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We have looked for an effect of 14th chromosomal genes linked to immunoglobulin heavy chain (IgCH) or D14S1 regions on susceptibility to rheumatoid arthritis (RA) by both linkage (sibling pair analysis) and association studies. There was no overall linkage between RA and either IgCH or D14S1. However, Gm haplotype similarity in affected siblings appeared greater in either DR4-positive as compared to DR4-negative sibships or in sibships without clinical or serological evidence of autoimmune thyroid disease when compared to sibships with such evidence. In association studies there were no associations at the D14S1 locus. Within the Ig CH region there were no overall associations. However, within the RA population G1m (z) and G3m (g) both appeared less frequent in DR4-negative RA versus both DR4-positive RA and versus control groups. Analysis of DNA variants at Ig CH loci showed differences at the gamma 4 locus with a 9.0 kb fragment appearing less frequently in DR4-positive RA versus DR4-negative RA and control groups. The results suggest a weak or HLA-DR dependent effect of genes linked to the Ig CH region on susceptibility to RA.
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