Mutation in Immunity Genes May Increase RA Risk

LEIDEN, The Netherlands, Sept. 20 -- At least some cases of rheumatoid arthritis appear to be set in motion by mutations in two immunity-related genes, leading to increased susceptibility and severity of the disease.

Single-nucleotide polymorphisms associated with complement component 5 (C5) and tumor necrosis factor receptor-associated factor 1 (TRAF1) occurred significantly more often in patients with rheumatoid arthritis than in control groups, Rene E.M. Toes of Leiden University Medical Center, and colleagues reported online in the open-access journal PLoS Medicine.

The authors speculated that a single-nucleotide polymorphism "in the TRAF1/C5 region increases the susceptibility to and severity of [rheumatoid arthritis], possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5."

Human leukocyte antigens account for about 30% of the heritable risk of rheumatoid arthritis, they said. But the identities of non-HLA genes that explain the remaining heritable component have remained largely unknown. Data from murine models of the disease suggested TRAF1/C5 as candidate genes for heritability.

So the researchers performed a multi-tiered case-control study of 40 polymorphisms from the TRAF1/C5 region in 290 Dutch patients with rheumatoid arthritis and 254 controls.

Stepwise replication of significant polymorphisms was performed in 2,429 arthritis patients and 1,745 controls from the Netherlands, Sweden, and the U.S.

The analysis revealed a significant association (P