Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations.
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 NFkappaB 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 NFkappaB 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.
Miterski
B
B
Department of Molecular Human Genetics, Ruhr-University, 44780 Bochum, Germany.
Böhringer
S
S
Klein
W
W
Sindern
E
E
Haupts
M
M
Schimrigk
S
S
Epplen
J T
JT
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000081242:B-Cell Lymphoma 3 Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors
D048868:Adaptor Proteins, Signal Transducing; D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D000949:Histocompatibility Antigens Class II; D016328:NF-kappa B; C120111:NFKBIL1 protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors