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 m ellitus and multiple sclerosis, has been associated with alleles of HLA cla ss II genes and loci in the TNF cluster in the central major histocompatibi lity complex (MHC) region. As recombination within this region is rare, it is difficult to determine which genes are important. This will be facilitat ed by the identification of functional polymorphisms. Hence we are sequenci ng reverse transcription-polymerase chain reaction products derived from ce ntral MHC genes in well characterized and conserved ancestral haplotypes. H ere we address the IKBL gene, which lies near the TNF cluster at the telome ric end of the central MHC. Although the IKBL cDNA sequence was conserved b etween 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 10 th 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.