Clinically and immunologically rheumatoid arthritis (RA) is possibly a heterogeneous disorder. Despite numerous efforts clearer definition of this heterogeneity has been of limited success. Measurements of rheumatoid factor (RF) and antinuclear antibodies (ANA) by conventional methods define subpopulations of patients with RA and in a few recent studies an association of human leucocyte antigens (HLA) undoubtedly indicates the immunogenetic differences in the susceptibility of RA patients with different status of autoantibodies. The studies on a few isolated non-HLA genetic markers in RA are controversial. To understand the role of genetic factors in susceptibility 24 single gene characters other than HLA were investigated in 225 patients with RA classified by humoral status (presence or absence of RF and ANA) into three groups and in 104 healthy control individuals from the north east of England. Locus by locus comparison suggested associations of MN, Lewis, and Bf system with RF positive patients. Although the associations with MN and Lewis blood groups require further investigations, the involvement of the Bf locus is in agreement with the immunological component of the disease suggested by HLA associations and it could be due to the phenomenon of linkage disequilibrium. Measures of genetic distance applied to the subpopulations of patients with RA, divided according to the presence or absence of humoral factors, suggest that RF+ ANA+, RF- ANA-, and RF+ ANA- subgroups are distinct genetic diseases, each affecting a different subsection of the population which is genetically distinct. Such genetic heterogeneity may suggest a different pathogenetic mechanism for each of these subpopulations of rheumatoid arthritis.
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