Genes and Immunity (2002) 3, 211–219  2002 Nature Publishing Group All rights reserved 1466-4879/02 $25.00 www.nature.com/gene Inhibitors in the NFB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations B Miterski 1 , S Bo ¨ hringer 1 , W Klein 1 , E Sindern 2 , M Haupts 3 , S Schimrigk 4 and JT Epplen 1 1 Department of Molecular Human Genetics, Ruhr-University, 44780 Bochum, Germany; 2 Department of Neurology, Kliniken Bergmannsheil, Bochum, Germany; 3 Department of Neurology, Knappschaftskrankenhaus, Bochum, Germany; 4 Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany Multiple sclerosis (MS) is an autoimmune disease displaying different clinical courses. In this multifactorial disease complex environmental as well as genetic predisposition factors contribute to the disease manifestation. Following the candidate gene approach we analysed several genes of the NFB cascade, which are prime candidates for MS because of their involvement in almost all immunological reactions. MS association was excluded for the NFKB1 and NFKB3 genes, which show remarkably low degrees of polymorphism. The genes of NFB inhibitors exhibit more sequence variations. In the IKBL gene a predisposing allele was identified (13.1% vs 7.5% in the control group, P  0.001). This difference in the allelic distribution was even increased in the group of MS patients with a relapsing remitting course of the disease (14.9%, P  0.0001). A protecting allele was found in the NFKBIA promotor for the patients with primary progressive MS (15.4% vs 28.4% in the control group, P  0.01). Given predisposing alleles increase MS risk dramatically in certain combinations. Genes and Immunity (2002) 3, 211–219. doi:10.1038/sj.gene.6363846 Keywords: multiple sclerosis; NFB; candidate genes; complex genetics Introduction Multiple sclerosis (MS) is an autoimmune disease charac- terized by perivascular inflammation and localized mye- lin destruction in the central nervous system. 1 Symptoms are usually perceived in young adulthood, and women outnumber men by nearly 2:1. 2 In 80% of patients the dis- ease manifests itself by relapses followed by remissions (RRMS). After a period of about 10 years, in 50% of cases the course becomes secondarily progressive (SPMS). 10% of MS patients exhibit a primary progressive (PPMS) course of the disease. 3 A plausible hypothesis for disease manifestation concerns the effect of still unknown environmental factors in genetically susceptible individ- uals. Concordance rates of 26% in monozygotic twins compared with 2.3% in dizygotic twins emphasize the relevance of the genetic contribution. 4 The presumed pathophysiology of MS is based on deranged auto- immune responses in genetically susceptible individuals. Putative autoantigens like myelin basic protein or mye- lin-oligodendrocyte protein are presented by MHC class II molecules on antigen presenting cells. T lymphocytes recognize the presented antigen via the T-cell receptor. Correspondence: JT Epplen, Department of Molecular Human Genetics, Ruhr-University Bochum, 44780 Bochum, Germany. E-mail: joerg.t.epplenruhr-uni-bochum.de This work was supported by BMBF (01GG9841), Stefan Bo ¨ hringer is supported by the Vogelsang foundation. Received 16 October 2001; revised 4 December 2001; accepted 12 December 2001 An inflammatory immune response commences, mediated by T and B cells as well as macrophages, and it leads to destruction of myelin sheaths. Different strategies are pursued to elucidate the genetic background of MS. Whole genome scans did not reveal concordant results for candidate regions with the excep- tion of the human leukocyte antigen complex (HLA) region on chromosome 6. HLA class II genes contribute to predisposition, for example the genotype HLA-DRB1* 15 implies a nearly four-fold relative risk (RR) to develop MS. 5 On the other hand, the candidate gene approach comprises the search for mutations, polymorphisms and sequence variations (MPSV) in a large number of genes relevant in the pathogenesis of the disease, eg in the regu- lation of the immune system. Therefore, we searched for MPSV in genes of the nuclear factor kappa B (NFB) cas- cade in order to investigate an association with MS. NFB is an ubiquitous transcription factor of particular impor- tance in inflammatory and immune responses. Activated NFB is a heterodimer composed usually of the p65 and p50 subunits. Other constituents include rel, relB, v-rel or p52. The different forms of NFB activate different target genes. 6 Each member of the subunits exhibits a conserved N-terminal region, the Rel-homology domain (RHD) con- taining the DNA-binding and dimerization domains and the nuclear localization signal (NLS). 7 In unstimulated cells NFB heterodimers are bound to inhibitory proteins (IBs) masking the NLS in order to prevent translocation from the cytoplasm into the nucleus. 6 These IB proteins belong to a functionally related family comprising IB, IB,IB,IB, BCL3, p100, p105, IKBL. 8 A common