GENETIC EPIDEMIOLOGY OF RHEUMATOID-ARTHRITIS

We conducted family studies and segregation analyses of rheumatoid art hritis (RA) that were based on consecutive patients with RA ascertaine d without regard to family history or known risk factors. First-degree relatives from 135 simplex and 30 multiplex families were included in the analyses. A highly penetrant recessive major gene, with a mutant allele frequency of .005, was identified as the most parsimonious gene tic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kap lan-Meier risk analysis demonstrated significant evidence for differen ces in the distribution of risk among first-degree relatives. These an alyses demonstrated that both proband gender and age at onset are impo rtant risk factors but that proband gender appears to be the more impo rtant determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. In addition, log-linear modeling iden tified proband gender, familiality (multiplex or simplex), and an inte raction term between these two variables as being adequate to define t he distribution of risk in families. The pattern of risk for RA among susceptible individuals and its inheritance is thus heterogeneous. For future genetic analyses, families with an excess of affected males ha ving a young age at onset may be the most informative in identifying t he putative recessive gene and its modifiers.