<p>Gilbert’s syndrome (GS) occurs in approximately 10% of the European population. The most common cause is homozygosity for UGT1A1*28, which is a TA repeat expansion in the promoter of UGT1A1. It is characterised by intermittent hyperbilirubinemia due to reduced hepatic activity of the  enzyme UDP-glucuronosyl-transferase 1A1(UGT1A1). GS also  alteres the pharmacokinetics of some drugs and increases the risk of drug toxicity. Irinotecan (Camptosar®, Campto®) is used in metastatic colorectal cancer and the active metabolite is inactivated by UGT1A1. Studies have shown that GS can be a risk factor for toxicity during irinotecan therapy.</p><p>Three different methods for genotyping of UGT1A1*28 have been tested.</p><p>PCR with electrophoresis used for size separation, melting temperature analysis and fluorescent PCR followed by fragment analysis on a capillary sequencer.</p><p>The last method was found to be superior. This method was used for genotyping of patients with colorectal cancer treated with irinotecan and 5-fluorouracil in the Nordic VI study. A significant association between UGT1A1 genotype and plasma bilirubin level before the start of irinotecan treatment was seen (ANOVA p<0.0001). Patients with GS had an overall increased risk of adverse drug reactions (Fishers Exact test p=0.02).</p><p>Gilbert’s syndrome can be diagnosed by genotyping UGT1A1*28 with a fragment analysis method. Genotyping of UGT1A1*28 can be used to identify patients with an increased risk of adverse reactions to irinotecan.<strong> </strong></p><p><strong> </strong></p> / <p>Gilberts syndrom (GS) drabbar upp till 10% av befolkningen i Västeuropa. GS beror på nedsatt aktivitet av enzymet UDP-glukuronosyltransferas 1A1 (UGT1A1) i levern. Den vanligaste orsaken är att individen är homozygot för en insertion av två baser i promotorn för genen UGT1A1. Denna genvariant kallas (TA)7TAA  eller UGT1A1*28. GS leder till intermittent stegring av bilirubin vid infektioner, men bilirubinstegring kan förekomma även utan utlösande agens. GS kan också leda till bilirubinstegring vid viss läkemedelsbehandling. Irinotekan (Campto®) används vid metastaserande colorektal cancer och dess aktiva metabolit inaktiveras av UGT1A1. Det finns rapporter om att GS ger ökad risk för toxiska biverkningar av irinotekan.</p><p>Tre metoder för att bestämma UGT1A1 har jämförts: PCR med elfores, PCR med smältpunktsanalys och PCR med fragmentanalys på sekvensator. Den sista metoden var bäst och användes för att genotypa UGT1A1 hos patienter med colorektal cancer från Nordic VI-studien. De behandlades med irinotekan i kombination med bolusinjektion eller infusion av 5-fluorouracil. Vi fann att  patienter med GS hade signifikant högre S-bilirubin före behandling jämfört med övriga patienter. De hade även ökad frekvens biverkningar av irinotekan (Fishers exakta test p=0,02).</p><p>Genotypning av UGT1A1 kan således användas för att diagnostisera Gilberts syndrom hos patienter med oförklarad bilirubinstegring. Det kan även användas för att identifiera patienter med ökad risk för biverkningar av irinotekan.</p>

Gilbert’s syndrome (GS) occurs in approximately 10% of the European population. The most common cause is homozygosity for UGT1A1*28, which is a TA repeat expansion in the promoter of UGT1A1. It is characterised by intermittent hyperbilirubinemia due to reduced hepatic activity of the  enzyme UDP-glucuronosyl-transferase 1A1(UGT1A1). GS also  alteres the pharmacokinetics of some drugs and increases the risk of drug toxicity. Irinotecan (Camptosar®, Campto®) is used in metastatic colorectal cancer and the active metabolite is inactivated by UGT1A1. Studies have shown that GS can be a risk factor for toxicity during irinotecan therapy. Three different methods for genotyping of UGT1A1*28 have been tested. PCR with electrophoresis used for size separation, melting temperature analysis and fluorescent PCR followed by fragment analysis on a capillary sequencer. The last method was found to be superior. This method was used for genotyping of patients with colorectal cancer treated with irinotecan and 5-fluorouracil in the Nordic VI study. A significant association between UGT1A1 genotype and plasma bilirubin level before the start of irinotecan treatment was seen (ANOVA p&lt;0.0001). Patients with GS had an overall increased risk of adverse drug reactions (Fishers Exact test p=0.02). Gilbert’s syndrome can be diagnosed by genotyping UGT1A1*28 with a fragment analysis method. Genotyping of UGT1A1*28 can be used to identify patients with an increased risk of adverse reactions to irinotecan. / Gilberts syndrom (GS) drabbar upp till 10% av befolkningen i Västeuropa. GS beror på nedsatt aktivitet av enzymet UDP-glukuronosyltransferas 1A1 (UGT1A1) i levern. Den vanligaste orsaken är att individen är homozygot för en insertion av två baser i promotorn för genen UGT1A1. Denna genvariant kallas (TA)7TAA  eller UGT1A1*28. GS leder till intermittent stegring av bilirubin vid infektioner, men bilirubinstegring kan förekomma även utan utlösande agens. GS kan också leda till bilirubinstegring vid viss läkemedelsbehandling. Irinotekan (Campto®) används vid metastaserande colorektal cancer och dess aktiva metabolit inaktiveras av UGT1A1. Det finns rapporter om att GS ger ökad risk för toxiska biverkningar av irinotekan. Tre metoder för att bestämma UGT1A1 har jämförts: PCR med elfores, PCR med smältpunktsanalys och PCR med fragmentanalys på sekvensator. Den sista metoden var bäst och användes för att genotypa UGT1A1 hos patienter med colorektal cancer från Nordic VI-studien. De behandlades med irinotekan i kombination med bolusinjektion eller infusion av 5-fluorouracil. Vi fann att  patienter med GS hade signifikant högre S-bilirubin före behandling jämfört med övriga patienter. De hade även ökad frekvens biverkningar av irinotekan (Fishers exakta test p=0,02). Genotypning av UGT1A1 kan således användas för att diagnostisera Gilberts syndrom hos patienter med oförklarad bilirubinstegring. Det kan även användas för att identifiera patienter med ökad risk för biverkningar av irinotekan.

Background Cardiovascular diseases, including myocardial infarction and stroke, are the main reason of death in Sweden and Western Europe. High iron stores are believed to produce oxygen radicals, which is the presumed putative mechanism behind lipid peroxidation, atherosclerosis and subsequent cardiovascular disease. Iron levels are associated with the hemochromatosis associated HFE single nucleotide polymorphisms C282Y and H63D. Bilirubin is an antioxidant present in relatively high levels in the human body. Several previous studies have found an association between high bilirubin levels and a lower risk for cardiovascular disease. Bilirubin levels are highly influenced by the common promoter polymorphism TA-insertion UGT1A1*28, the main reason for benign hyperbilirubinemia in Caucasians. There is a lack of prospective studies on both the association of iron and bilirubin levels, and the risk for myocardial infarction and ischemic stroke. Material and methods Iron, transferrin iron saturation, TIBC, ferritin and bilirubin were analyzed and HFE C282Y, HFE H63D and UGT1A1*28 were determined in myocardial infarction and stroke cases, and their double matched referents within the Northern Sweden Health and Disease Study Cohort. Results There were no associations between iron levels in the upper normal range and risk for myocardial infarction or stroke. No associations were seen for HFE-genotypes, except for a near fivefold increase in risk for myocardial infarction in HFE H63D homozygous women. Plasma bilirubin was lower in cases vs. referents both in the myocardial infarction and the stroke cohort. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk for myocardial infarction or stroke. Conclusion High iron stores are not associated with increased risk for neither myocardial infarction, nor stroke. There was no association between UGT1A1*28 and the risk for myocardial infarction or stroke. Consequently data suggests that other factors, which also may lower bilirubin, are responsible for the elevated risk observed in conjunction with lower bilirubin levels.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

Indiana University-Purdue University Indianapolis (IUPUI) / Colorectal cancer is the third most common type of cancer and the third most common cause of cancer-related mortality. There are three types of treatment available to patients, either individually or in combination. Treatments are radiation, chemotherapy, and surgery. In a Phase II clinical trial at IUSM, a multimodality approach was chosen. The patients with locally advanced rectal cancer received preoperative treatment with capecitabine and irinotecan (CPT-11) combination followed by chemoradiation with capecitabine and finally surgery to improve response and decrease local recurrence. Irinotecan and Capecitabine are both prodrugs activated in vivo to SN-38 and 5-FU, respectively. Identification of the molecular markers for 5-FU and Irinotecan efficacy and toxicity is important for the development of more efficient and less toxic treatment strategies for patients with colorectal cancer. The goal of this study was to determine the expression levels of the genes involved in activation and metabolism of capecitabine and irinotecan in pre and post treatment specimens from these patients. The genes quantitated by real-time PCR were carboxylesterase 1 and 2 (CES1 and CES2), thymidylate synthase (TS), β-glucoronidase (β-GUS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and topoisomerase I (Topo I). The UGT1A1*28 polymorphism in UDP glucuronosyltransferase 1 is associated with SN-38 toxicity. Therefore, the UGT1A1*28 polymorphism status in patients was determined by PCR-sequencing. Correlative analysis of gene expression and UGT1A1*28 mutation with clinical outcome in this Phase II study was completed.