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

• Published in: Balkan journal of medical genetics 2018-10, Vol.21 (1), p.59-68
• Main Authors: Vukovic, M, Radlovic, N, Lekovic, Z, Vucicevic, K, Maric, N, Kotur, N, Gasic, V, Ugrin, M, Stojiljkovic, M, Dokmanovic, L, Zukic, B, Pavlovic, S
• Format: Article
• Language: English
• Subjects: Acrylamide; Alleles; Bilirubin; Differential diagnosis; DNA sequencing; Enzymatic activity; Enzymes; Genotype & phenotype; Genotypes; Genotyping; Gilbert syndrome (GS); Hyperbilirubinemia; Medical diagnosis; Original; Pediatrics; Polymerase chain reaction; Population pharmacogenetics; population pharmacogenetics, ugt1a1 (ta)n promoter variants; promoter variants; TA; Unconjugated hyperbilirubinemia
• ISSN: 1311-0160; 2199-5761; 1311-0160
• DOI: 10.2478/bjmg-2018-0012

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 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 (TA) promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of (TA) promoter genotyping in pediatric GS patients. Correlation of the (TA) 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 (TA) 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 (TA) promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, (TA) 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 (TA) promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant (TA) promoter genotypes was 63.0%, pointing out that (TA) promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia.