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Pharmacogenomics of responsiveness to interferon IFN‐β treatment in multiple sclerosis: A genetic screen of 100 type I interferon‐inducible genes
Author(s) -
Cunningham Stephen,
Graham Colin,
Hutchinson Michael,
Droogan Aidan,
O'Rourke Killian,
Patterson Chris,
McDonnell Gavin,
Hawkins Stanley,
Vandenbroeck Koen
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.08.018
Subject(s) - interferon , pharmacogenomics , multiple sclerosis , odds ratio , gene , recombinant dna , biology , genotype , promoter , genetics , immunology , medicine , gene expression
Objectives Interferon IFN‐β is indicated for the treatment of multiple sclerosis. A significant proportion of patients show a poor clinical response to therapy. Type I interferon exerts its effect at least partially through interaction of specific transcription factors with interferon‐stimulated response elements (ISREs), mostly located in promoter regions of its target genes. We hypothesized that polymorphisms may occur within or close to ISRE elements, altering type I interferon inducibility and ultimately leading to a modified clinical response in carriers. Methods We selected 100 ISRE‐containing genes and sequenced their promoter regions in small genomic deoxyribonucleic acid pools of responding and nonresponding patients, as well as healthy control subjects. A selection of polymorphisms discovered by this approach was scrutinized subsequently in a collection of individual deoxyribonucleic acid samples. Results We identified 4 genes containing polymorphisms associated with response to recombinant IFN‐β: IFNAR1 ( P = .036), LMP7 ( P = .002; odds ratio [OR], 6.37 [95% confidence interval (CI), 1.84–24.1]), CTSS ( P = .02; OR, 0.38 [95% CI, 0.18–0.84]), and MxA ( P = .015; OR, 3.37 [95% CI, 1.11–11.4]). Logistic regression analysis with treatment outcome used as the dependent variable and genotype as the independent variable revealed 2 genes, LMP7 (OR, 0.55 [95% CI, 0.34–0.89]) and MxA (OR, 0.41 [95% CI, 0.19–0.88]), that were independently associated with treatment response. Conclusions Our work confirms and extends previous indications for a polygenic mechanism involved in bringing about responsiveness to recombinant IFN‐β. The identification of 2 genes active in the antigen processing and presentation cascade; that is, LMP7 , coding for the proteasome subunit β, and CTSS , coding for cathepsin S; as potential response modifiers may identify this pathway as being of particular relevance to phenotypic expression of response heterogeneity. Clinical Pharmacology & Therapeutics (2005) 78 , 635–646; doi: 10.1016/j.clpt.2005.08.018