UGT1A1 (TA)_n promoter genotype: Diagnostic and population pharmacogenetic marker in Serbia

Abstract

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1 (TA)n promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1 (TA)n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1 (TA)n genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1 (TA)n variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)n promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)n promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1 (TA)n promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1 (TA)n promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)n promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia.

Gilbert Syndrome and Genetic Findings in Children: A Tertiary-Center Experience from Turkey

“…In a study from Serbia, GS non-risk UGT1A1 (TA)n promoter genotypes TA 6/6 and TA 6/7 were detected in 3.9% of patients and 15.8% of patients, respectively. 9 In our study, (TA) 6/7 heterozygous mutation was detected in the UGT1A1 promoter region of 1 patient (2%), and (TA)6/6 mutation was detected in 22.5%. The patient, who had (TA)6/7 mutation with mild hyperbilirubiemia, had no complaints.…”

“… 8 This situation leads to GS, a mild form of intermittent unconjugated hyperbilirubinemia that lacks hemolysis or hepatocellular injury. 9 …”

Analysis of the low functional allele 7(TA) of the UGT1A1 gene in healthy population in the Western region of Ukraine

“…ІІ -денатурація -95°С, 30 с, відпал праймерів -55°С, 30 с, елонгація -72°С, 30 с × 35 циклів ІІІ -елонгація -72°С, 7 хв. Використовували суміш dDNTP та термостійку DreamTaq Green ДНК полімеразу, суміш для HRM аналізу Eva Green (ThermoFisher scientific, USA) та наступні олігонуклеотиди: F5' -TGT TGC ATG AGA AAA CGC CA, R5' -GTC GCC TGT TCA CCA AGG AT (Vukovic et al, 2018).…”

The Genetics of Glucose-6-Phosphate-Dehydrogenase (G6PD) and Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) Promoter Gene Polymorphism in Relation to Quantitative Biochemical G6PD Activity Measurement and Neonatal Hyperbilirubinemia

“…(2) the hepatic bilirubin-conjugating enzyme uridine-diphosphate glucuronosyl transferase 1A1 (UGT1A1) [13,[15][16][17]19,20,24,28,[30][31][32][33][34][35][36][37][38][39][40][41]; and (3) the hepatic solute carrier organic anion transporter polypeptide 1B1 (OATP1B1)-the bilirubin transporter localized to the sinusoidal membrane of hepatocytes, which is the blood-hepatocyte interface that limits bilirubin hepatic uptake [18][19][20]42]. These genetic variants may interact with each other or with environmental contributors to produce significant NHB [19,20].…”

“…Alternatively, G6PD mutations can lead to severe NHB by causing low-grade hemolysis coupled with UGT1A1 gene polymorphisms [17,22,[27][28][29][30]35]. UGT1A1 promoter and coding sequence gene variants may cause significant NHB via decreased hepatic bilirubin conjugation [15][16][17][18][30][31][32][33][34][37][38][39][40][41].…”