LACK OF ASSOCIATION OF TUMOR NECROSIS
FACTOR-α G–308A AND TRANSFORMING GROWTH
FACTOR-β1 C–509T POLYMORPHISMS IN PATIENTS
WITH DEEP NECK SPACE INFECTIONS
Jevtović-Stoimenov T1, Despotović M1,*, Pešić Z2, Ćosić A2
*Corresponding Author: Milena Despotović, M.D., Department of Biochemistry, Faculty of Medicine, University
of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; Tel.: +381-62-606-036; Fax: +381-18-423-8770;
E-mail: milena.despotovic@ymail.com
page: 59
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DISCUSSION
Deep neck infections are less common in the
antibiotic era but they often have a rapid onset and can
progress to life-threatening complications, especially
in the elderly and patients with systemic diseases
associated with impaired functional immunologic
response. The most common source of inflammation
of deep neck spaces in adults are odontogenic
infections with the involvement of the submandibular
space [12].
The presence of the functional polymorphisms
in cytokine genes affect cytokine expression, and
thus may have an important role in the genetic regulation
of the inflammatory response and resistance
or susceptibility to infections [13]. The gene for
TNF-a is located in chromosome 6 (region p21.3)
within the class III region of the major histocompatibility
complex. The substitution of guanine (G)
with adenine (A) at the -308 site of the TNF-a gene
generates two alleles, TNF -308G and TNF -308A.
The less common TNF -308A allele is considered
to be associated with higher TNF gene transcription
and TNF-a overproduction [9]. A number of studies
indicate that the TNF-a G-308A polymorphism is
associated with the higher susceptibility for a variety
of inflammatory and autoimmune diseases [14-18].
In oral and maxillofacial pathology, the TNF-a G-
308A polymorphism has been studied in patients with
burning mouth syndrome, aph-thous stomatitis and periodontal disease. Some investigators observed a
higher TNF-a production in the carriers of the TNF
-308A allele, while others found no functional significance
of this SNP [19,20].
To the best of our knowledge, there are no reported
studies concerning the association of the TNF-a
G-308A polymorphism with infections of deep neck
spaces. However, our study did not confirm significant
differences in the genotype and allele frequency
distribution of the patient and control groups. Even
though it is well known that TNF-a is a potent chemotactic
factor for WBCs, our study did not show any
association of the TNF-a -308 polymorphism with
WBC count. Moreover, proinflammatory response of
TNF-a results in its increased secretion, and releasing
of the messenger cytokine, interleukin-6 (IL-6),
that stimulates the liver to secrete CRP, which is reliable
marker of the acute phase response to infectious
burdens and/or inflammation [21]. In healthy adults,
the TNF AA genotype is associated with increased
plasma CRP levels in Caucasian and Black men and
in Caucasian women, suggesting that this polymorphism
contributes to variability in plasma CRP levels
[22]. Our results showed a 5- to 60-fold over the
baseline rise of CRP levels in patients with deep neck
space infections, but without significant differences
in CRP values in the presence of the TNF -308A allele.
This can partially be explained by the very low
number of homozygous TNF -308A allele carriers,
reflecting the low frequency of the AA genotype in
this study population. These results are in accordance
with those previously reported in the literature that approximately
60.0-70.0% of the Caucasian populations
are homozygous for the wild type TNF -308G allele,
30.0-40.0% are heterozygous, and only 1.5-3.0% are
homozygous for the variant TNF -308A allele [23].
The TGF-b1 polymorphism provides chemotactic
stimuli for leukocyte migration, but in contrast to
its che-motactic effects, it also shows anti-inflammatory
effects [24,25]. The TGF-b1 gene is located on
chromosome 19 (q13.1-13.3). A C>T SNP at position
-509 relative to the first major transcription start site
was found to be differentially related to transcription
factor binding to the the TGF-b1 promoter, transcriptional
activity of TGF-b1, and TGF-b1 plasma concentration
[11]. This polymorphism was previously
studied in asthma, chronic obstructive pulmonary
disease, hepatocelluar and gastric cancer [26-29]. In
oral pathology, the TGF-b1 C-509T promoter polymorphism
was mostly studied in chronic periodonitis
[30,31]. To the best of our knowledge, this is the first
study to examine the association of the TGF-b1 C-
509T polymorphism with deep neck infections. Our
results suggest that this polymorphism is not associated
with deep neck space infections. Additionally,
no association of the TGF-b1 C-509T polymorphism
with WBC counts and CRP levels was observed in
patients with deep neck space infections.
This study also showed no association of the
TNF-a G-308A and TGF-b1 C-509T polymorphisms
with certain diagnoses such as abscess or phlegmon.
No difference between CRP levels and WBC counts
was obtained after the classification of the samples
by diagnosis.
Since the cytokines act in a highly complex coordinated
network, it would be of great importance
to investigate the common influence of the genetic
polymorphisms that regulate their production. Particularly,
TGF-b1 is known to have a potent immunosuppressive
activity, downregulating the transcription
of other proinflammatory cytokines, including TNF-a
[30]. In order to evaluate the common association
of polymorphic alleles, we have investigated the association
of the combination of high producing TNF
-308A and TGF -509T alleles. However, no statistically
significant differences were observed. Generally,
the discrepancies in observed results, besides
the genetic heterogeneity of the study populations,
might also be explained by population stratification
and population bias.
In conclusion, this is the first study examining
the association of the SNPs of the TNF-a and TGFb1
genes in patients with deep neck infections. The
present study did not confirm the specific role of
the TNF-a G-308A and TGF-b1 C-509T polymorphisms
in patients with the infections of deep neck
spaces. However, further studies are needed to examine
genetic markers that can be used for following
the disease progression and early identification of
individuals at high risk of developing complications.
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