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Polymorphisms for Interleukin 1ß Exon 5 and Interleukin 1 Receptor Antagonist in Taiwanese Children With Febrile Convulsions
Fuu-Jen Tsai, MD, PhD;
Yao-Yuan Hsieh, MD;
Chi-Chen Chang, MD;
Cheng-Chieh Lin, MD;
Chang-Hai Tsai, MD, PhD
Arch Pediatr Adolesc Med. 2002;156:545-548.
ABSTRACT
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Objective To investigate whether interleukin 1ß (IL-1ß) exon 5 and IL-1
receptor antagonist (IL-1Ra) gene polymorphisms can be used as markers of
susceptibility to febrile convulsions in children.
Methods Children were divided into 2 groups: those with febrile convulsions
(group 1; n = 51) and normal control subjects (group 2; n = 83). Polymorphisms
for IL-1ß exon 5 and IL-1Ra gene polymorphisms were detected by polymerase
chain reaction. Genotypes and allelic frequencies for IL-1ß exon 5 and
IL-1Ra gene polymorphisms in both groups were compared.
Results Genotype and allele frequencies for IL-1ß exon 5 in both groups
were not significantly different. Proportions of E1
homozygotes and E1/E2 heterozygotes for IL-1ß
exon 5 were 50 (98.1%) and 1 (1.9%), respectively, in group 1 and 82 (98.8%)
and 1 (1.2%), respectively, in group 2. Frequencies of alleles E1 and E2 for IL-1ß exon 5 were 101 (99.0%)
and 1 (1.0%), respectively, in group 1 and 165 (99.4%) and 1 (0.6%), respectively,
in group 2. Genotype proportions and allele frequencies for IL-1Ra between
groups were significantly different. Proportions of genotypes I/I and I/II for IL-1Ra were 49 (96.1%) and
2 (3.9%) in group 1 and 69 (83.1%) and 14 (16.9%) in group 2. Frequencies
of alleles I and II for
IL-1Ra were 100 (98.0%) and 2 (2.0%) in group 1 and 152 (91.6%) and 14 (8.4%)
in group 2.
Conclusions The IL-1Ra allele I is associated with a higher susceptibility to febrile
convulsion, which may become a useful marker for predicting the development
of febrile convulsions. The IL-1ß exon 5 gene polymorphisms are not a
useful marker for predicting the susceptibility to febrile convulsions.
INTRODUCTION
FEBRILE CONVULSIONS, the most common form of childhood seizures, occur
in 2% to 5% of children before the age of 5 years.1
Febrile convulsions are marked by high or rapidly rising fever and short duration;
uncomplicated convulsions do not predispose to epilepsy and are not associated
with neurologic abnormalities.2 The pathogenesis
of febrile convulsions remains obscure. Possible causes include viral infection
of the central nervous system and lowered threshold for convulsions in the
presence of fever.3 Recently, febrile convulsions
have been suggested to be a gene-related disease.4
In fact, febrile convulsions of children involve a complex interaction between
the immunoinflammatory process, cytokine activation, and genetic factors.5
Cytokine is a key factor of the host response to infection, and its
effects include induction of fever, leukocytosis, and acute-phase protein
synthesis.6 Cells from children prone to seizures
may produce more proinflammatory cytokines that may induce convulsions or,
alternatively, higher levels of anti-inflammatory cytokines as a defense mechanism
against seizure.7 Proinflammatory cytokines,
including interleukin 1ß (IL-1ß), are known to modulate effects
of neurotoxic neurotransmitters discharged during excitation or inflammation
in the central nervous system.8 Some cytokine
polymorphisms might be related to febrile convulsions, including IL-1 ,
IL-1ß, and IL-1 receptor antagonist (IL-1Ra) gene polymorphisms.8 Interleukin 1 belongs to a cytokine family modulating
cellular proliferation and has the capacity to induce other cytokines. It
is a primary mediator of the inflammatory response and has been shown to induce
prostaglandin synthesis.9
The IL-1 genes are associated with several immunoinflammatory diseases.10 The IL-1ß polymorphisms are associated with
enhanced production of IL-1ß and the increased risk of both hypochlorhydria
induced by Helicobacter pylori and gastric cancer.11 The IL-1ß polymorphisms were related to the
regulation of cytokine and growth factor expression in articular chondrocytes
and the final development of osteoarthritis.12
Allele E2 in IL-1ß exon 5 was related to an
increased risk of erosive arthritis.13 The
action of IL-1 is complex and regulated in part by its naturally occurring
inhibitor, the IL-1Ra.
Genetic studies of multifactorial diseases such as febrile convulsions
are difficult to approach because of the uncertainty of polygenic traits.
In our laboratory, we have observed that the IL-1ß-511*T allele could be used as a genetic marker of susceptibility to Kawasaki
disease (Yi-Ru Shi, MS, F.-J.T., and C.-H.T., unpublished data, 2001). In
contrast, we noted that the IL-1ß (IL-1ß-511 promotor, IL-1ß
exon 5) and IL-1Ra were not useful markers to predict susceptibility to endometriosis
and rheumatoid arthritis.14 We also noted that
the IL-1ß-511 promotor polymorphism is not a useful marker for prediction
of the susceptibility to febrile convulsions and epilepsy (F.-J.T., Y.-Y.H.,
C.-C.C., and C.-H.T., unpublished data, 2001). On the basis of these experiences,
we further tried to evaluate whether these polymorphisms are useful markers
for predicting susceptibility to febrile convulsions in children.
SUBJECTS AND METHODS
The study included Taiwanese children with febrile convulsions (group
1; n = 51) and normal control subjects (group 2; n = 83). This study was approved
by the Ethical Committee of the China Medical College Hospital, Taichung,
Taiwan. Informed consent was signed by all parents of the patients who donated
their blood. There were nonsignificant differences between the groups in age,
weight, and height. The diagnosis of febrile convulsions was made after the
exclusion of other causative agents, including bacterial or viral infection.
All children underwent peripheral blood sampling for genotype analyses.
Genomic DNA was isolated from peripheral blood by means of a DNA extractor
kit (Genomaker DNA extraction kit; Blossom, Taiwan). A total of 50 ng of genomic
DNA was mixed with 20 pmol of each polymerase chain reaction (PCR) primer
in a total volume of 25 µL containing 10mM Tris hydrochloride, pH 8.3;
50mM potassium chloride; 2.0mM magnesium chloride; 0.2mM each deoxyribonucleotide
triphosphate; and 1 U of DNA polymerase (Amplitaq; Perkin-Elmer, Foster City,
Calif). Four PCR primers were used to amplify the correlated gene. The sequences
of these primers were as following (from 5' to 3' end): IL-1ß
exon 5: upstream, GTTGTCATCAGACTTTGACC; downstream, TTCAGTTCATATGGACCAGA;
and IL-1Ra: upstream, CTCAGCAACACTCCTAT; downstream, TCCTGGTCTGCAGGTAA. The
PCR conditions were as follows: 35 cycles at 94°C for 1 minute, 60°C
for 1 minute, and 72°C for 2 minutes, then stand at 72° for 30 minutes
and hold at 4°. Biallelic base polymorphisms in exon 5 at position +3953
(IL-1ß+3953) for IL-1ß gene were detected. The IL-1ß+3953 exon
5 polymorphism was analyzed by PCR amplification followed by Taq I restriction analysis.15 The PCR
products were directly analyzed for IL-1Ra by electrophoresis on agarose gel,
and each allele was recognized according to its size. Allelic frequencies
are expressed as a percentage of the total number of alleles. Genotypes and
allelic frequencies for IL-1ß and IL-1Ra polymorphisms in both groups
were compared.
The SAS system with  2 and Fisher exact test were used
for statistical analyses. P<.05 was considered
statistically significant.
RESULTS
Genotype proportions and allele frequencies for IL-1ß exon 5 in
both groups were not significantly different (Table 1). The most common genotype for IL-1 gene in both groups
was E1 homozygote. Proportions of E1 homozygote and E1/E2 heterozygote for IL-1ß
exon 5 were as follows: group 1, 98.0% and 1.9%, respectively; group 2, 98.8%
and 1.2%, respectively. There were no E2 homozygotes.
Allele E1 and E2 frequencies
for IL-1ß exon 5 were as follows: group 1, 99.0% and 1.0%, respectively;
group 2, 99.4% and 0.6%, respectively (Table 1).
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Table 1. Genotypes and Allele Frequency of IL-1ß Exon 5 in Children
With Febrile Convulsions and Normal Control Subjects*
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In contrast, the genotype proportions and allele frequencies for IL-1Ra
between the groups were significantly different. The most common genotype
for IL-1 gene in both groups was I/I. Proportions
of I/I and I/II for IL-1Ra
were as follows: group 1, 96.1% and 3.9%, respectively; group 2, 83.1% and
16.9%, respectively (Table 2).
Allele I for IL-1Ra was associated with febrile convulsions.
Allele I/II for IL-1Ra was found in the following
proportions: group 1, 98.0% and 2.0%, respectively; group 2, 91.6% and 8.4%,
respectively (Table 2).
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Table 2. Genotypes and Allele Frequency of IL-1 Receptor Antagonist
in Children With Febrile Convulsions and Normal Control Subjects*
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COMMENT
Cytokines are proteins that play a role in the communication link between
the immunologic system and brain tissue. Cytokines are related to leukocyte
function and migration, angiogenesis, hematopoiesis, antitumoral effects,
and atherosclerosis.16 They are produced by
peripheral monocytes and also by astrocytes and glial cells within the central
nervous system.17 Cytokines from peripheral-blood
mononuclear cells may cross the blood-brain barrier and may thus be involved
in the pathogenesis of fever.18
The IL-1 response from sensitized mononuclear cells may have a role
in the development of febrile convulsions.3
During the acute phase of febrile convulsions, patients have significantly
increased plasma IL-1ß levels, which may be responsible for the pathogenesis
of febrile convulsions.18 Differences in the
distribution of the biallelic polymorphism in the promotor region of the IL-1ß
gene were found among patients exhibiting temporal lobe epilepsy.8 Interleukin 1 also regulates the development of glial
scars at sites of central nervous system injury.8
In contrast, Ichiyama et al19 found no correlation
between the cytokines tumor necrosis factor , IL-1ß, and IL-6
in the cerebrospinal fluid and the presence of febrile seizures.
Genetic factors play a major role in the etiology of febrile convulsions.
Cytokine genes may be related to cytokine expression and regulation of the
immune-mediated pathogenetic process. Cytokine gene polymorphisms have recently
attracted considerable interest because distinct alleles of cytokine genes
have been discovered to be associated with different immunoinflammatory diseases.7 Single nucleotide polymorphisms are the most abundant
types of DNA sequence variation in the human genome.20
Single nucleotide polymorphism markers provide a new way to identify complex
gene-associated diseases such as febrile convulsions in children.
Interleukin 1 exists in 2 forms, IL-1 and IL-1ß, which are
encoded by distinct genes but share the same receptors and biological properties.21 The loci for IL-1 and IL-1ß are located
on the proximal region of the long arm of chromosome 2.22
The IL-1ß polymorphism has been correlated with IL-1ß expression.23 These results indicate that the genotype of the IL-1ß
polymorphisms may affect IL-1ß production in an intricate and complicated
manner. Different polymorphisms have been described in the IL-1ß gene,
and at least 2 of them could influence protein production: one located in
the promotor region at position -511 (IL-1ß-511)12
and the other in exon 5.15 In our previous
research, we noted the lack of association between febrile convulsions and
IL-1ß-511 promotor polymorphism (F.-J.T., Y.-Y.H., C.-C.C., and C.-H.T.,
unpublished data, 2001). These genes code several proteins that may be key
components in the pathogenesis of febrile convulsions.
The IL-1 or IL-1Ra polymorphisms have been found to be related to susceptibility
or disease activities for individual diseases, including Alzheimer disease,24 Parkinson disease,25
temporal lobe epilepsy,8 schizophrenia,26 erosive arthritis,13
polymyositis and dermatomyositis,27 multiple
sclerosis,28 lymphocytic leukemia,29 atherosclerosis,30
coronary artery disease,31 alcoholic liver
disease,32 idiopathic pancreatitis,33 inflammatory bowel disease,34
and IgA nephropathy.35 The regulation of IL-1ß
and IL-1Ra may be coordinated during inflammation.36
The level of IL-1ß messenger RNA showed a positive correlation with that
of IL-1ß and a negative correlation with the level of IL-1Ra messenger
RNA.37
In contrast, some investigators have found no correlation between genetic
polymorphisms of IL-1ß and susceptibility to rheumatoid arthritis,13 chronic obstructive pulmonary disease,38
multiple myeloma,39 diabetes mellitus,40 postmenopausal osteoporosis,41
and ischemic heart disease.42 Furthermore,
IL-1 genes may have a role in the severity of the disease rather than in susceptibility
to the disease itself.10 In our previous study,
we also observed an association between disease activity of rheumatoid arthritis
and a polymorphic IL-1ß–511*C gene sequence
(Chun-Ming Huang, MD, F.-J.T., and C.-H.T., unpublished data, 2001).
The IL-1Ra is structurally related to IL-1 and IL-1ß and
competes with these molecules for occupation of IL-1 cell surface receptors.
The presence of the IL-1Ra allele II was associated
with enhanced IL-1ß production in vitro.43
The IL-1Ra allele II is associated with a variety
of epithelial-related chronic inflammatory diseases including systemic lupus
erythematosus,44 psoriasis,45
alopecia areata,46 lichen sclerosus,47 and ulcerative colitis.48
In this study, we observed that the IL-1Ra allele I
is associated with higher susceptibility to febrile convulsions. The results
further suggest that the IL-1Ra allele II as well
as the increased production of IL-1ß might play a role in preventing
febrile convulsions. Genotype distributions and allelic frequencies for IL-1Ra
gene polymorphism may be the candidate genetic markers in the susceptibility
to febrile convulsion. In contrast, the IL-1ß exon 5 gene polymorphism
is not useful in predicting the susceptibility to febrile convulsion. This
discrepancy may be due to different illness classifications and racial and
disease variation.
In conclusion, IL-1Ra is a useful marker for predicting susceptibility
to febrile convulsions. In contrast, febrile convulsions are not associated
with IL-1ß exon 5 gene polymorphisms. This could provide the database
for further survey of the IL-1 and IL-1Ra polymorphisms. However, the real
roles of the IL-1 polymorphisms in febrile convulsions remain to be clarified.
Furthermore, the impact of other cytokine polymorphisms on development of
febrile convulsions merits further study.
| What This Study Adds
Interleukin 1ß exon 5 and IL-1Ra may be related to the pathogenesis
of febrile convulsions. This study examines the potential usefulness of these
markers in predicting susceptibility to febrile convulsions in children. We
found that interleukin 1 receptor antagonist is a useful marker for predicting
susceptibility to febrile convulsions.
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AUTHOR INFORMATION
Accepted for publication February 7, 2002.
Corresponding author and reprints: Fuu-Jen Tsai, MD, PhD, Department
of Pediatrics and Medical Genetics, China Medical College Hospital, No. 2
Yuh-Der Rd, Taichung, Taiwan (e-mail: d0704{at}hpd.cmch.org.tw).
From the Departments of Pediatrics and Medical Genetics (Drs F.-J.
Tsai and C.-H. Tsai), Obstetrics and Gynecology (Drs Hsieh and Chang), and
Family Medicine (Dr Lin), China Medical College Hospital, Taichung, Taiwan.
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