IL4R mutations predict erosive disease in rheumatoid arthritis

Prots I et al. (2006) Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis. Arthritis Rheum 54: 1491–1500

Early treatment of inflammation in patients with rheumatoid arthritis (RA) is thought to limit the progression of joint destruction, so prompt identification of patients at risk of developing erosive disease is important. Genome-wide studies have suggested that the interleukin 4 receptor (IL4R) gene is associated with susceptibility to and/or progression of disease in RA. Prots et al. investigated the influence of two known single nucleotide polymorphisms in IL4R (the resulting amino-acid substitutions Ile50Val and Gln551Arg cause functional changes in its product, IL-4R) on RA susceptibility and progression.

This multicenter study enrolled 471 patients with RA and 371 controls. The presence of erosive disease was determined by examination of hand and foot radiographs taken 2 years after disease onset.

Neither mutation was associated with RA susceptibility, but the Ile50Val variant of IL-4R was associated with the development of erosive disease within the first 2 years of the disease (odds ratio 3.86). Two copies of the allele that resulted in the Ile50Val substitution conferred more than twice the risk observed with one copy; the predictive value of a single copy of this allele for the development of early erosive changes in RA was similar to that of existing markers (including rheumatoid factor).

The authors found that the Ile50Val mutation impaired the function of IL-4R, reducing its response to IL-4. They suggest that this impairment could cause an increase in T_H1-mediated effects of IL-4 (at the expense of T_H2-mediated effects), which could, in turn, worsen inflammation and cause rapid joint damage.