¹Applied Genomics Research Group, McClay Center for Pharmaceutical Sciences, School of Pharmacy, Queen's University of Belfast, Belfast; Centre of Medical Genetics, Belfast City Hospital, Belfast; Department of Neurology, St Vincent's University Hospital, and University College, Dublin; Neurology Department, Royal Victoria Hospital, Belfast; Department of Epidemiology and Public Health, School of Medicine, Queen's University of Belfast, Belfast; School of Medicine, Queen's University of Belfast, Belfast.

Correspondence: Koen Vandenbroeck, PhD, Chair in Applied Genomics, School of Pharmacy, Queen's University of Belfast, 97 Lisburn Rd, Belfast, BT9 7BL UK. E-mail: k.vandenbroeck@qub.ac.uk

^*This work was supported by grant RRG11.5 from the Northern Ireland Health and Personal Social Services Research and Development (HPSS R&D) Office.

Received 18 May 2005; Accepted 23 August 2005.

Abstract

Objectives: Interferon IFN- 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-: 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-. The identification of 2 genes active in the antigen processing and presentation cascade; that is, LMP7, coding for the proteasome subunit , 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.