Pharmacogenomics of responsiveness to interferon IFN-beta treatment in multiple sclerosis: a genetic screen of 100 type I interferon-inducible genes.
OBJECTIVE
Interferon IFN-beta 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-beta: 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-beta. The identification of 2 genes active in the antigen processing and presentation cascade; that is, LMP7, coding for the proteasome subunit beta, 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.
Cunningham
Stephen
S
Applied Genomics Research Group, McClay Center for Pharmaceutical Sciences, School of Pharmacy, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, N. Ireland, UK.
Graham
Colin
C
Hutchinson
Michael
M
Droogan
Aidan
A
O'Rourke
Killian
K
Patterson
Chris
C
McDonnell
Gavin
G
Hawkins
Stanley
S
Vandenbroeck
Koen
K
D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D009103:Multiple Sclerosis / Q000235:genetics* / Q000517:prevention & control*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
D016899:Interferon-beta