Rheumatoid factor isotypes in monozygotic and dizygotic twins discordant for rheumatoid arthritis.
MacGregor AJ., Ollier WE., Venkovsky J., Mageed RA., Carthy D., Silman AJ.
OBJECTIVE: To examine the influence of genetic factors in determining the occurrence of rheumatoid factor (RF) isotypes. We investigated the hypothesis that, in twin pairs discordant for rheumatoid arthritis (RA), a genetic influence would be indicated by a higher rate of occurrence of RF among the unaffected monozygotic (MZ) when compared with the unaffected dizygotic (DZ) co-twins of seropositive affected twins. METHODS: IgM, IgA, and IgG RF were measured by ELISA in 70 MZ and 84 DZ disease discordant pairs using a cutoff for seropositivity defined using a normal control population. The risk of seropositivity in the unaffected twins of MZ when compared with DZ seropositive index twins was examined using odds ratios (OR). RESULTS: For all 3 RF isotypes, levels in the unaffected twins of seropositive index twins were higher than in the control population. MZ unaffected twins showed an increased risk for seropositivity for IgM and IgG RF when compared with DZ unaffected twins: IgM OR = 2.2 (95% CI 0.9-5.4), IgG OR = 2.4 (95% CI 0.9-6.6). The greatest excess risk for seropositivity occurred for IgM RF amongst the unaffected twin of an index twin with past or current documented evidence of RF seropositivity, OR = 3.4 (95% CI 1.4-8.5). For IgA RF, seropositivity risk in MZ unaffected twins was not increased, OR = 1.0 (0.3-3.1). The seropositivity risk for all 3 isotypes was independent of the age of the pair, the age of disease onset in the index twin, and the sex, HLA-DRB1*01 and DRB1*04 status of the unaffected twin. CONCLUSION: Genetic factors are important in determining the level of IgM and IgG RF. A genetic contribution to RA seropositivity exists that is independent of HLA-DR.