DO GENE POLYMORPHISMS PLAY A ROLE IN NEWBORN HYPERBILIRUBINEMIA?
Hakan N, Aydin M, Ceylaner S, Di̇lli̇ D, Zenci̇roğlu A, Okumuş N
*Corresponding Author: Assoc. Prof. Nilay Hakan, MD, Division of Neonatology, Sitki Koçman University School of Medicine, Orhaniye Mah., Haluk Ozsoy Sk., 48000, Muğla / Türkiye, Phone: +90 (252) 214 13 26, Fax: +90 (252) 211 13 45, E-mail: nhakan@hotmail.com
page: 51
|
|
DISCUSSION
Neonatal jaundice is a good example of a complex
condition in which the usual clinical factors examined
alone cannot reveal the real cause. Although a few studies
have been conducted to define the mechanisms involved
in NH, more attention has recently begun to be paid to ge-
netic factors as a contributing cause [8]. This study aimed
to elucidate the contribution of multiple genetic modi-
fiers affecting bilirubin metabolism to the development
of pathological hyperbilirubinemia in Turkish newborns.
UGT is the key enzyme of bilirubin conjugation. 211G >
A (Gly71Arg), one of the most common UGT1A1 gene
polymorphisms in the coding region, may cause unconju-
gated hyperbilirubinemia by reducing enzymatic activity
[9]. Recently, in a meta-analysis of 21 studies including
4738 newborns, it was reported that UGT1A1 Gly71Arg
variation may increase the risk of NH in Asian and Afri-
can children [10]. There are two studies investigating the
relationship between hyperbilirubinemia and the G71R
variant in Turkish newborns. Kilic et al. [11] showed the
frequency of heterozygous G71R variants in pathological
jaundice, prolonged jaundice and control groups as 8.7%,
20.8% and 4.3%, respectively; however, these differences
were not statistically significant. Narter et al. [12] reported
a frequency of 33.3% and 27.1% for heterozygous G71R
variants and 7.7% and 5.7% for homozygous G71R vari-
ants in the hyperbilirubinemia and control groups, respec-
tively, and no statistically significant difference was found
between these frequencies. Our study showed that the
frequency of heterozygous G71R variants in idiopathic hy-
perbilirubinemia, prolonged jaundice, and control groups
was 3.8%, 22.2%, and 7.9%, respectively. But these differ-
ences were not statistically significant. The frequency of
homozygous G71R variant in idiopathic hyperbilirubine-
mia was 3.8%. However, no homozygous G71R variant
was found in the prolonged jaundice and control groups.
SLCO1B1/B3, the gene encoding the hepatic solute
transporter organic anion transporter 1B1, a putative bili-
rubin transporter, may also be associated with increased
susceptibility to NH by limiting bilirubin uptake [6, 13].
In our study, SLCO1B1 A388G in both the heterozygous
and homozygous variants was found 72.2%, 75% and
53.7% in the idiopathic hyperbilirubinemia, prolonged
jaundice and control groups, respectively. Other studies of
SCLO1B1 in different countries showed similar findings
to our study in terms of the incidence of polymorphism.
In studies conducted on newborns with hyperbilirubine-
mia, the SLCO1B1 A388G variant was found at a rate of
77.7% in India and 87.7% in Malaysia [14, 15]. All these
studies show that more than half of the studied popula-
tion has the A388G variant. Our study showed that the
SLCO1B1 A388G variant was not a significant risk factor
for idiopathic and prolonged hyperbilirubinemia. There
is tentative evidence from different studies in different
populations regarding the association between SLCO1B1
A388G and high bilirubin levels in newborns. In a study
conducted on Taiwanese newborns in 2004 by Huang et al.
[16], it was reported that A388G was seen more frequently
in babies with hyperbilirubinemia. Liu et al. [17] found that
the A388G variant in Chinese newborns was associated
with hyperbilirubinemia in the Guangdong population,
but not in the Yunnan population. In our country, Büyük-
kale et al. [18] reported that polymorphic forms of 388
nucleotides of the SLCO1B1 gene were risk factors for
idiopathic hyperbilirubinemia. Other studies conducted
in Malaysian, Brazilian, American or Thai populations
also failed to prove the association of the A388G variant
with NH [15, 19-21].
In our study, there was no statistically significant
difference in NH risk between SLCO1B1 T521C allele
carriers (T/C+C/C) and T/T allele carriers; the same result
was observed in the SLCO1B1 T521C variant when the
T allele was compared with the C allele. A meta-analysis
including five case-control studies (637 subjects with
hyperbilirubinemia and 918 control subjects) from three
countries examined the association between the SLCO1B1
T521C variant and NH. This meta-analysis reported that
the SLCO1B1 T521C variant conferred protection for NH
in the Chinese population but not in the Malaysian, Tai-
wanese, Brazilian, or American populations; when the T
allele was compared with the C allele, the same situation
was observed in the SLCO1B1 T521C variant [17].
Analysis of the SLCO1B1 C463A variant in our study
showed a crossover variant in 14 of 61 (23%) neonates
with idiopathic hyperbilirubinemia (13 heterozygous and
one homozygous) and in 8 of 28 (28.6%) neonates with
prolonged jaundice (7 heterozygous and one homozygous),
and 7 of 39 (24.75%) control subjects (all heterozygous).
The SLCO1B1 C463A variant was not a significant risk
factor for idiopathic and prolonged hyperbilirubinemia in
the present study. A meta-analysis of three case-control
studies involving 286 cases of hyperbilirubinemia and 456
controls from three countries examined the association be-
tween the SLCO1B1 C463A variant and NH [17]. In studies
conducted on Taiwanese and Thai newborns, carriage of
the C to A substitution at nucleotide 463 was not detected
[16, 21]; however, the study conducted by Watchko et al.
[20] including American subjects showed that in those 31
of 153 newborns (20.26%) with hyperbilirubinemia (one
homozygous and 30 heterozygous) and 74 of 299 control
subjects (24.75%) (nine homozygous and 65 heterozygous).
In that study (20), no statistically significant difference was
found in the risk of NH between allele carriers (C/A+A/A)
and (C/C) in the SLCO1B1 C463A variant; the same situ-
ation was observed when the A allele in the SLCO1B1
C463A variant was compared with the C allele; the same
situation was observed when the A allele was compared
with the C allele in the SLCO1B1 C463A variant.
There was no mutant allele in SLCO1B1 at Nt 1463
G>C. However, according to our research, no study in-
vestigating this variant has been found in the literature.
Similar to SLCO1B1 polymorphisms in this study,
SLCO1B3 polymorphisms did not show statistical differ-
ences in genotype distribution. It was found in the present
study that only the G allele at nt 344 of SLCO1B3 may be
a protective factor for idiopathic NH. However, it does not protect against prolonged jaundice. No study investigat-
ing the relationship between SLCO1B3 nt 334 variant and
NH has been found in the literature. However, there are
very few studies on the C727+118G and C1865+19721T
polymorphisms of this gene. Alencastro de Azevedo et al.
[19] reported that the allelic and genotypic frequencies
of SLCO1B3 gene C727+118G and C1865+19721T vari-
ants did not differ between idiopathic hyperbilirubinemia
and control groups. They stated that only the T allele at
nt 1865+19721 could be protective against NH in those
without ABO incompatibility.
During the bilirubin conjugation process in hepato-
cytes, bilirubin binds to GST, also known as ligandin [22].
GST binds both bilirubin and bilirubin conjugates and re-
duces hepatocyte reflux into plasma [23]. The present study
found that there is no statistically significant difference
in the genotype and allele frequencies of GSTP1 A313G
and C341T among the idiopathic hyperbilirubinemia, pro-
longed jaundice, and control groups. Muslu et al. [24],
from Türkiye, reported that the frequencies of GSTM1 and
GSTT1 were similar in newborns with hyperbilirubinemia
and control groups.
In this study, no significant difference was found in
terms of peak total bilirubin levels and onset time of hy-
perbilirubinemia in newborns in the idiopathic hyperbili-
rubinemia group with different genotypes.
The limitation of the present study is that the need
for phototherapy was taken as a criterion, which does not
have a strong discriminatory feature in determining genetic
variability differences. Another limitation of our study is
the small number of cases.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
