Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced bya second gene telomeric of the TNF cluster

Susceptibility to multiple sclerosis (MS) is clearly associated with human leukocyte antigen (HLA)DRB1*1501, but some studies show associations with H LA-B7 and -B18. These are often co-expressed with DRB1*1501 in the ancestra l haplotypes (AH) denoted 7.1 (HLA-A3, B7, tumor necrosis factor [TNF]a11b4 , DRB1*1501) and 18.1 (HLA-A25, B18, TNFa10b4, DRB1*1501). Here we present a systematic study of 218 patients and 274 controls typed at all standard c lass II and TNF microsatellite loci, and a novel non-synonymous polymorphis m in the central major histocompatibility complex gene, inhibitor of kappa B-like protein (IKBL). The C allele at IKBL+738 is only found on the 7.1 ha plotype. HLA-DRB1*1501 was associated with disease, as expected. When subje cts expressing DRB1*1501 were analyzed separately, TNFa11b4 and IKBL+738C w ere less common in the patients and, hence, mark an allele that mediates re sistance which lies telomeric of IE;DL. TNFa10b4 and TNFa1b5 were more comm on in DRB1*1501 patients than in controls. These alleles have been associat ed with the 18.1 and 18.2 AH, respectively. Since no component of these hap lotypes was an independent risk factor in this study, ir appears likely tha t: a gene linked to TNFa10b4 and TNFa1b5 modifies the effect of the suscept ibility locus marked by HLA-DRB1*1501. Potential candidate genes telomeric of che TNF cluster are discussed. (C) American Society for Histocompatibili ty and Immunogenetics, 1999. Published by Elsevier Science Inc.