UGT1A1 (TA)n PROMOTER GENOTYPE:
DIAGNOSTIC AND POPULATION
PHARMACOGENETIC MARKER IN SERBIA
Vukovic M, Radlovic N, Lekovic Z, Vucicevic K, Maric N, Kotur N,
Gasic V, Ugrin M, Stojiljkovic M, Dokmanovic L, Zukic B, Pavlovic S
*Corresponding Author: Sonja Pavlovic, Ph.D., Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and
Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, PO BOX 23, 11010 Belgrade, Serbia.
Tel: +38111-3976445. Fax: +38111-3975808. E-mail: sonya@sezampro.rs
page: 59
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INTRODUCTION
Uridin diphospho-glucuronosyl transferases (UGT)
are a family of enzymes responsible for glucuronidation
of numerous endobiotics, xenobiotics and drugs. Glucuronidation
is a process of biotransformation of substrate to
water soluble, mainly non-toxic products ready for excretion
[1]. The human UGT superfamily is divided into four families:
UGT1A, UGT2, UGT3 and UGT8 [2]. The UGT1A
family is encoded by the UGT1A gene complex located
on chromosome 2q37. This gene complex at the 5’ region
has 13 variable exons, linked to four common exons at the
3’ region of the UGT1A gene. Each of the 13 5’ exons has
its own TATA promoter elements. Four of 13 first exons
are pseudoexons, and nine exons are viable, independently
transcribed as the first exon. Those nine different first exons
with highly conserved regions from exon 2 to exon
5, generate nine different transcripts (UGT1A1, UGT1A3
through UGT1A10). Each transcript has identical 3’ ends
and a unique 5’ end. Variable first exon provides substrate
specificity, while highly conserved common exons contain sites for interactions with UDP glucuronic acid as common
substrate [3]. The UGT1A1 gene is expressed in the liver,
colon, intestine and stomach [4,5]. The UGT1A1 enzyme
has a main role in glucuronidation of bilirubin. There are
no alternative metabolic pathways for efficiently detoxification
and elimination of bilirubin. Currently, more than 130
UGT1A1 variants have been reported as a cause of Gilbert
syndrome (GS), Crigler-Najjar syndrome type 1 and Crigler-
Najjar syndrome type 2 [6]. Allelic variations were found
in both the exonic and promoter sequences [7]. The most
common variants detected in the UGT1A1 gene are different
numbers of TA repeats in its promoter, rs8175347 [8,9].
Wild-type UGT1A1 contains six TA repeats [A(TA)6TAA]
in its promoter region. UGT1A1*28, UGT1A1*37 and UGT1A1
*36 variants have seven, eight and five TA repeats,
respectively. Transcriptional activity of the UGT1A1 gene
and, consequently, the activity of the UGT1A1 enzyme,
depends on the number of TA repeats. A higher number of
TA repeats causes decreased enzyme activity. Heterozygous
status of UGT1A1*28 results in 25.0% decreased enzyme
activity and homozygous status of this variant reduced transcription
activity by 70.0% [7]. This leads to GS, a mild form
of intermittent unconjugated hyperbilirubinemia, that lacks
hemolysis or hepatocellular injury. Therefore, six TA repeats
in the UGT1A1 gene promoter is considered as non-risk
GS allele and seven or eight TA repeats are responsible for
development of GS (risk GS allele).
Gilbert syndrome is a benign hereditary condition,
commonly presented in 3.0-13.0% in the general population.
Gilbert syndrome is inherited in an autosomalrecessive
manner, but several cases have been reported as
dominantly inherited [10,11]. Gilbert syndrome is rarely
clinically manifested until before puberty. Males are more
often diagnosed than females, two-to-seven times, because
there is a bigger bilirubin load per kilogram body weight
in males, and/or androgen steroid hormone suppresses
hepatic bilirubin clearance [12,13].
The UGT1A1*28 and UGT1A1*37 variants have been
shown to contribute to hyperbilirubinemia and increased
likelihood of gallstone formation in several inherited hemolytic
conditions [14]. They are also associated with
increased risk of breast cancer, neonatal hyperbilirubinemia
and the risk of developing gallstones in cystic fibrosis.
Shorter erythrocyte life and damage in transport of unconjugated
bilirubin further contributes to development of GS.
Gilbert syndrome does not require therapy as it is
considered to be a benign condition. However, fasting,
excessive physical stress, febrile conditions and hormone
changes during menstrual cycles additionally potentiate
hyperbilirubinemia and could be treated with phenobarbitone
which stimulates the UGT1A1 enzyme activity [15].
Sometimes, for cosmetic purposes, GS could be treated to
moderate the subicterus.
The complete or nearly complete lack of ability of
glucuronidation of bilirubin is not compatible with life.
Genetic variations within exons 2 to 5 of the UGT1A1 gene
locus, resulting in total absence of bilirubin glucuronide
formation, cause Crigler-Najjar syndrome type 1 [8]. Also,
some genetic variations in introns resulting in frameshifts
and a premature stop codon have been described. Lack of
UGT1A1 activity leads to a high level of bilirubin shortly
after birth (20.0-50.0 mg/dL), causing bilirubin encephalopathy,
kernicterus and death. Crigler-Najjar syndrome
type 1 could be managed by repeated exchange transfusions,
long-term phototherapy, plasmapheresis, hemoperfusion
and finally, the only successful therapy is liver
transplantation. Several single nucleotide variations in the
UGT1A1 gene have been reported to cause substitution
of a single amino acid and reduce enzyme activity to less
than 10.0% of normal activity, but total bilirubin levels do
not exceed 20.0 mg/dL. This condition is recognized as a
Crigler-Najjar syndrome type 2 [15]. In this case, optimal
therapy is phenobarbital that stimulates UGT1A1 activity.
Taking into account that a number of medications are
metabolized by the UGT1A1 enzyme, UGT1A1 (TA)n promoter
variants are recognized as clinically relevant pharmacogenetic
markers [16].
The presence of seven or eight TA repeats in the
promoter of the UGT1A1 gene could severely impact
the ability to metabolize certain medications, including
antineoplastic drugs used in oncology: irinotecan (solid
tumors, lymphoma and colorectal cancer treatment), belinostat
(peripheral T-cell lymphoma treatment), epirubicin
(breast cancer treatment), 5-fluorouracil (colorectal cancer
treatment), axitinib and busulfan (various hematological
and non hematological cancers), atazanavir and ritonavir
(HIV infections treatment) and widely used analgesic/antipyretic
drug acetaminophen (paracetamol). Alterations in
hepatic metabolism may result in life-threatening toxicities
in various organ systems [17,18]. Recommendations for
pharmacogenomic testing for several of these drugs are
given and have already been applied in routine clinical
practice [19].
The aim of this study was to analyze if UGT1A1 (TA)n
promoter variants can be efficient diagnostic tools for
easier and faster diagnosis of GS, by using accurate and
cost-effective methodology for detection of number of TA
repeats in the UGT1A1 promoter. Correlation of UGT1A1
(TA)n promoter genotypes, risk GS and non-risk GS, with
levels of unconjugated bilirubin at diagnosis and after hypocaloric diet and phenobarbitone tests in pediatric GS
patients will be used for assessment of diagnostic value of
UGT1A1 (TA)n promoter variants genotyping.
Additionally, given that the UGT1A1 enzyme is very
important for metabolism of various drugs and that, in the
case of presence of defined UGT1A1 (TA)n promoter variants,
numerous drugs can present unwanted side effects or
toxicities, the aim of this study was to assess pharmacogenetic
potential of those variants in Serbia. The results will
point out if pharmacogenetic testing should be performed
in Serbia before administration of medications whose metabolism
is UGT1A1 (TA)n genotype-dependent.
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