance of genes can be quantified by calculating the disease heritability using the data from twin studies. The heritability of a disease is an estimate of the extent to which genes explain risk of disease in a population. Heritability estimates for rheumatoid arthritis in studies performed in Northern Europe are between 53% and 65%, suggesting that genetic factors account for more that half of disease susceptibility in these populations.

Which genes are responsible for increased risk of rheumatoid arthritis?

The pattern of inheritance of rheumatoid arthritis within families suggests that many genes are involved in predisposing individuals to developing the disease. Each gene contributes a small amount to the overall risk. The genes involved may vary between individuals and between populations in different parts of the world.

Finding genes that affect the risk of developing RA when they only have a small effect on that risk is difficult but progress has been made recently. This has been made possible by two important developments. The first is the advances in technology which have made it technically possible to test a large proportion of the genome relatively quickly and affordably in large numbers of individuals. The second is the large number of patient and control samples that have been donated by patients and collected by researchers collaborating in different parts of the world. “Whole genome association scans” performed using samples from several thousands of patients are the result of these advances and since 2007 these have identified several new genes that are associated with rheumatoid arthritis.

Different results may be reported by different studies. This may reflect true differences in genetic risk factors in different populations (genetic heterogeneity) or may reflect problems with the study design. The conflicting results can make it difficult to be certain whether some genes are involved in rheumatoid arthritis or not. In this article the genes for which there are strong evidence to support them as risk factors for rheumatoid arthritis are discussed. There are many other genes for which the evidence is not clear, but these are not described here.

One group of genes that is definitely involved is the group that determines our human leucocyte antigens (HLA). These can be thought of as the genes that determine our tissue type and were initially discovered to be important in determining whether a tissue transplant will survive or be rejected. The proteins encoded by these genes play a crucial role in the presentation of foreign proteins to our immune system. The importance of these genes was first discovered in the 1970s and these findings have since been repeated in many different populations. The gene that is most strongly associated with rheumatoid arthritis is the HLA-DRB1 gene. There are many different variants (alleles) of this gene, and several are associated with increased risk of developing rheumatoid arthritis. These high-risk alleles of HLA-DRB1 seem to predispose individuals to develop anti-cyclic citrullinated peptide (CCP) antibodies in their serum and this puts them at increased risk of developing rheumatoid arthritis. The exact mechanisms behind this are not understood. There is also some evidence of an interaction between genetic and environmental factors as the risk of developing rheumatoid arthritis is particularly increased in individuals who smoke and who also have the high risk HLA-DRB1 alleles.

The second gene to be associated with an increased risk of rheumatoid arthritis is protein tyrosine phosphatase 22 (PTPN22), which encodes an enzyme called lymphoid tyrosine phosphatase (LYP). Interestingly this gene is associated with several other autoimmune diseases, for example type 1 diabetes mellitus and autoimmune thyroid disease, as well as rheumatoid arthritis. LYP is involved in controlling the level of activation of different types of white blood cell, including T-cells, but it is not yet clear exactly how this predisposes to autoimmune disease. The association of this gene with rheumatoid arthritis seems to be stronger in those who have anti-CCP antibodies.

Another gene that has been associated with several autoimmune diseases including rheumatoid arthritis is the cytotoxic T-lymphocyte antigen-4 ( CTLA4 ) gene. This gene encodes a molecule which is present on the surface of T-cells, and regulates the activation and proliferation of T-cells that occurs when foreign peptides are presented to them. The association of this gene with rheumatoid arthritis is less strong than that of either HLA-DRB1 or PTPN22, but just like the other genes it is probably mainly a risk factor in those with anti-CCP antibodies.

A fourth gene for which there is good evidence for association with rheumatoid arthritis is that encoding the enzyme peptidylarginine deiminase 4 ( PADI4 ). This was first identified as increasing susceptibility to disease in a Japanese population, and although it is also a risk factor in white North Americans, the effect appears to be much stronger in the Japanese, Korean and in other Asian populations.

There is strong evidence for associating RA with a region on the genome encoding two genes – complement component 5 (C5) and tumour necrosis factor (TNF) receptor-associated factor 1 (TRAF1). Either or both of these genes may be involved as both play important parts in the process of inflammation and further research is being done to try and answer this question. Signal transducer and activator of transcription 4 (STAT4) is also definitely associated with RA, although the effect that it has on the risk of disease seems to be smaller. STAT4 is also strongly associated with systemic lupus erythematosus, another autoimmune rheumatic disease, in which it seems to have a stronger effect. STAT4 plays an important role in the immune system in the development of some types of white blood cell including T cells.

Two studies have reported that there are genetic variants that are associated with RA in a region of the long arm of chromosome 6. It is not yet clear which gene or genes is/are responsible for this but TNF alpha induced protein 3 seems likely, particularly as it has an important role in TNF signalling. Associations have also been confirmed in a region of the long arm of chromosome 4 and genes that are likely to be implicated include those for the cytokines interleukin-2 and interleukin-21.

It is likely that several other genes also contribute to susceptibility to rheumatoid arthritis and this is an area where our understanding is constantly evolving.

Why is it important to identify which genes are involved?

The identification of the individual genes which are responsible for increased risk of disease will lead to a greater understanding of the actual mechanisms underlying disease. Although it has taken a considerable amount of effort to identify genes that increase the risk of disease, the hard work has only just begun! Much more work is needed to understand how variations in these genes alter the immune system and the inflammatory process. The hope is that this in turn should reveal new targets for treatment allowing patients’ disease to be more effectively controlled.

This work may also help in the identification of the environmental factors that increase the risk of disease. Individuals identified as being at risk because of their genes may then be able to avoid such environmental exposure, and thus prevent the disease occurring.

It is also possible that in the future genetic testing many enable individuals at risk of having more severe disease to be identified, and for their treatment to be adjusted accordingly. At present genetic tests are not used. This is because they do not provide any more useful information than that provided by standard tests that are currently in use such as anti CCP antibodies. 

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