Pharmacogenomics of infliximab therapy, impact of TNFRSF1A andTNFRSF1B gene polymorphisms
2013
Introduction. Anti-TNF alpha monoclonal antibodies present an
effective way of treating Crohn's disease ( CD). Despite their
high benefits, there is about 30% rate of a primary
non-response. The main target of infliximab is the soluble form
of TNF alpha, which blocks its pro-inflammatory activity and
the induction of apoptosis via the TNF alpha membrane form. The
activity of TNF alpha and balance between its pro-inflammatory
and pro-apoptotic effect is mediated by the interaction with
its receptors (TNFR). Mechanisms of signaling via TNF
alpha-TNFR interaction has been recently intensively studied
from a perspective of selecting appropriate candidates for the
infliximab treatment. Aim. The aim of this study was to
evaluate whether polymorphisms in TNFRSF1A and TNFRSF1B genes
influence the efficacy of the infliximab therapy. Methods. A
total of 116 Caucasian CD patients treated with infliximab were
genotyped. After initial 10 weeks of the infliximab therapy,
effectiveness was determined and patients were divided into
responders (n=98) and non-responders (n=18). Genotypes TNFRSF1A
(T4672G, G3794C) and TNFRSF1B (T11695C, T587G) were determined
by PCR-RFLP. Results. Frequencies of variant alleles of
TNFRSF1A were comparable between responders and non-responders.
Variant allele TNFRSF1B 11695C was more common in
non-responders (41.7% vs. 30.1%). Similarly, the frequency of
TNFRSF1B 587G allele in non-responders was 33.3% vs. 18.9% in
responders. Homozygotes for variant alleles of TNFRSF1B 11695C
were found more often (P=0.013; OR 5.89, CI 95% 1.6-22.1) in
non-responders (n=5, 27.8%) than in responders (n=6, 6.1%). Our
results imply that TNFRSF1B 11695C variant allele is associated
with a low therapeutic effect of infliximab.
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