INTERLEUKIN-1β AND TUMOR NECROSIS FACTOR-α GENE POLYMORPHISMS IN SYSTEMIC SCLEROSIS
Hakami M.A1, Alotaibi B.S1, Alkhalil S.S1, Das S2, Nasreen N3, Jeraiby M.A4, Jawed A5, Lohani M5, Dar S.A5*
*Corresponding Author: *Corresponding Author: Sajad Ahmad Dar, Department of Nursing, College of Nursing and Health Sciences, Jazan University, Jazan – 45142, Saudi Arabia; Email: sdar@jazanu.edu.sa
page: 59
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DISCUSSION
Cytokine production and release are key events in SSc
pathogenesis as they are involved in T and B cell activa-tion leading to inflammation, auto-antibodies production,
microvascular damage and fibrosis [21]. The Th1/Th2/
Th17/Treg balance is one of the hallmarks of SSc patho-
genesis, as the Th2 and Th17 cytokines response leads to
tissue fibrosis, whereas Th1 and Th17 cytokines promote
inflammation in SSc patients.
IL-1α and IL-1β are proinflammatory cytokines in-
volved in a number of autoimmune diseases. Patients who
have SSc have increased circulating levels of IL-1α and
IL-1β. Genetic associations with IL-1β have been investi-
gated in patients with SSc and significant associations of
the IL-1β -31 C and IL-1β -511 T alleles have been found
[17]. Our results provide evidence suggesting that the T
alleles of IL-1β -511 and IL-1β +3962 are associated with
SSc in our population. Polymorphism in the human IL-1β
gene has been reported to influence cytokine expression
[22]. IL-1β stimulates the production of prostaglandin E2,
which is an important cofactor for the induction of T-helper
lymphocyte activity towards Th2 direction. A shift towards
the Th2 system has been indicated in SSc [11].
Changes in IL-1β expression levels may reflect the
genetic variation in IL-1β gene. The findings on biological
roles of IL-1β polymorphisms, however, have not been
consistent across studies. TT genotype of IL-1β -511 has
been associated with higher gastric mucosa IL-1β levels in
Helicobacter pylori positive population [23]. On the other
hand, subjects with CC genotype showed an increased
release of IL-1β from mononuclear cells after stimulation
with lipopolysaccharide [24]. Recent studies suggest that
the functional role of IL-1β -511 may depend on IL-1β
promoter region haplotypes including IL-1β -511 [25].
Although the findings are inconsistent, these previous stud-
ies suggest that IL-1β -511 could affect the expression
levels of IL-1β. On the other hand, the influence of IL-1β
+3962 on IL-1β expression levels has not been previously
reported. Polymorphisms in IL-1β, particularly SNPs IL-1β
+3962 and IL-1β -511, have been identified as risk factors
for susceptibility, progression, and severity of periodontal
disease across various populations [26,27]. Elevated IL-
1β levels in gingival crevicular fluid, saliva, and serum of
periodontitis patients further support these associations
[27]. Additionally, existing literature links inflammation
associated with SSc etiology to the development of oral
conditions like periodontitis [28]. Together, these findings
suggest that IL-1β gene polymorphisms may contribute to
the development of SSc in our study population.
A significant association of TNF-α -308 G allele and
TNF-α -238 A allele with SSc was observed in this study.
TNF-α, a member of TNF-superfamily, is a potent pro-
inflammatory cytokine which affects different aspects of
immune response, cell growth, differentiation and activa-
tion [29]. Due to its broad spectrum of pro- inflammatory
functions TNF-α has been implicated in the pathogenesis
of many immune disorders including all connective tissue
diseases [29]. Increased production of TNF-α by PBMCs
as well as elevated serum concentrations of TNF-α have
been demonstrated SSc patients [30]. The enhanced pro-
duction of TNF-α by PBMCs of SSc patients is associ-
ated with increased synthesis of TNF-α mRNA indicating
increased expression of the TNF-α gene in SSc patients
[31]. Moreover, elevated concentrations of TNF-α have
been demonstrated in bronchoalveolar lavage fluid of SSc
patients with interstitial lung disease [32]. Similarly, el-
evated serum TNF-α concentration in SSc patients were
found in SSc patients with pulmonary fibrosis [33]. Re-
cent studies have revealed inconsistent results regarding
correlation of TNF-α polymorphisms with periodontitis
susceptibility [34].
In our study, despite the patients and controls being
of the same ethnic origin and from the same geographic
region, we identified a strong association between the
TNF-α -308 G allele and SSc. The functional significance
and transcriptional impact of this allele remain a topic of
debate, as some studies have found no direct link between
TNF-α -308 polymorphisms and TNF-α production [35].
However, it is possible that an unidentified gene in link-
age disequilibrium with the TNF-α -308 G allele may play
a role in the increased susceptibility to SSc observed in
individuals carrying this allele. In contrast, the TNF-α
-238 A allele and GA genotype have also been previously
associated with SSc [36]. Collectively, these findings sug-
gest that TNF-α gene polymorphisms contribute to the
pathogenesis of SSc in our study population.
The IL-10 gene promoter region contains several
SNPs including –1082 G/A, –819 C/T and –592 C/A in
the transcription factor-binding region. Alleles of all three
polymorphisms are in linkage disequilibrium, giving rise
to only three major allele combinations out of possible
eight in Caucasian populations: the GCC haplotype is
responsible for higher IL-10 secretion, whereas ACC and
ATA haplotypes are associated with its lower production.
Although we observed significant differences in the geno-
types of the three IL-10 SNPs, no significant difference
in haplotype (GCC/ATA/ACC) distribution between SSc
patients and healthy individuals was observed. The G allele
at −1082, and haplotypes containing this allele, have been
associated with high IL-10 production, while the A allele
and the ATA haplotype have been associated with low IL-
10 production [37]. Our study does not show a possible
correlation between IL-10 SNPs and its production in SSc
patients. However, a significant association of IL-10 SNPs
have recently been shown with chronic periodontitis [38].
The importance of TGF-β in SSc pathogenesis has
been demonstrated well. TGF-β, its receptor, and down-stream signaling molecules are expressed at increased
levels in affected organs in SSc. TGF-β activates dermal
fibroblasts leading to increased production of extracellu-
lar matrix. Given the importance of TGF-β in SSc, it has
been hypothesized that polymorphisms in its gene may
contribute to SSc susceptibility. However, there is a pau-
city of studies in this direction and the findings have been
conflicting [39-41]. In this study we found no association
between the SNP in TGF-β1 codon10 and SSc. However,
significant differences were observed in TGF-β1 codon25
genotypes between patients and controls. Given the strong
linkage disequilibrium among the SNPs in this gene, it is
difficult, if not impossible, to assess which, if any, of these
SNPs is truly responsible for the quantitative variation in
TGF-β1 level. Possibly, particular alleles at these loci ad-
ditively (or interactively) influence the quantitative (and
possibly qualitative) expression of this cytokine.
The significant association between IL-1β (-511,
+3962) and TNF-α (-308, -238) SNPs with SSc suggests
a genetic predisposition to the disease, highlighting their
potential as biomarkers for early diagnosis, risk assess-
ment, and targeted therapies. These SNPs may contribute
to SSc pathogenesis by dysregulating key inflammatory
cytokines, promoting fibrosis and vascular damage. Ad-
ditionally, they could help explain disease heterogeneity,
offering insights into the severity of SSc and enabling
better patient stratification. Given their role in other auto-
immune conditions, these findings also provide broader
implications for shared pathogenic mechanisms and thera-
peutic strategies, with the potential for inclusion in genetic
screening panels for at-risk individuals.
Our study is limited by a small sample size and a
restricted number of SNPs, as genetic susceptibility to SSc
likely involves a broader combination of genes, along with
environmental and epigenetic factors. Additionally, we did
not adjust p-values for multiple testing, which complicates
the determination of statistical significance and requires
further investigation. While our findings suggest a po-
tential association between IL-1β and TNF-α SNPs and
SSc, larger studies are needed to confirm these results.
The higher proportion of females in the SSc patient group
compared to the control group reflects the well-known
female predominance in systemic sclerosis [42], which
is more common in women, especially in younger and
middle-aged adults. While this sex distribution aligns with
existing epidemiological data, the small sample size and
sex imbalance may reduce the study’s statistical power
and affect the generalizability of the results. Larger, more
balanced studies are needed to confirm these findings and
explore potential sex-specific genetic associations.
Future research should explore the functional roles of
these SNPs through in vitro expression studies to evalu-
ate their effects on cytokine production and immune cell
activation. Employing genome-editing technologies like
CRISPR-Cas9 could also provide insights into how these
SNPs influence gene expression and cellular responses
in relevant immune cells. Longitudinal cohort studies in
diverse populations would further elucidate how these
variants correlate with disease progression and treatment
outcomes. These approaches would offer valuable insights
into the mechanisms underlying SSc and help identify
potential therapeutic targets, providing clearer directions
for future studies in this field.
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