The role of genetic determinant in the development of severe perinatal asphyxia
The frequency of GSTT1 and GSTM1 gene deletion polymorphism was determined in a case-control study of full-term Ukrainian newborns including patients with perinatal asphyxia. Multiplex polymerase chain reaction was used for genotyping 245 full-term newborns. The investigated full-term newborns with...
Gespeichert in:
| Datum: | 2010 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | English |
| Veröffentlicht: |
Інститут клітинної біології та генетичної інженерії НАН України
2010
|
| Schriftenreihe: | Цитология и генетика |
| Schlagworte: | |
| Online Zugang: | http://dspace.nbuv.gov.ua/handle/123456789/66794 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Zitieren: | The role of genetic determinant in the development of severe perinatal asphyxia / N.G. Gorovenko, Z.I. Rossokha, S.V. Podolskaya, V.I. Pokhylko, G.A. Lundberg // Цитология и генетика. — 2010. — Т. 44, № 5. — С. 41-46. — Бібліогр.: 36 назв. — англ. |
Institution
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
irk-123456789-66794 |
|---|---|
| record_format |
dspace |
| spelling |
irk-123456789-667942014-07-23T03:01:27Z The role of genetic determinant in the development of severe perinatal asphyxia Gorovenko, N.G. Rossokha, Z.I. Podolskaya, S.V. Pokhylko, V.I. Lundberg, G.A. Оригинальные работы The frequency of GSTT1 and GSTM1 gene deletion polymorphism was determined in a case-control study of full-term Ukrainian newborns including patients with perinatal asphyxia. Multiplex polymerase chain reaction was used for genotyping 245 full-term newborns. The investigated full-term newborns with perinatal asphyxia were subdivided in the subgroups depending of severity of perinatal asphyxia and neonatal outcome. No significant differences in allele frequencies of homozygous null genotypes of GSTT1 and GSTM1 gene were detected among newborns with moderate perinatal asphyxia and healthy control. However, association with the development of severe perinatal asphyxia was detected for the deletion polymorphism in GSTT1 gene and the combination of the GSTT1 absent/GSTM1 absent in the newborns. The study shows that severe perinatal asphyxia may develop in the consequence of genetic predisposition to this condition as compare with moderate. Представлены результаты определения частоты делеционного полиморфизма генов GSTT1 и GSTM1 у доношенных новорожденных в Украине. В исследовании, организованном по принципу случай–контроль, были обследованы новорожденные с перинатальной асфиксией и клинически здоровые новорожденные. Для генотипирования 245 доношенных новорожденных проведена мультиплексная полимеразная цепная реакция. Обследованные новорожденные с перинатальной асфиксией были поделены на две группы в зависимости от степени тяжести перинатальной асфиксии и течения неонатального периода. При сравнении частот делеционного полиморфизма исследованных генов у новорожденных с умеренной асфиксией и клинически здоровых новорожденных не было зарегистрировано достоверных различий. Выявлена ассоциация делеционного полиморфизма гена GSTT1 и комбинации делеционного полиморфизма обоих исследованных генов с развитием тяжелой перинатальной асфиксии у новорожденных. При проведении исследования установлено, что тяжелая перинатальная асфиксия у новорожденных в отличие от умеренной может быть следствием генетической склонности к развитию этого состояния. 2010 Article The role of genetic determinant in the development of severe perinatal asphyxia / N.G. Gorovenko, Z.I. Rossokha, S.V. Podolskaya, V.I. Pokhylko, G.A. Lundberg // Цитология и генетика. — 2010. — Т. 44, № 5. — С. 41-46. — Бібліогр.: 36 назв. — англ. 0564-3783 http://dspace.nbuv.gov.ua/handle/123456789/66794 575.191–02:616–001.8–053.31–06 en Цитология и генетика Інститут клітинної біології та генетичної інженерії НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Оригинальные работы Оригинальные работы |
| spellingShingle |
Оригинальные работы Оригинальные работы Gorovenko, N.G. Rossokha, Z.I. Podolskaya, S.V. Pokhylko, V.I. Lundberg, G.A. The role of genetic determinant in the development of severe perinatal asphyxia Цитология и генетика |
| description |
The frequency of GSTT1 and GSTM1 gene deletion polymorphism was determined in a case-control study of full-term Ukrainian newborns including patients with perinatal asphyxia. Multiplex polymerase chain reaction was used for genotyping 245 full-term newborns. The investigated full-term newborns with perinatal asphyxia were subdivided in the subgroups depending of severity of perinatal asphyxia and neonatal outcome. No significant differences in allele frequencies of homozygous null genotypes of GSTT1 and GSTM1 gene were detected among newborns with moderate perinatal asphyxia and healthy control. However, association with the development of severe perinatal asphyxia was detected for the deletion polymorphism in GSTT1 gene and the combination of the GSTT1 absent/GSTM1 absent in the newborns. The study shows that severe perinatal asphyxia may develop in the consequence of genetic predisposition to this condition as compare with moderate. |
| format |
Article |
| author |
Gorovenko, N.G. Rossokha, Z.I. Podolskaya, S.V. Pokhylko, V.I. Lundberg, G.A. |
| author_facet |
Gorovenko, N.G. Rossokha, Z.I. Podolskaya, S.V. Pokhylko, V.I. Lundberg, G.A. |
| author_sort |
Gorovenko, N.G. |
| title |
The role of genetic determinant in the development of severe perinatal asphyxia |
| title_short |
The role of genetic determinant in the development of severe perinatal asphyxia |
| title_full |
The role of genetic determinant in the development of severe perinatal asphyxia |
| title_fullStr |
The role of genetic determinant in the development of severe perinatal asphyxia |
| title_full_unstemmed |
The role of genetic determinant in the development of severe perinatal asphyxia |
| title_sort |
role of genetic determinant in the development of severe perinatal asphyxia |
| publisher |
Інститут клітинної біології та генетичної інженерії НАН України |
| publishDate |
2010 |
| topic_facet |
Оригинальные работы |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/66794 |
| citation_txt |
The role of genetic determinant in the development of severe perinatal asphyxia / N.G. Gorovenko, Z.I. Rossokha, S.V. Podolskaya, V.I. Pokhylko, G.A. Lundberg // Цитология и генетика. — 2010. — Т. 44, № 5. — С. 41-46. — Бібліогр.: 36 назв. — англ. |
| series |
Цитология и генетика |
| work_keys_str_mv |
AT gorovenkong theroleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT rossokhazi theroleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT podolskayasv theroleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT pokhylkovi theroleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT lundbergga theroleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT gorovenkong roleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT rossokhazi roleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT podolskayasv roleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT pokhylkovi roleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia AT lundbergga roleofgeneticdeterminantinthedevelopmentofsevereperinatalasphyxia |
| first_indexed |
2025-07-05T16:58:34Z |
| last_indexed |
2025-07-05T16:58:34Z |
| _version_ |
1836826980030349312 |
| fulltext |
УДК 575.191–02:616–001.8–053.31–06
N.G. GOROVENKO 1, Z.I. ROSSOKHA 2,
S.V. PODOLSKAYA 1, V.I. POKHYLKO 3, G.A. LUNDBERG 4
1 Department of Medical Genetics, National Medical Academy
for Post�graduate Education named after P.L. Shupyk, Kyiv
2 Reference�centre for molecular diagnostic, Ministry of Public Health
of Ukraine, Kyiv
3 Department of Paediatrics, Ukrainian Stomatology Academy, Poltava
4 Division of Clinical Medicine, School of Health and Medical Sciences,
Örebro University, Sweden
E�mail: medgen2006@mail.ru
THE ROLE OF GENETIC DETERMINANT
IN THE DEVELOPMENT OF SEVERE
PERINATAL ASPHYXIA
The frequency of GSTT1 and GSTM1 gene deletion poly�
morphism was determined in a case�control study of full�term
Ukrainian newborns including patients with perinatal asphy�
xia. Multiplex polymerase chain reaction was used for geno�
typing 245 full�term newborns. The investigated full�term
newborns with perinatal asphyxia were subdivided in the sub�
groups depending of severity of perinatal asphyxia and neona�
tal outcome. No significant differences in allele frequencies of
homozygous null genotypes of GSTT1 and GSTM1 gene were
detected among newborns with moderate perinatal asphyxia
and healthy control. However, association with the develop�
ment of severe perinatal asphyxia was detected for the deletion
polymorphism in GSTT1 gene and the combination of the
GSTT1 absent/GSTM1 absent in the newborns. The study
shows that severe perinatal asphyxia may develop in the con�
sequence of genetic predisposition to this condition as compare
with moderate.
Introduction. Perinatal asphyxia (PA) is often
associated with adverse neurological outcomes
including the development of multiorgan injuries
and may result in neurological injury with long�
term disabilities, later disorder with behavioral
consequences (cerebral palsy, mental retardation,
hearing or visual impairment, and attention deficit
hyperactivity disorder) [1–4]. Brain injury in the
neonates remains a significant social and health
problem, especially with the existence of an unfa�
vorable neurological prognosis [5]. PA occurs
approximately in 4 of 1000 term births and more
frequently among preterm delivery neonates. The
neonatal mortalities are higher for the neonates
with PA, 23 % of neonatal mortalities world wide
is connected with the condition in the neonates.
PA is causing more then 8.5 % child deaths [2, 5].
PA is a heterogeneous group with different burden
of clinical symptoms with expected adverse out�
come [3, 6–8].
A number of studies focused on the pathologi�
cal changes in the newborns with asphyxia, a few
have been concerned with genetic differences
which predispose to this disorder development
[9–12]. One of the pathogenic changes demon�
strated in asphyxia development is decompensate
oxidative stress which causes the metabolic reac�
tions that lead to primary and secondary dysfunc�
tion of many organs and systems. This may explain
the polyorganic effects of decompensate oxidative
stress in patients with asphyxia [2, 4].
Сells produce free radicals and reactive oxygen
species (ROS) as one part of physiological metabo�
lic processes. Biological systems at cellular level
interact with external environmental factors, which
determine the increase of ROS level. Antioxidant
enzymes (AOEs) may protect the cells from ROS�
mediated injury. However in addition, oxidative
stress is physiological protection against unfavor�
able exogenous and endogenous factors [12–14].
Glutathione transferases (GSTs, EC2.5.1.18) are
part of an important enzymatic system of the cellu�
lar mechanism of detoxification that protects cells
against reactive oxygen metabolites due to the con�
jugation of glutathione with electrophilic com�
pounds. Recent results show that different metabo�
lites of endogenous molecules may also be substrates
for GSTs [13–18].
GSTs are a superfamily of enzymes consisting in
humans of α, β, π, μ and θ families with sequence
similarity and shared properties for reaction of
gluthatione with reactive substrates. These GSTs
ІSSN 0564–3783. Цитология и генетика. 2010. № 5 41
© N.G. GOROVENKO, Z.I. ROSSOKHA, S.V. PODOLSKAYA,
V.I. POKHYLKO, G.A. LUNDBERG, 2010
are mainly found in the cytoplasm of the cell and
catalytically active as dimeric proteins. They occur
in most instances in multiple forms [15–17].
The homozygous presence (presence in both alle�
les) of deletion polymorphism in GSTT1 gene and
GSTM1 gene is defined as null genotype for these
genes, with lack of enzyme activities [15, 16].
Many studies found that genetic variation in GSTs
may predispose to the development of diseases in
consequence of oxidative stress damage. The asso�
ciation of the GSTT1 deletion and GSTM1 dele�
tion gene polymorphisms has been reported in
numerous investigations with higher risk of diseases
development or higher individual susceptibility to
diseases [16–19].
Embryonic and fetal development is shown to
be dependent of genetic determined variability in
GSTs and other AOEs including mother tissues,
placenta and embryos or fetuses tissues. The risk of
intrauterine damage in embryos and fetus during
early ontogenesis is higher for individuals with
genetically determined lack of enzyme or lower
level of their activity. Genetic variants of GSTT1 and
GSTM1 have been shown a role in the abnormal
development of fetuses, neonates and children, espe�
cially with influence of unfavorable factors [20–27].
The intrauterine condition of intracellular fetal
AOEs may influence the perinatal capacity of the
antioxidant defense in the neonates and predispose
to the development of perinatal pathologies and
pathological states such as PA.
The newborns with severe PA need special
treatment immediately after labour though they do
not show any distinct symptoms of severe damage
of the brain and other organs [28]. No significant
prognostic biochemical or genetic markers of brain
injury exist today for the newborns in the perinatal
period [29, 30]. Therefore, it is necessary to inves�
tigate the genetic differences in the development
risk of PA.
Thus, the purpose of this study was to evaluate
the influence of GSTT1 and GSTM1 genes dele�
tion polymorphism on the development risk of PA
with neurological complications in full�term new�
borns.
Materials and methods. Study population. In the
case�control study 135 full�term newborns with
PA and 110 clinical healthy full�term newborns
were involved. The newborns with PA were subdi�
vided into two groups depending of the value accord�
ing to Apgar scale and neurological disorders dur�
ing the first several days after birth: newborns with
severe PA (n = 50), newborns with moderate PA (n =
= 85). 110 clinically healthy full�term newborns
formed a control group. The 135 full�term new�
borns with moderate and severe asphyxia were
treated in the division of intense therapy in the
maternity hospitals in 2006–2007 years.
The diagnosis was performed according to
World Human Organization (WHO) recommen�
dation ICD�10 (http://www.who.int/classifica�
tions/apps/icd/icd10online/), version 2007. The
inclusion criteria were clinical symptoms of PA
and gestational age of 38–40 weeks. The exclusion
criteria were congenital defects, intrauterine infec�
tion, gestational age less then 38 weeks, weight less
then 2500 g. The newborns of the three groups
were not significantly different regarding anthro�
pometric indexes and gestational age. Standard
general and laboratory methods of investigation
were performed in the newborns. The study was
according to the declaration of Helsinki and was
approved by the local Medical Ethical Committee
of National Medical Academy of Postgraduate
Education named after P.L. Shupyk.
Genetic analyses. Peripheral blood samples of
2.7 ml were obtained in Monovettes containing
EDTA («Sarstedt», Germany). Genomic DNA
was isolated from the blood samples using DNK
sorb B kit («AmpliSens», Russia). The GSTT1 and
GSTM1 gene polymorphism was determined in the
investigated newborns using primers previously
described by Arand et al. [31].
The multiplex PCR was performed in a total
volume of 25 μl containing 150 ng of human DNA,
5 μL 5 � PCR buffer, 1.5 mM MgSO4, 200 μM of
each dNTP, 20 pM of each primer and 1 unit of
Taq DNA polymerase («AmpliSense», Russia). The
PCR protocol was performed as described earlier
through the initial denaturation at 94 °С for 2 min,
followed by 35 cycles of 1 min at 94 °С, 1 min at
64 °С, 1 min at 72 °С, with an ensuing 5�min exten�
sion at 72 °С in a thermocycler Applied Biosystems
2700 («Perkin Elmer», USA). Fragments were
separated by electrophoresis in a 1.5 % agarose gel.
The results of electrophoresis were subsequently
visualized by UV detection. A characteristic multi�
plex PCR for the presence or absence of GSTT1 and
GSTM1 genes in examined newborn patients with
PA and healthy newborns are presented in Figure.
ISSN 0564–3783. Цитология и генетика. 2010. № 542
N.G. Gorovenko, Z.I. Rossokha, S.V. Podolskaya, V.I. Pokhylko, G.A. Lundberg
This method do not discriminate heterozygous
null individuals (+/–) from homozygous individu�
als with wild type alleles of GSTT1 (+/+) or
GSTM1 (+/+). The addition of the internal albu�
min amplification control allowed the unequivocal
discrimination between samples from double null
individuals (–/–) and samples that failed to
amplify because of a low amount of starting DNA
or the presence of interfering impurities.
Statistical analyses. The genotyping results and
the data obtained from collected maternal ques�
tionnaires, past and neonatal case histories were
analyzed using following statistical methods. Diffe�
rences in comparative groups were assessed by
Yates corrected χ2 and Fisher analyses (the Yates
corrected Сhi�square test and Fisher�test in elec�
tron version Microsoft Excel Table). P < 0.05 was
considered to be statistically significant.
Results. We observed no differences in anthro�
pometric indexes and gestational age for the new�
borns of the three groups, see Table 1.
Perinatal and maternal risk factors for the PA
development were analysed in all investigated groups.
This analyzes included mother’s diseases, complicat�
ed obstetric and gynecological past histories, course
of current and preceding pregnancies, labor (results
not shown). No significant difference were found
among newborns with PA and healthy controls in
the maternal and perinatal risk factors frequencies.
The frequency of GSTT1 null genotype was sig�
nificantly increased in newborns with severe PA as
compared with healthy controls (χ2 = 23,72, р =
= 0,0001) and newborns with moderate PA (χ2 =
= 8,68, р = 0,003), see Table 2. No significant dif�
ferences were detected in the frequency of
GSTT1 null genotype between newborns with
moderate PA and healthy newborns (χ2 = 3,28, р =
= 0,07). No significant difference was detected in
the frequencies of GSTM1 null genotype between
the newborns of all investigated groups.
No significant differences were detected in the
frequency of certain variant combinations for two
genes in the newborns of the analyzed groups
except GSTT1 absent/GSTM1 absent combina�
tion. We observed significant increase of the fre�
quences in combination of the GSTT1 absent/
GSTM1 absent (р < 0,001) in the newborns with
severe PA compared to healthy controls. The
results of distribution in combined GSTT1 and
GSTM1 polymorphic variants among newborns
with severe or moderate PA, respectively, and
healthy controls are shown in Table 3.
Discussion and conclusions. The frequency of
polymorphic variants of many genes shows diversities
ІSSN 0564–3783. Цитология и генетика. 2010. № 5 43
The role of genetic determinant in the development of severe perinatal asphyxia
The analysis of multiplex PCR products by electrophoresis
on an 1.5 % agarose gel. GSTT1 480 bp, GSTM1 215 bp and
internal albumin control 350 bp. Samples: 1, 3, 10, 11 –
GSTT1present/GSTM1absent; 2, 9 – GSTT1absent/
GSTM1absent; 4–8,12–14 – GSTT1present/GSTM1pre�
sent; 15 – DNA Ladder
Table 1
Basic characteristics of the study population of newborns
with perinatal asphyxia (PA) compared to healthy controls
Parameter
Severe PA
(n = 50)
Moderate PA
(n = 85)
Healthy
controls
(n = 110)
Sex, male/fe�
male
Gestational
age ± SE
Length, cm ±
± SE
Weight, g ± SE
26/24
38.1 ± 0.5
50.1 ± 0.42
3312.2 ± 0.52
44/41
38.2 ± 0.4
50.2 ± 0.43
3215.3 ± 0.53
57/53
38.6 ± 0.6
50.3 ± 0.43
3270.4 ± 0.55
Genotype
Severe PA
(n = 50)
Moderate PA
(n = 85)
Healthy
controls
(n = 110)
GSTT1
absent*
present**
GSTM1
absent*
present**
27 (54)
23 (46)
27 (54)
23 (46)
23 (27)
62 (73)
38 (45)
47 (55)
17 (15)
93 (85)
51 (46)
59 (54)
Table 2
The distribution of polymorphic variants in GSTT1
and GSTM1 genes in the newborns, n (%)
* –/– genotype (deletion polymorphism); ** +/+ and
+/–genotypes.
in population and ethnicity with inter� and intraeth�
nicity variability. The frequency of GSTT1 null geno�
type was reported for the Caucasians with a small
degree of no significant differences between 13–26 %
(for example, Sweden – 13 %, Germany – 19 %).
The same was found for the frequency of GSTM1 null
genotype among the Caucasians with differences bet�
ween 42–60 %, Sweden – 55 %, Germany – 51 %
[32]. Our results in healthy controls had no signifi�
cant differences in comparison with the other popu�
lation in the Caucasians: GSTT1 null genotype –
15 %, GSTM1 null genotype – 46 %.
This study shows that an important factor for
developing severe PA is the presence of GSTT1 null
genotype in combination with GSTM1 null geno�
type. We initially studied the prevalence of GSTT1
and GSTM1 gene polymorphism in newborns with
perinatal pathologies, including perinatal brain
damage, respiratory distress syndrome, necrotiz�
ing enterocolitis, neonatal jaundice. The preva�
lence of GSTT1 deletion polymorphism and its
combination with GSTM1 deletion polymorphism
was significantly higher in newborns with perinatal
pathologies [33]. These initial studies showed that
most of newborns had PA onset before develop�
ment of mention above neonatal syndrome. In
agreement with the initial studies we have focused
on perinatal hypoxic state such as PA in full�term
newborns. The obtained correlation have demon�
stratied the influence of genetic diversity on the
risk of PA development. The earlier studies found
that the newborns and the children with these gene
deletions had higher risk of lung immaturity and
development disorder depending of impairment
factors and genotype of investigated GSTT1 and
GSTM1 genes [23–27].
Several studies demonstrated that GSTs gene
expression identifes the sensitivity to chemical
compounds from environment in early stages of
ontogenesis [13, 22, 23, 26, 27]. The GSTs gene
expression was found in investigations in human
embryonic and fetal tissues [20, 21]. It was shown
that the individuals with deletion variation in
GSTT1 and GSTM1 genes have higher susceptibil�
ity to cellular damage from environmental toxins
and oxidant stress�related products [13, 16, 19].
Genetic differences influencing metabolic
processes of the fetus are important for prenatal
development and the initiation of labour [24, 26].
Becher et al. [34] discussed that brain damage
leading to birth asphyxia exists before starts of
labour. Genetically influenced functional changes
in the cellular antioxidant pathways may occur in
newborns with PA and lead to different reactions on
the environmental toxicants. Therefore, the prob�
lem of abnormalities and severe PA onset is con�
nected, besides increased ROS, also with increased
environmental influence and gene�environmental
interaction. On the other hand, delivery related mal�
practice was due to severe PA in one descriptive
study in Sweden [6]. Though also, the other peri�
natal risk factors were considered involved in the
PA occurrence in some studies, for example –
using of local anaesthetics [7].
The lack of significant distinctions in maternal
and perinatal risk factors in our investigation may
be caused by low prevalence of these factors among
subjects included in this study of newborns or it
may be explain that severe PA is really a genetically
determined state. The obtained association between
the presence of deletion in GSTT1 gene and the
development of severe PA has proved the necessity
of determining these and other genetic markers in
the development of PA and to estimate the severi�
ty of the developing pathological hypoxic state.
The newborns with severe PA require timely
started forced treatment. Some efforts of finding
prognostic biomarkers focused on the examination
of neuron specific enolase (NSE) and S 100 pro�
tein concentration [28, 29, 35]. The obtained results
were inconsistent. The encouraging results were
ISSN 0564–3783. Цитология и генетика. 2010. № 544
N.G. Gorovenko, Z.I. Rossokha, S.V. Podolskaya, V.I. Pokhylko, G.A. Lundberg
Table 3
The distribution of polymorphic variant combinations
of GSTT1 and GSTM1 genes in the newborns with severe
and moderate PA compared to healthy controls, n (%)
* –/– genotype (deletion polymorphism); ** +/+ and +/–
genotypes.
Polymorphic variants
combination
Severe PA
(n = 50)
Moderate
PA
(n = 85)
Healthy
controls
(n = 110)
GSTT1absent/
GSTM1absent*
GSTT1 present/
GSTM1present**
GSTT1present/
GSTM1absent
GSTT1absent/
GSTM1present
13 (26)
15 (30)
16 (32)
6 (12)
12 (14)
31 (36)
28 (33)
14 (16)
6 (5)
48 (44)
45 (41)
11 (10)
obtained in the examination of NSE in cerebrospinal
fluid of asphyxiated newborns with correlation to
severity. But the serum or whole blood samples are
more available in general practice [28].
Majority of studies concerning the analyses of
genetic factors in the development of severe PA and
neurological disorders observed gene polymorphism
in different cytokines. It was demonstrated that apo�
ptosis of nervous cells was stimulated at certain poly�
morphic variants of cytokines genes [11]. Cytokines
are involved in the apoptosis pathways in intrauter�
ine infection and hypoxia [36], but the prediction
algorithm must be based on earlier prognosis after
labour than appearance of cytokines.
The described genetic reason of cerebral palsy
[9] was in one investigation spontanious dominant
genetic mutation, that type of mutations usually
doesn’t prevalence widely, rather it was one case.
This interesting finding applied to development of
neurological outcome from intrauterine mutation
process. It is infrequent occurrence as to cerebral
palsy with intrauterine brain damage stimulating
birth asphyxia.
Severe PA was associated in our investigation
with combined deletion polymorphism in GSTT1
and GSTM1 genes. The abnormal function of addi�
tional polymorphic variants may intensify greater
defects in the antioxidant pathways. The investi�
gated distribution of polymorphic variants in GSTT1
and GSTM1 genes among newborns with moderate
PA suggests the idea about its heterogeneity stipu�
lated by the obstetric assistance peculiarities.
The obtained results in our study have demon�
strated the necessity of further studies of several
genes as genetically determined changes of antiox�
idant defense have a significant influence on the
development of severe hypoxia impairments in the
perinatal period with the consequence of damaged
nervous system.
Н.Г. Горовенко, З.И. Россоха,
С.В. Подольськая, В.И. Похилько, Г.А. Лундберг
РОЛЬ ГЕНЕТИЧЕСКОЙ ДЕТЕРМИНАНТЫ
В РАЗВИТИИ ТЯЖЕЛОЙ ПЕРИНАТАЛЬНОЙ
АСФИКСИИ
Представлены результаты определения частоты де�
леционного полиморфизма генов GSTT1 и GSTM1 у до�
ношенных новорожденных в Украине. В исследовании,
организованном по принципу случай–контроль, бы�
ли обследованы новорожденные с перинатальной ас�
фиксией и клинически здоровые новорожденные. Для
генотипирования 245 доношенных новорожденных
проведена мультиплексная полимеразная цепная реак�
ция. Обследованные новорожденные с перинатальной
асфиксией были поделены на две группы в зависимос�
ти от степени тяжести перинатальной асфиксии и тече�
ния неонатального периода. При сравнении частот деле�
ционного полиморфизма исследованных генов у ново�
рожденных с умеренной асфиксией и клинически здо�
ровых новорожденных не было зарегистрировано
достоверных различий. Выявлена ассоциация делецион�
ного полиморфизма гена GSTT1 и комбинации делеци�
онного полиморфизма обоих исследованных генов
с развитием тяжелой перинатальной асфиксии у ново�
рожденных. При проведении исследования установлено,
что тяжелая перинатальная асфиксия у новорожденных
в отличие от умеренной может быть следствием генети�
ческой склонности к развитию этого состояния.
REFERENCES
1. Nicholson A., Alberman E. Cerebral palsy�an increasing
contributor to severe mental retardation? Archf. Dis.
Childhood. 1992; 67:1050–1055.
2. Handel M., Swaab H., Jongmans M.J. Long�term cog�
nitive and behavioral consequences of neonatal en�
cephalopathy following perinatal asphyxia: a review.
Eur. J. Pediatr. 2007; 166:645–654.
3. Hjern A., Thorngren�Jerneck K. Perinatal complications
and socio�economic differences in cerebral palsy in
Sweden – a national cohort study. BMC Pediatrics 2008,
8:49, http://www.biomedcentral.com/1471–2431/8/ 49.
4. Shah P., Riphagen S., Beyene J., Perlman M. Multiorgan
dysfunction in infants with post�asphyxial hypoxic�
ischaemic encephalopathy. Arch. Dis. Child. Fetal.
Neonatal. Ed. 2004; 89:152–155.
5. Lawn J.E., Manandhar A., Haws R.A., Darmstadt G.L.
Reducing one million child deaths from birth asphyxia –
a survey of health systems gaps and priorities. Health.
Res. Pol. and Sys. 2007, 5:4, http://creativecommons.
org/licenses/by/2.0.
6. Berglund S., Grunewald S., Pettersson H., Cnattingius S.
Severe asphyxia due to delivery�related malpractice in
Sweden 1990–2005. Int. J. Obstet. and Gynaecol. 2008;
115:316–323.
7. Pignotti M.S., Indolfi G., Ciuti R., Donzelli G. Perinatal
asphyxia and inadvertent neonatal intoxication from
local anaesthetics given to the mother during labour.
Brit. Med. J. 2005; 330:34–35.
8. Odd D.E., Doyle P., Gunnell D. et al. Risk of low Apgar
score and socioeconomic position: a study of Swedish
male births. Acta Pædiatrica 2008; 97: 1275–1280.
9. Fletcher N.A., Foley J. Parental age, genetic mutation,
and cerebral palsy. J. Med. Genet. 1993; 30:44–46.
10. Schmitz T., Chew Li�Jin. Cytokines and myelination in
the central nervous system. Scien. World. Journ. 2008;
8:1119–1147.
ІSSN 0564–3783. Цитология и генетика. 2010. № 5 45
The role of genetic determinant in the development of severe perinatal asphyxia
11. Hasegava K., Ichiyama T., Isumi H. et al. NFk B acti�
vation in peripheral blood mononuclear cells in neona�
tal asphyxia. Clin. Exp. Immunol. 2003; 132:261–264.
12. Fardy C.H., Silverman M. Antioxidants in neonatal lung
disease. Arch. Dis. Childhood. 1995; 73: Fl12–Fl17.
13. Godschalk R.W.L., Kleinjans J.C.S. Characterization of
the exposure–disease continuum in neonates of moth�
ers exposed to carcinogens during pregnancy. Basic &
Clin. Pharm. & Toxicol. 2008, 102:109–117.
14. Hong Y., Lee K., Yi C. et al. Genetic susceptibility of
term pregnant women to oxidative damage. Toxicol. Let.
2002; 129:255–262.
15. Hayes J.D., Flanagan J.U., Jowsey I.R. Glutathione trans�
ferases. Annu. Rev. Pharmacol. Toxicol. 2005; 45:51–88.
16. Eaton D.L., Bammler T.K. Concise review of the glu�
tathione S�transferases and their significance to toxi�
cology. Toxicol. Sciencе 1999; 49:156–164.
17. Strange R.C., Spitery M.A., Ramachandram S., Fryer A.A.
Glutathione�S�transferase family of enzymes. Mut.
Research 2001; 482:21–26.
18. Brockmoller J., Cascorbi I., Kerb R. et al.
Polymorphisms in xenobiotic conjugation and disease
predisposition. Toxicol. Let. 1998; 102:173–183.
19. Onaran I., Ozaydin A., Akbas F. et al. Are individuals
with glutathione S�transferase GSTT1 null genotype
more susceptible to in vitro oxidative damage? J.
Toxicol. Environ. Health. 2000; 1:15–26.
20. Raiymakers M.T., Steegers E.A., Peters W.H.
Glutathione S�transferases and thiol concentrations in
embryonic and early fetal tissues. Hum. Reprod. 2001;
11:2445–2450.
21. Asikainen T.M., Raivio K.O., Saksela M., Kinnula V.L.
Expression and developmental profile of antioxidant
enzymes in human lung and liver. Am. J. Respir. Cell
Mol. Biol. 1998; 6:942–949.
22. Anguiano O.L., Caballero de Castro A., Pechen de
DґAngelo A.M. The role of glutathione conjugation in
the regulation of early toad embryosґ tolerance to pes�
ticides. Comp. Biochem. Physiol. 2001; 128:35–43.
23. Sram R.J., Binkova B., Dejmek J. et al. Association of
DNA adducts and genotypes with birth weight. Mut.
Research 2006; 608:121–128.
24. Wang X., Zuckerman B., Kaufman G. et al. Molecular
epidemiology of preterm delivery: methodology and
challenges. Paed Perin Epidem. 2001; 15:63–77.
25. Gilliland F., Gauderman W., Vora H. et al. Effects of
glutathione�S�transferase M1, T1, and P1 on child�
hood lung function growth. Am. J. Resp. Crit. Care Med.
2002; 166:710–716.
26. Tomoko N., Day A., Richard D. et al. Maternal/new�
born GSTT1 null genotype contributes to risk of
preterm, low birth weight infants. Pharmacogen. 2004;
14:569–576.
27. Lammber E., Shaw G., Lovannisci D., Finnell R.
Maternal smoking, genetic variation of glutathione S�
transferases, and risk for orofacial clefts. Epidemiol
2005.16:698–701.
28. McPherson R.J., Juul S.E. Recent trends in erythropoie�
tin�mediated neuroprotection. Int. J. Dev. Neurosci.
2008; 26:103–111.
29. Thornberg E., Thiringer K., Hagberg H., Kjellmer I.
Neuron specific enolase in asphyxiated newborns:
association with encephalopathy and cerebral function
monitor trace. Arch. Dis. Childhood. 1995; 72:39–42.
30. Wijnberger L.D.E., Nikkels P.G.J. et al. Expression in
the placenta of neuronal markers for perinatal brain
damage. Pediatr. Res. 2002; 51:492–496.
31. Arand M., Muhlbauer R., Hengstler J. et al. A multiplex
polymerase chain reaction protocol for the simultane�
ous analysis of the glutathione S�transferase
GSTM1 and GSTT1 polymorphisms. Anal. Biochem.
1996; 236:184–186.
32. Garte S., Gaspari L., Alexandrie A.K. et al. Metabolic
gene polymorphism frequencies in control populations.
Cancer Epid, Biomarkers & Prevention 2001;
10:1239–1248.
33. Gorovenko N., Rossokha Z., Podolskaya S. Genetic
polymorphism of glutathione�S�transferase T1 and
M1 in the newborns with neonatal syndromes in
Ukrainian population. J. Hum. Gen. 2007; 15: P0745.
34. Becher T.J.C., Bell J.E., Keeling J.W. et al. The Scottish
perinatal neuropathology study: clinicopathological
correlation in early neonatal deaths. Arch. Dis. Child.
Neonatal. Ed. 2004; 89: F399–F407.
35. Sedaghat F., Notopoulos A. S100 protein family and its
application in clinical practice. Hippokratia 2008;
12:198–204.
36. Hofstetter A.O., Saha S., Silijehav V. et al. The induced
prostaglandin E2 pathway is a key regulator of the res�
piratory response to infection and hypoxia in neonates.
Proc. Nat. Acad. Sci. USA 2007; 104:9894–9899.
Received 29.12.09
ISSN 0564–3783. Цитология и генетика. 2010. № 546
N.G. Gorovenko, Z.I. Rossokha, S.V. Podolskaya, V.I. Pokhylko, G.A. Lundberg
|