A Second Susceptibility Gene for Developing Rheumatoid Arthritis in the Human MHC Is Localized within a 70-kb Interval Telomeric of the TNF Genes in the HLA Class III Region

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with a multifactorial genetic basis. However, pathogenic genes for RA other than the human leukocyte antigen (HLA)-DRB1 gene have yet to be identified. Here, we investigated whether there is a second susceptibility locus for RA within the human major histocompatibility complex using 18 microsatellite markers distributed from the centromeric (HSET) to the telomeric end (P5-15) of the 3.6-Mb HLA region. Statistical studies of associated alleles on each microsatellite locus showed that one pathogenic gene for RA in the HLA region is localized in the DRB1 gene, as expected. Further, a second susceptibility gene of RA was suggested to be present in the HLA class III region, narrowed to 70 kb, that is just telomeric of the TNF gene cluster (TNFA and LTA) and that is located between the microsatellites TNFa and C1-2-A. In this critical segment, four expressed genes have been thus far identified, NFKBIL1 (IκBL), ATP6G, BAT1, and MICB, all of which are candidate genes for determining susceptibility to RA. These results exclude the possibility of involvement of the TNFA genes (TNF-α) in the development of RA, which was suggested previously to be a strong candidate for RA in the class III region.