Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
BACKGROUND
Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy.


METHODS
Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.


RESULTS
Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline.


CONCLUSIONS
These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbeta.
van Baarsen
Lisa G M
LG
Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands.
Vosslamber
Saskia
S
Tijssen
Marianne
M
Baggen
Josefien M C
JM
van der Voort
Laura F
LF
Killestein
Joep
J
van der Pouw Kraan
Tineke C T M
TC
Polman
Chris H
CH
Verweij
Cornelis L
CL
D000328:Adult; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000494:pharmacology*; D007372:Interferons / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics / Q000379:methods*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D016899:Interferon-beta; D007372:Interferons