Differences in Interferon-gamma gene may predict severity of RA

Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis, Khani-Hanjani et al, 2000

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Definitions

Interferon-gamma (IFN-y) is an immunostimulating cytokine that is secreted by certain types of immune cells, called natural killer cells and T-lymphocytes. It stimulates many actions of immunity (e.g., increases the activity of macrophages and antibody production from B-cells) and is associated with many autoimmune diseases, including rheumatoid arthritis. IFN-y is produced by T-lymphocytes in inflamed synovial tissue in RA patients.

Polymorphisms, at least as used in this article, are basically different versions of the same gene in a certain region, meaning they have a different sequence. They can also be of varying lengths, as is the case in this paper. These polymorphisms can loosely be referred to as alleles, as is done in this paper. If a person has the same allele on both chromosomes (we have a pair of each, excluding the X/Y chromosomes), they are homozygous. If they have a different allele, they are heterozygous.

The genetic sequence of a gene is made up of introns and exons. Exons are the coding region, or the part of the gene that actually codes for the protein. Introns are the "rest" of the sequence. This article explains it well.

What did they study?

The researchers selected patients with mild or severe rheumatoid arthritis and compared the genetic make-up of the first intron on the gene that codes for IFN-y to normal (non-RA) patients. Severe RA was defined as patients who had failed to respond to treatment with three DMARDs and were taking cyclosporin. Mild RA was defined as patients who had well-controlled RA for three years on antimalarials, took no other DMARDs, and had fewer than 4 swollen and 0 deformed joints. A total of 60 severe, 39 mild, and 65 normal people were examined.

They looked at a range of six alleles of different lengths within the first intron, on both chromosomes (the gene is found on number 12): 120 base pairs (bp), 122 bp, 124 bp, 126 bp, 128 bp, and 130 bp.

What were the results?

The 120, 124, 128, and 130 bp alleles were present in approximately the same proportion of normal, mild, and severe patients. The 122 bp allele was much more common in normal or mild RA patients (80% and 64%, respectively) compared to severe RA patients (7%). Meanwhile, the 126 bp allele was more common in severe RA patients (73%) compared to normal or mild RA patients (12% and 21%, respectively). Furthermore, patients with severe RA were more likely to be homozygous for the 126 bp allele, while only 3% of mild patients and 0 normal patients were. Conversely, no severe RA patients were homozygous for the 122 bp allele, while 8% of mild RA patients and 17% of normal patients were.

What does this mean?

While this paper did not get into the significance of these genotypes with regards to IFN-y expression; however, in another paper (Dabora et al, 2002) they mention that the 126 bp allele described in this paper is associated with increased IFN-y production in vitro. Thus, from this study we not only learn that perhaps there is a detectable genotype that can predict potential severity of disease, but that the severity may be related to increased IFN-y production. This makes sense, as IFN-y increases immune activity and thus joint damage in RA patients.

Reading these articles, I think it is very notable that there is not a clear path or mechanism or really just one disease going on here. Rheumatoid arthritis is really a syndrome that has many causes: genetic or environmental. 

Genes and RA: What makes us more susceptible?

Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis, van der Woude et al, 2009

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What did they study?

Rheumatoid arthritis patients tend to be positive for anti-citrullinated protein antibody (ACPA), with 67% of patients testing positive. Patients who are ACPA positive tend to have a higher rate of joint destruction than seronegative patients, and a positive result is also more predictive of patient outcomes (i.e., how sick they will become) than RF.

Although several genes have been linked to ACPA-positive RA, the gene HLA-DRB1 is the most associated with ACPA-positive RA. In this study, the researchers examined pairs of identical and fraternal twins in which at least one of the twins had RA to examine the heritability of RA overall as well as ACPA seropositivity or negativity.

A total of 64 identical twins (of which 74 had RA) and 84 fraternal twins (of which 87 had RA) were studied. Concordance, which is a measure of the likelihood both twins in a pair will both have RA, and heritability, which is a measure of the amount that genetic differences affect the likelihood of developing RA, were measured.

What were the results?

In identical twin pairs, if one twin had RA the other was much more likely to have RA (15.6% concordance compared to 3.6% in fraternal twins). The heritability was 66%, meaning that genetic factors have a significant effect on the likelihood an individual will develop RA. ACPA-positive and negative RA were similarly heritable.

ACPA-positive people tended to have the HLA-DRB1 gene (89%), while many fewer (47%) ACPA-negative people did. 

What does this mean?

This study demonstrated again that RA is clearly impacted by an individual's genetic makeup. However, while there is clearly a link between this particular gene and seropositive RA, the results are clearly impacted by the overall low number of people who were ACPA-negative (with RA) on the study. Further study on the genome of positive and especially negative patients is needed to determine a clear pattern of genes that could indicate a patient is very likely to develop RA. 

As discussed in the previous post, early diagnosis and treatment is vital to reducing disability and increasing remission rates. If people can understand their risk, they are more likely to be able to realize the significance of early RA symptoms and seek treatment early.