The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15

Susceptibility to several disorders, including insulin-dependent diabetes mellitus and multiple sclerosis, has been associated with alleles of HLA class II genes and loci in the TNF cluster in the central major histocompatibility complex (MHC) region. As recombination within this region is rare, it is difficult to determine which genes are important. This will be facilitated by the identification of functional polymorphisms. Hence we are sequencing reverse transcription-polymerase chain reaction products derived from central MHC genes in well characterized and conserved ancestral haplotypes. Here we address the IKBL gene, which lies near the TNF cluster at the telomeric end of the central MHC. Although the IKBL cDNA sequence was conserved between most ancestral haplotypes, a synonymous nucleotide substitution, a 3' untranslated region substitution, and a single nonsynonymous substitution were identified. The latter (IKBL+738) was present in multiple examples of the 7.1 haplotype [HLA-A3, B7, DR2 (DR15)] and resulted in a cysteine to arginine substitution in a predicted protein kinase C phosphorylation site. This polymorphism did not occur in 18 other common haplotypes from the 10th International Histocompatibility Workshop and thus appears haplospecific. A role for IKBL+738 in the association between HLA-A3,B7,DR2(DR15) and susceptibility to multiple sclerosis is discussed.