ARTICLE
Auteur(s) : Csaba
Hermann1,5, Dóra Krikovszky2, George
Füst3, Margit Kovács3, Anna
Körner4, András Szabó4, Ádám
Vannay2, László Madácsy2
1Department of Anesthesiology and Intensive Therapy,
Semmelweis University, Budapest
2Research Group of Pediatrics and Nephrology, Hungarian
Academy of Science, Budapest
3Third Department of Medicine, Semmelweis University and
Research Group of Metabolism and Atherosclerosis, Hungarian Academy
of Sciences, Budapest
4First Department of Paediatrics, Semmelweis University,
Budapest
5Kiss Áron u. 22/A, H-1125 Budapest, Hungary
Type 1 diabetes mellitus (T1DM) is a multifactorial, autoimmune
disease characterized by the destruction of β-cells, with both
environmental and genetic factors contributing to the development
of the disease. The events that trigger and maintain the local
autoimmune process remain elusive. However, the importance of local
inflammatory processes has been established [1]. Multiple immune
mediators are implicated in the destruction or protection of the
pancreatic β-cells including tumor necrosis factor (TNF)-α,
interleukin (IL)-1β and IL-6.TNF-α and IL-1β are pro-inflammatory
cytokines produced primarily by activated macrophages that
infiltrate the islets during the pathogenesis of diabetes [2, 3]
and play a central role in β-cell destruction [4, 5]. Both TNF-α
and IL-1β stimulate interleukin (IL)-6 expression [6]. In
transgenic, non-diabetes-prone mice, islet overexpression of IL-6
produces a complex, localized host response. IL-6 may contribute
not only to inflammatory processes that occur in autoimmune
diabetes, but also to cellular neogenesis, which may indicate a
role in tissue repair [7].Higher serum levels of TNF-α and IL-6
were found in newly diagnosed T1DM children compared to cases with
longer standing DM and nondiabetic controls [8]. IL-6 was also
shown to be present in the islets of recently diagnosed patients
with T1DM who died shortly after diagnosis of the disease
[9].Cytokines playing a role in local inflammatory processes may
influence the pace of β-cell destruction and this way the onset age
of diabetes. Transgenic expression of IL-6 by β-cells in mice
generated on the NOD (non-obese diabetic) background promoted
insulitis but delayed the onset of diabetes [10].Single nucleotide
polymorphisms (SNPs) of IL-6, TNF-α and IL-1β may influence the
expression of the coded cytokine and in this way these candidate
genes may play a role in the pathomechanism of T1DM. The
interaction of these SNPs can result not only in the development of
T1DM, but in a delayed onset of diabetes as well. In our study, we
aimed to determine the genotype association of IL-6 G(-174)C (IL-6
production: C < G), TNF-α G(-308)A (TNF-α production: G < A)
and IL-1β C(3954)T (IL-1β production: C < T) SNPs and the
clinical characteristics (age-at-onset, insulin dose,
HbA1C level, weight, height, body mass index, serum
total cholesterol, triglyceride and creatinine levels) of T1DM in
children.
Methods
Blood samples were taken from 165 children with T1DM (84 boys and
81 girls), treated in the First Department of Paediatrics,
Semmelweis University, Budapest. Table 1( Table
1 ) shows the clinical characteristics of the population
studied.
Total genomic DNA was extracted from whole blood samples using
the method of Miller et al. [11]. IL-6 G(-174)C, TNFα G(-308)A and
IL-1β C(3954)T SNPs were determined by PCR and RFLP methods as
previously described [12-14]. The study was approved by the
Institutional Ethics Committee (6008/26/ETT/2001), informed consent
was obtained from the subjects and/or from their parents.
Statistical analysis was performed using the SPSS software,
version 11.5 (Chicago, IL, USA). The Kruskal-Wallis test was used
for the comparison of age-at-onset of T1DM between patients with
different cytokine genotypes. Dunn’s multiple comparison test was
used as a post hoc test. Normally distributed variables (insulin
dose, HbA1C level, weight SDS (standard deviation
score), height SDS, BMI (body mass index) SDS, serum total
cholesterol, triglyceride and creatinine levels) of patients with
different genotypes were compared using the T-test for independent
samples.
We divided T1DM patients into two different groups on the basis
of their age at the onset of the disease (< or ≥ 6 years,
because the median age-at-onset was 6 years) and multiple logistic
regression analyses were performed to assess the independent
association of IL-6, with the age-at-onset of T1DM. Gender and
TNF-α and IL-1β genotypes were included in the model. In addition,
by the using the same type of statistical analysis interaction as
used for the IL-6, the other two cytokine polymorphisms were also
determined. The level of statistical significance was set at p <
0.05.
Table 1 Clinical characteristics of the study
population
|
n (boys/girls)
|
165 (84/81)
|
|
Median age–years (25 and 75 percentiles)
|
17 (14 and 19)
|
|
Median age at diagnosis – years (25 and 75 percentiles)
|
6 (min:1, max:15)
|
|
Median duration of diabetes – years (25 and 75 percentiles)
|
9 (min: 3, max:19)
|
|
Insulin dose (U/kg/day)*
|
0.83 ± 0.26
|
|
HbA1c (%)*
|
8.00 ± 1.07
|
|
Weight SDS*
|
0.11 ± 0.86
|
|
Height SDS*
|
0 ± 1.12
|
|
BMI (kg/m2) SDS*
|
0.23 ± 0.97
|
|
Total cholesterol (mmol/l)*
|
4.91 ± 1.31
|
|
Triglycerides (mmol/l)*
|
1.43 ± 1.02
|
|
Creatinine (μmol/l)*
|
83.15 ± 18.07
|
Results
Table 2( Table 2 ) shows TNF-α, IL-1β
and IL-6 genotype distribution in our T1DM population. TNF-α and
IL-6 SNPs fulfilled the Hardy-Weinberg criteria, but the IL-1β
polymorphism differed significantly from these criteria in the T1DM
population studied. Insulin dose, HbA1C level, weight
SDS (standard deviation score), height SDS, BMI (body mass index)
SDS, serum total cholesterol, triglyceride and creatinine level
were associated with none of the polymorphisms studied (data not
shown)
We found a significant difference in the age-at-onset of T1DM in
patients with different IL-6 genotypes (table 2), but the
onset age was not associated with TNF-α and IL-1β genotypes.
Patients were divided into two groups based on their age-at-onset
of diabetes (early onset: < 6 years of age and late onset
disease: > 6 years of age), because the median
age-at-onset was 6 years. It turned out that early onset T1DM
occurred frequently (19/28 (67.8%)) among patients with the IL-6
(-174)CC genotype, whereas only 23/65 (35.4%) of the patients
carrying only the G allele experienced early onset disease
(table 3( Table 3 )). We calculated
the odds ratio for having early onset T1DM for the patients with
the IL-6 (-174)CC genotype as compared to those with the GG or GC
genotype. The unadjusted odds ratio was found to be 2.875
(1.214-6.812), p = 0.016. Next we adjusted this association to the
gender of the patients as well as for TNF-α and IL-1β polymorphisms
using an adjusted multiple regression analysis (table 4( Table 4 )). Patients with the IL-6 (-174) CC
genotype had more than a 3.0-fold (95% CI: 1.26-7.30) increased
risk of developing diabetes before the age of 6 years, whereas no
significant association with gender and the other two cytokine
polymorphisms was found (table 4).
Since at the gender-adjusted, multiple logistic regression
analysis we found a significant interaction for the association
with the onset of disease between the IL-6 -174 SNP and the TNF-α
-308 SNP, and the IL-6 -174 SNP and the IL-1β 3954 SNP (p = 0.021
and p = 0.006, respectively), we also investigated the presence of
the association between IL-6 SNP and the age-at-onset of T1DM in
different subgroups: low ((-308)GG) and high ((-308)A allele
carrier state) TNF-α producer, and low ((3954)CC) and high ((3954)T
allele carrier state) IL-1β producer genotypes (table 5( Table 5 )). We found that the association
between IL-6 polymorphism and the age-at-onset of T1DM could only
be detected in patients with a high IL-1β and high TNF-α producer
genotype. In the IL-1β (3954)T allele carriers and in TNF-α (-308)A
allele carrier patients, the presence of the IL-6 (-174)CC genotype
has a 5.2-fold (95% CI: 1.3-20) and a 3.4-fold (95% CI: 1.09-11.23)
increased risk of developing diabetes before the age of 6 years
than IL-6 (-174)G allele carrier patients, respectively.
Table 2 Genotype distribution of TNF-α, IL-1β and IL-6
polymorphisms and the median (and 25 and 75 percentiles)
age-at-onset of the disease in different genotypes. IL-6 genotype
distribution in early (< 6 years) and later (≥ 6 years) onset
T1DM groups
|
TNFα G(-308)A
|
(-308)GG
|
(-308)GA
|
(-308)AA
|
(-308)A allele
|
p
|
|
T1DM n = 165 (%)
|
89 (54)
|
69 (42)
|
7 (4)
|
0.25
|
|
|
Median age-at-onset of T1DM -
|
6
|
6
|
6
|
|
N.S.
|
|
year (25 and 75 percentiles)
|
(4 and 10)
|
(3 and 9.5)
|
(5 and 11)
|
|
|
|
IL-1β C(3954)T
|
(3954)CC
|
(3954)CT
|
(3954)TT
|
(3954)T allele
|
p
|
|
T1DM n = 165 (%)
|
73 (44)
|
82 (50)
|
10 (6)
|
0.31
|
|
|
Median age-at-onset of T1DM -
|
7
|
5
|
7
|
|
N.S.
|
|
year (25 and 75 percentiles)
|
(3 and 10)
|
(4 and 9.5)
|
(3.7 and 10.2)
|
|
|
|
IL-6 genotype
|
(-174)CC
|
(-174)CG
|
(-174)GG
|
(-174)C allele
|
p
|
|
T1DM n = 165 (%)
|
28 (17)
|
72 (44)
|
65 (39)
|
0.38
|
|
|
Median age-at-onset of T1DM -
|
4.5
|
6
|
8
|
|
< 0.01*
|
|
year (25 and 75 percentiles)
|
(2 and 7)
|
(4 and 10)
|
(4 and 10)
|
|
|
Table 3 Frequency of early* onset (< 6 years
old) and late** onset (> 6 years old) disease among 165
T1DM patients with different IL-6 genotypes
|
IL-6 genotype
|
(-174)CC
|
(-174)CG
|
(-174)GG
|
All patients
|
|
Number (%) of patients
|
|
Early onset disease
|
19 (24.7)
|
35 (45.5)
|
23 (29.9)
|
77 (100.0)
|
|
Late onset disease
|
9 (10.2)
|
37 (42.0)
|
42 (47.7)
|
88 (100.0)
|
|
P value (χ2 test)
|
0.014
|
|
Table 4 Results of the logistic regression analysis of
the association between the IL-6 (-174)CC genotype and the age at
onset of the disease, adjusted for gender, as well as TNF-α and
IL-1β genotype IL-6 polymorphism
|
Carrier state
|
Odds ratio* (95% confidence interval)
|
P value
|
|
Gender girls versus boys
|
1.273 (0.674–2.402)
|
0.456
|
|
IL-1β (3954)TT or TC versus CC genotype
|
1.403 (0.737–2.671)
|
0.303
|
|
TNFα (-308)AA or GA versus GG genotype
|
0.948 (0.497–1.808)
|
0.871
|
|
IL-6 (-174)CC or GC versus GG genotype
|
3.034 (1.262–7.299)
|
0.013
|
Table 5 Association between the IL-6 (-174)CC genotype
carrier state and the age-at-onset of T1DM in different subgroups
of patients as calculated by gender-adjusted multiple regression
analysis. Subgroups were created on the basis of TNF-α and IL-1β
genotypes
|
Subgroups- carriers of the:
|
Odds ratio* (95% confidence interval)
|
P value
|
|
IL-1β (3954)CC genotype
|
1.994 (0.571–6.958)
|
0.279
|
|
IL-1β (3954)TC or TT genotype
|
5.230 (1.351–20.238)
|
0.017
|
|
TNF-α (-308)GG genotype
|
2.437 (0.647–9.186)
|
0.188
|
|
TNF-α (–308)GA or AA genotype
|
3.540 (1.100–13.341)
|
0.034
|
Discussion
In our study, we investigated the association between the
age-at-onset of T1DM and TNF-α G(-308)A, IL-1β C(3954)T and IL-6
G(-174)C polymorphisms in children. Our results indicate that the
IL-6 (-174)CC genotype carrier state is associated with a younger
age-at-onset, whereas the IL-6 (-174)G allele carrier state is
associated with older age-at-onset of T1DM, but only in the
presence of high IL-1β and TNF-α producer genotypes.
IL-6 is known to be involved in both the amplification of and
protection against inflammatory reactions [15, 16]. It is a
pleiotropic cytokine expressed by a wide variety of cells: T and B
cells, macrophages, dendritic cells, smooth muscle cells,
fibroblasts, endothelial and pancreatic β-cells. IL-6 is released
in response to infection, burns, trauma, and neoplasia, and its
functions range from key roles in acute-phase protein induction to
B- and T- cell growth and differentiation. IL-6 can have direct
effects on cells, mediate the effects of other cytokines, be
coagonistic or antagonistic in conjunction with other cytokines,
and interact with glucocorticoids. The main effect of IL-6 depends
on the place where it is produced, on the cell type which produce
it, and also on the receptor which mediates its biological
activities. As far as systemic effects are concerned, IL-6 is the
major initiator of the acute phase response by hepatocytes, and a
primary determinant of hepatic CRP production [17]. It has also
been found to play an important role in atherosclerosis and
myocardial infarction [18].
However, in the development of T1DM, IL-6 supposedly acts
locally and has mostly β-cell-protecting effects [19, 20]. The
higher serum levels of IL-6 found in newly diagnosed T1DM
individuals [21] do not conflict with its protective role in the
pathomechanism of T1DM, because these higher serum IL-6 levels may
be induced by the hyperglycemia [22] that accompanies the
manifestation of T1DM. This hyperglicaemia has nothing to do with
the autoimmune process leading to the β-cell destruction. Higher
IL-6 production may also be induced by both TNF-α or IL-1β [23-25].
Lo et al. [26] found a significantly positive correlation between
TNF-α and IL-6 serum levels in children with T1DM. Higher serum
levels of TNF-α and IL-6 were also found in newly diagnosed T1DM
children compared to cases with longer standing DM and nondiabetic
controls [27]. These higher IL-6 levels were measured at the time
of diagnosis, but there are no data available regarding IL-6 levels
at the time when the autoimmune process had begun. So the higher
serum levels of IL-6 might also be the result of the metabolic
state, and not the main cause of the autoimmune process. In
addition, it is likely enough (however it cannot be measured in
human) that serum levels of IL-6 in type 1 diabetic individuals are
not indicative of the local IL-6 levels found in the islets of
Langerhans.
Regarding the association between the IL-6 G(-174)C polymorphism
and T1DM, conflicting results are available. Recently, a
case-control study of type 1 diabetics in the UK demonstrated a
higher prevalence of the IL-6 (-174)GG genotype in Caucasoid T1DM
patients than in the control population [28]. In contrast,
Kristiansen et al. [29] found in 253 Danish T1DM families that the
IL-6 (-174)C allele was associated with T1DM, but only in females
and they also demonstrated, in accordance with Gillespie et al.
[30], that the IL-6 (-174)CC genotype was associated with younger
age-at-onset of T1DM in females, but not in males. In these studies
[29, 30], the average age-at-onset of diabetes was more than 10
years: the authors attributed this different effect of IL-6 on the
pathomechanism of T1DM in males and females to the stimulated
activity of the IL-6 gene by estrogen. Estrogen plays a central
role in puberty in females, and is switched on from ± 9 years
onwards. As in our study population, the median age at the onset of
diabetes was 6 years, we cannot expect to see the difference caused
by estrogen.
We demonstrated that the IL-6 (-174)G carrier state is
associated with older age-at-onset of T1DM, only in the presence of
high cytokine producer IL-1β ((3954)T carriers) and TNF-α ((-308)A
carriers) genotypes. Both IL-1β and TNF-α are proinflammatory
cytokines, they both play a central role in the pathogenesis of
T1DM, and they stimulate IL-6 expression [31]. In patients with the
IL-6 (-174)G allele, high IL-1β or TNF-α producer genotypes can
enhance IL-6 production, and the IL-6 can exert its
diabetes-protective effect. In accordance with this hypothesis,
previous studies have found that local production of human IL-6
retards the onset of insulin-dependent diabetes mellitus in
non-obese diabetic mice [32], and that IL-6 protects β-cells from
inflammatory cytokine-induced cell death and functional impairment
both in vitro and in vivo [33].
We found no association between TNF-α or IL-1β SNPs and the
age-at-onset of the disease. However, in accordance with previous
studies, the prevalence of the high TNF-α producer and the high
IL-1β producer genotypes were increased in the T1DM population,
compared to the Hungarian healthy reference values [34, 35].
In conclusion, our results indicate that the (-174)G carrier
state of the IL-6 gene is associated with older age-at-onset of
T1DM, in the presence of high cytokine producer IL-1β and TNF-α
genotypes. We suppose that in these cases, higher IL-6 production
associated with the (-174)G allele in Langerhans islets, might have
a protective effect against the autoimmune process and might delay
the destruction of the β-cells.
Acknowledgements
We are grateful for the technical assistance of Mária Bernáth. This
study was supported by OTKA (Hungarian Scientific Research
Foundation) Grant No. T043178.
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