| Summary: | Rheumatoid Arthritis (RA) is a chronic musculoskeletal disease of unknown aetiology. RA is a complex polygenic and multifactorial disease and has not been analysed comprehensively among South Asians, specifically in the East Midlands. Two genetic approaches were used; case-control and sib-TDT analyses. Ten polymorphisms of eight genes (ACE, VDR, A2M, GSTTt and GSTMt, TNFRII, FcyRIIIA and CRH) were analysed in South Asians (134 patients, 66 unaffected sibs, 149 random controls) and Caucasians (137 pateints, 83 unaffected sibs, 150 random controls). The epidemiological results suggest that the South Asians were progressing to the disease significantly earlier (X2 = 21.01, 5 df, P < 0.005). The gender distribution (male:female) was 1:4 in South Asians and 1:3 in Caucasians. Significant genetic associations were observed with VDR Bsm I B-B genotype (OR= 2.08, Cl 1.23- 3.52, P < 0.05), A2M 2-2 genotype (OR= 3.99, Cl 1.19- 17.18, P < 0.05), and GST Tinull genotype (OR= 2.81, Cl 1.40- 5.77, P < 0.002) among South Asian RAs. In Caucasians, TNFRII R-R (OR= 3.16, Cl 1.20-9.26, P < 0.05), A2M 1- 1 (OR= 2.09, Cl 1.21-3.64, P < 0.05) and GST Ttnull (OR= 1.97, Cl 1.07- 3.68, P < 0.05) genotypes were associated with RA. In the majority of cases, recessive and multiplicative modes of inheritance explained the observed associations. There were no confounding interactions between the genotypes showing significant associations in both groups. Overall this study demonstrates that ethnic and genetic variation plays a significant role in RA susceptibility and progression. The observed genetic associations may have pharmacogenetic and diagnostic implications. Mechanisms to some of the possible pathogenic changes observed in RA are suggested by the study.
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