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

Background Rheumatoid arthritis ranges from a mild, non-deforming arthropat hy with little long-term disability to severe, incapacitating, deforming ar thritis which may be refractory to conventional disease-modifying agents. E pidemiological studies show an important genetic influence in rheumatoid ar thritis, and MHC region genes and cytokine genes within and outside this re gion have been considered as candidates. We did a case-control study to tes t whether polymorphisms in the interferon-gamma gene are associated with se verity of rheumatoid arthritis. Methods Interferon gamma dinucleotide repeat polymorphisms were examined wi th quantitative genescan technology, and HLA-DR alleles were identified by PCR and restriction-fragment-length polymorphism analysis. We studied 60 pa tients with severe rheumatoid arthritis, 39 with mild disease, and 65 norma l controls. Findings Susceptibility to, and severity of, rheumatoid arthritis were rela ted to a microsatellite polymorphism within the first intron of the interfe ron-gamma gene. A 126 bp allele was seen in 44 (73%) of 60 patients with se vere rheumatoid arthritis, compared with eight (21%) of 39 with mild diseas e (odds ratio 10.66 [95% CI 4.1-24.9]), and with eight (12%) of 65 normal c ontrols (19.59 [7.7-49.9]). Conversely, a 122 bp allele at the same locus w as found in four (7%) patients with severe disease compared with 25 (64%) o f those with mild disease (0.04 [0.01-0.1]) and with 52 (80%) of controls ( 0.018 [0.005-0.06]). Interpretation This association may be valuable for understanding the mecha nism of disease progression, for predicting the course of the disease, and for guiding therapy.