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TABLE 3.1
Association between iRF5 Genotypes and Clinical Response outcome measures
Genotype vs
MRI-Based Non-
Responders (One
or more new T2
Lesions)
Genotype vs
Pharmacological
Response
Genotype vs MRI-
Based Les
i
on Load
Genotype vs Time
to First Relapse
rs2004640
TT
rs4728142
AA
rs2004640
TT
rs4728142
AA
rs2004640
TT
rs4728142
AA
rs2004640
TT
rs4728142
AA
P
=
0.0006
a
P
=
0.0023
a
VUmc patients
(
n
= 30)
NA
NA
P
=
0.003
b
P
=
0.013
c
P
= 0.103
b
P
= 0.201
c
P
=
0.010
b
P
= 0.073
c
P
= 0.154
b
P
= 0.440
c
VUmc + CEM-Cat
patients (
n
= 28 + 45)
NA
NA
BWH + VUmc
validation cohort
(24 months follow-up)
NA
NA
NA
NA
NA
NA
P
=
0.037
NS
BWH validation
cohort (long
follow-up)
NA
NA
NA
NA
NA
NA
P
=
0.030
P
= 0.067
a
Student's t test.
b
Kruskal-Wallis.
c
Mann-Whitney.
(Adapted with permission from: Vosslamber S; van der Voort LF; van den Elskamp IJ; Heijmans R; Aubin C; Uitdehaag BM, et al. Interferon
regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferon beta therapy in multiple sclerosis. Genes Immun. 2011;
12: 466-72.)
Abbreviations: BWH, Brigham and Women's Hospital in Boston; CEM-Cat, Centre d'Esclerosi Múltiple de Catalunya in Barcelona; NA, not
applicable; NS, not significant; VUmc, VU University medical center. P-values
<
0.05 are shown in bold.
observation was that non-responders have aggressive Th17 cells reflected by the increase in
IL17F production, and IFN-β was produced to counteract inflammation. Alternatively, endog-
enous IFN-β acts in a pro-inflammatory manner during Th17 cell driven disease. However, the
role of IL17F as predictor of the response to IFN-β could not be confirmed in an independent
cohort
[70]
.
Genetic studies revealed a contribution for variants in the gene encoding Interferon
Regulatory Factor 5 (IRF5), a master regulator of the IFN
/
TLR pathway. IRF5 is a transcrip-
tion factor that functions as a central mediator of Toll-like receptor signaling and is involved
in the production of type I IFN, apoptosis, cell-cycle regulation, cell adhesion and pro-
inflammatory reactions
[71,72]
. Moreover, expression of IRF5 is induced after activation of
the IFN type I receptor, indicative that IRF5 is not only important in the production of type
I IFN, but also in the regulation of IFN type I-induced gene activity
[73]
. Genetic variation
in the IRF5 gene has been found to be strongly associated with SLE, a disease wherein type
I IFNs are clearly associated with disease activity and severity, and IFN response gene activ-
ity
[74-76]
.
Vosslamber and colleagues found that RRMS patients with the IRF5 rs2004640-TT and
rs47281420-AA genotype showed a poor pharmacological response to IFN-β compared with
patients carrying the respective G-alleles (p = 0.0006 and p = 0.0023, respectively) (
Table 3.1
,
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