Identification of IκBL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with a complex etiology in which environmental factors within a genetically susceptible host maneuver the innate and adaptive arms of the immune system toward recognition of autoantigens. This ultimately leads to joint destruction and clinical symptomatology. Despite the identification of a number of disease-susceptibility regions across the genome, RA's major genetic linkage remains with the major histocompatibility complex (MHC), which contains not only the key immune-response class I and class II genes but also a host of other loci, some with potential immunological relevance. Inside the MHC itself, the sole consistent RA association is that with HLA-DRB1, although this does not encode all MHC-related susceptibility. Indeed, in a set of Japanese patients with RA and a control group, we previously reported the presence of a second RA-susceptibility gene within the telomeric human leukocyte antigen (HLA) class III region. Using microsatellites, we narrowed the susceptibility region to 70 kb telomeric of the TNF cluster, known to harbor four expressed genes (IkappaBL, ATP6G, BAT1, and MICB). Here, using numerous single-nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms, we identify the second RA-susceptibility locus within the HLA region, as the T allele of SNP 96452 (T/A), in the promoter region (position 5 62) of the IkappaBL gene (P = .0062). This -62T/A SNP disrupts the putative binding motif for the transcriptional repressor, deltaEF1, and hence may influence the transcription of IkappaBL, homologous to IkappaBalpha, the latter being a known inhibitor of NFkappaB, which is central to innate immunity. Therefore, the MHC may harbor RA genetic determinants affecting the innate and adaptive arms of the immune system.