Identification of IκBL as the Second Major Histocompatibility Complex–Linked Susceptibility Locus for Rheumatoid Arthritis

Abstract

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 (I kappa BL, 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 -62) of the I kappa BL gene (P=.0062). This -62T/A SNP disrupts the putative binding motif for the transcriptional repressor, delta EF1, and hence may influence the transcription of I kappa BL, homologous to I kappa B alpha, the latter being a known inhibitor of NF kappa B, which is central to innate immunity. Therefore, the MHC may harbor RA genetic determinants affecting the innate and adaptive arms of the immune system.

Is there a future for TNF promoter polymorphisms?

“…There is strong evidence for two further genetic loci in RA, besides the well established risk attributable to HLA DRB1, but these loci extend over a large region including many genes. 136 The recent identification of the IkBL (NFKBIL1) gene as the second MHC susceptibility locus for RA with the identification of a IkBL promoter SNP (À62) as disrupting a putative binding motif for a transcription repressor 43 demonstrates that broad mapping of the MHC is a powerful strategy. Interestingly, this locus was also identified in studies of myocardial infarction 44 and breast cancer susceptibility.…”

“…Studies of the haplotype structure of the TNF locus have described many haplotypes in this genomic region 41 and suggested that the TNF region contains a gene that makes a contribution to susceptibility independently of the contribution of HLA-DRB1. 24,42 This gene was then identified as IkBL (NFKBIL1), 43 which has also been implicated in susceptibility to myocardial infarction. 44 Further studies are needed to show that the variants of IkBL or LTA are functional and directly contribute to the pathogenesis of RA and further fine mapping of the TNF region must rule out linkage to other disease loci.…”

“…43,44,136,156 From the studies discussed above it is clear that certain diseases are not associated in any way with the TNF region, including MS and the response to interferon-alpha therapy of hepatitis, but the inconsistency of the reports with regard to other diseases perhaps suggests that in these cases a genuine linkage may exist to a nearby disease-causing locus. In the light of the factors discussed above, this impression may simply result from a small number of poorly conducted studies, or from ethnic factors determining linkage, but confirmation requires large studies that include a broad region of the MHC.…”

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis

“…We first used microsatellite markers to investigate the HLA-linked susceptibility loci. These microsatellite markers were used in earlier studies to discover the susceptibility loci of various diseases, including chronic rheumatoid arthritis, 24,30,31 Takayasu arteritis, 28,32 and autoimmune pancreatitis, 26 which suggested that these markers might capture specific haplotypes of HLA or non-HLA genes. However, because we investigated only 15 microsatellite markers, these markers might not be enough to capture all the susceptibility genes for DVTnegative CTEPH.…”

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

“…The exciting exception came very recently with the discovery that STAT4 accounts for the 2q33 locus (Peter K Gregersen, personal communication). 14 Association studies identified PTPN22, CTLA-4, PADI-4, [15][16][17] IkBL 18 and SCL22A4 19 as susceptibility genes, but only the first three, particularly PTPN22 have been replicated. While these new findings have generated great excitement, it remains unclear how these genes operate to regulate disease, and whether they will become feasible targets for therapeutic intervention.…”