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
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.
