UGT1A1 Polymorphisms Research Articles

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial.

AimsPupillography is a noninvasive and cost‐effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP‐binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics.MethodsTwenty‐four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro‐aripiprazole and olanzapine plasma concentrations were measured by high‐performance liquid chromatography–tandem mass spectrometry.ResultsAripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro‐aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes.ConclusionsIn conclusion, aripiprazole and its main metabolite, dehydro‐aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro‐aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.

Correlation between UGT1A1 gene polymorphism and irinotecan chemotherapy in metastatic colorectal cancer: a study from Guangxi Zhuang

BackgroundThere are obviously ethnic differences between the UGT1A1 gene polymorphisms. Due to the difference of genetic background and environment, the treatment with colorectal cancer patients of Guangxi Zhuang should not completely follow the Euramerican or Chinese han patients. The study aimed to explore the correlation of UGT1A1 gene polymorphism of Guangxi Zhuang metastatic colorectal cancer (mCRC) with irinotecan -based chemotherapy, in order to develop an individualized irinotecan regimen for mCRC patients of Guangxi Zhuang.MethodsFrom June 2013 and June 2015, a total of 406 patients of Guangxi who were histologically diagnosed as metastatic colorectal cancer with 102 patients of this cohort with three generations of Zhuang, and 86 patients that conformed to inclusion and exclusion criteria were competitively enrolled. The distribution of UGT1A1 gene polymorphism was analyzed-retrospectively in all patients. Pyrosequencing method was used to detect the UGT1A1*28 and*6 gene polymorphism in the 86 Guangxi Zhuang mCRC patients. After first-line chemotherapy with FOLFIRI regimen, the relationship between gene polymorphism of UGT1A1 and adverse reactions, and efficacy of Irinotecan were analyzed with χ2 test and Kaplan-Meier method.ResultsUGT1A1*28 wild-type (TA6/6), heterozygous mutant (TA6/7) and homozygous mutant (TA7/7) accounted for 69.8, 30.2 and 0%, respectively. UGT1A1*6 wild type (G/G), heterozygous mutation type (G/A) and homozygous mutant (A/A) accounted for 76.7%, 20.9 and 2.3%, respectively. UGT1A1*28 TA6/7 type could increase the risk of grade 3~4 diarrhea (p = 0.027), which did not increase the risk of grade 3~4 neutropenia (p = 0.092). UGT1A1*6G/A and A/A type could increase the risk of grade 3~4 diarrhea and neutropenia (p = 0.001; p = 0.017). After chemotherapy with FOLFIRI, there was no significant difference in response rate (RR) (p = 0.729; p = 0.745) or in median progression-free survival (mPFS) between the wild-type, mutant treatment of UGT1A1*28 and UGT1A1*6 (7.0 m vs 7.4 m, p = 0.427; 6.9 m vs 7.0 m p = 0.408).ConclusionsThe distribution of UGT1A1*28 and UGT1A1*6 gene polymorphism in Guangxi Zhuang patients were differed from the existing reported of European people and Chinese Han population. The UGT1A1 gene polymorphism with irinotecan chemotherapy-associated diarrhea and neutropenia were closely related. There was no significant association between UGT1A1 gene polymorphism and therapeutic efficacy of irinotecan.

Worsening of Kidney Transplant Function During 2-Year Follow-up Is Associated With the Genetic Variants of CYP3A4, MDR1, and UGT1A9

BackgroundCalcineurin inhibitors (CNIs), tacrolimus and cyclosporine, undergo pharmacokinetic processes. Enzymes and transport proteins found in various organs are involved. It is possible that genetic polymorphisms of these proteins influence CNIs pharmacokinetics and the generation of CNIs metabolites. CNIs may be nephrotoxic, and it is thought that some CNIs’ metabolites may have a similar effect.The study was aimed at the assessment of the relationship between selected gene polymorphisms for enzymes and transport proteins and change of estimated glomerular filtration rate (eGFR) during a 2-year follow-up in kidney transplant (KTX) patients. MethodsThe study involved 366 patients after KTX (160 women; 43.7%) receiving tacrolimus (62.57%) and cyclosporine (37.43%). The mean age was 50.1 years, and the median time after KTX was 60.5 months. The study protocol conformed with the Declaration of Helsinki.The percent of difference between eGFR at baseline and at 24 months (ΔeGFR) was calculated. We evaluated selected genetic polymorphisms of CYP3A4, CYP3A5, MDR1, UGT1A9, UGT2B7, UGT1A8, and MRP2. ResultsIn the tacrolimus group, there were no significant differences of ΔeGFR between groups distinguished based on analyzed genotypes. In the cyclosporine group, differences were found for CYP3A4∗22 C/C -12.3 (-26.8 to -1.8) versus C/T 13.2 (12.4 to 13.9), P = .034; MDR1 3435C>T C/T -18.2 (-31.5 to -5.7) versus C/C -1.8 (-17.1 to 6.9) vs T/T -8.1 (-18.4 to 12.4), P = .031; and UGT1A9 2152C>T C/C -9.0 (-25.5 to 2.8) versus C/T -26.8 (-31.9 to -24.1), P = .017. ConclusionThe study results suggest that in KTX metabolic transformations and transport, especially of cyclosporine, dependence on the genetic variability of CYP3A4, UGT1A9, and MDR1 may contribute to kidney damage.

The relationship between hyperbilirubinemia and the promoter region and first exon of UGT1A1 gene polymorphisms in Vietnamese newborns.

To investigate the relationship between unexplained indirect hyperbilirubinemia of Vietnamese newborns and the polymorphism of the promoter TATA box and exon 1 of bilirubin uridine diphosphate glucuronosyltransferase (UGT1A1) gene. A total of 149 neonates were divided into the hyperbilirubinemia group (n = 99) and control group (n = 50). The gene polymorphisms of UGT1A1 gene in the two groups were detected by PCR and direct sequencing, which revealed the relationship between UGT1A1 polymorphism with neonatal hyperbilirubinemia of neonates. The types of UGT1A1 polymorphism in the hyperbilirubinemia group and the peak total serum bilirubin (PSB) levels with different genotypes were observed. (1) (TA)7 insertion mutation, 211G>A, 189C>T, 190G>A, 378C>T and 686C>A were detected. (2) The allele frequency of 211G>A allele mutation was significantly different between the two groups (p < 0.05). (3) Logistic regression analysis showed that homozygosity and heterozygosity of 211G>A were both significantly associated with neonatal hyperbilirubinemia. (4) In the hyperbilirubinemia group, the peak total serum bilirubin level of 211G>A homozygous neonates was higher than that of the wild-type neonates (p < 0.05). We noted that there was an association between neonates with unexplained indirect hyperbilirubinemia in Vietnam and the polymorphism of UGT1A1c.211G>A. In addition, the homozygous 211G>A polymorphism was related to the degree of hyperbilirubinemia. Our article provided data on UGT1A1 polymorphism distribution in the Vietnamese population, which have not been reported yet. Our findings revealed that mutations in UGT1A1 gene are risk factors for unexplained hyperbilirubinemia in Vietnamese neonates. Our article will strengthen the cognition of neonatal jaundice at the genetic level in the pediatric field in Vietnam.

The correlation between UDP-glucuronosyltransferase polymorphisms and environmental endocrine disruptors levels in polycystic ovary syndrome patients.

Background:In recent years, there has been an interest in whether environmental endocrine disruptors (EEDs) may contribute to the endocrine disorders in patients with polycystic ovary syndrome (PCOS). The clearance of EEDs from the human body is regulated by the glucuronidation of UDP-glucuronosyltransferases (UGT). This study aimed to analyze the relationship of UGT1A1, UGT2B7, and UGT2B15 polymorphisms with the metabolism of EEDs in patients with PCOS.Methods:A total of 357 Chinese women (119 PCOS cases and 238 controls) were genotyped for polymorphisms of UGT1A1G71R, UGT2B7H268Y, and UGT2B15D85Y. The plasma concentrations of EEDs were measured by the gas chromatography-mass spectrometry method. The association between UGT polymorphisms and the serum level of EEDs in patients with PCOS was analyzed.Results:The UGT2B7H268Y single nucleotide polymorphism was associated with an increased risk of PCOS. The homozygous polymorphism (TT) of UGT2B7H268Y showed higher bisphenol A and PAEs concentrations in serum. However, a single nucleotide polymorphism on UGT2B15D85Y expression was associated with a decreased risk of PCOS. Subjects homozygous for the T allele of UGT2B15D85Y had a significant effect on phthalates in the blood. In addition, our results also showed that the homozygous polymorphism (TT) of UGT2B7H268Y and UGT2B15D85Y was associated with the capacity of the excretion of androgen in patients with PCOS.Conclusions:Our study reported the novel associations between the UGT polymorphisms and EEDs concentrations in patients with PCOS, supporting the relevance of genetic differences in EEDs metabolism, which might be considered as an etiology of PCOS.

Influence of Polymorphisms on Mycophenolate Mofetil - Induced Diarrhoea in Renal Transplanted Children

Purpose: The objective of this study was to investigate the factors involved in mycophenolate mofetil (MMF) disposition on the risk of diarrhoea in renal transplanted children. Methods: Patients’ characteristics, immunosuppression and polymorphisms of UGT1A8, UGT1A9, UGT2B7, ABCC2, IMPDH1, and IMPDH2 genes were explored. Statistical analyses were performed using logistic regression. Results: Eighty three renal transplanted patients were included and 28/83 (33%) developed diarrhoea requiring MMF discontinuation or switched to the enteric-coated formulation EC-MPS during follow-up. In the multivariate analysis, the risk of diarrhoea was significantly higher in ABCC2 -24CC wild-type patients carrying IMPDH2 IVS7 + 10 T>C variant. Conclusion: IMPDH2 (IVS7+10T>C) and ABCC2 (c.-24C>T) are biomarkers associated with diarrhoea in children treated with MMF.

Genotypic and allelic frequencies analysis of the 19 T˃G polymorphism of the UGT1A6 gene in Mexican mestizo population of the state of Puebla

UGT1A6 catalyzes the glucuronidation of several xenobiotics and drugs widely used. Changes in the glucuronidation rate are attributed to inter-personal and inter-ethnic variations, that can impact the expression or enzyme function. Frequencies of genetic polymorphisms of UGT1A6 have been reported in another countries; however, there are no date of frequencies in the Mexican population. The aim of this work was to determine the genotypic and allelic frequencies of UGT1A6 19T˃G in a Mexican mestizo population of the state of Puebla and compare them with the frequencies observed in other populations. Peripheral blood DNA was obtained from 60 healthy adults and 19 T˃G alleles were identified by the PCR-RFLP technique. Our results were compared with those observed in other ethnic groups, and we observed that our frequencies were lower than those reported in Chinese, Korean, Japanese, Hindu, and Greek populations. These results must be considered to make decisions when choosing the drugs administered to different ethnic groups.

UGT1A1*28 gene polymorphism was not associated with the risk of neonatal hyperbilirubinemia: a meta-analysis

Background This study aimed to evaluate the relationship between UGT1A1*28 gene polymorphism and the risk of neonatal hyperbilirubinemia (NHBI). Methods The studies meet certain selection condition which was obtained from databases such as PubMed, Embase, and Cochrane Library. Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed according to criteria such as country. Hardy–Weinberg’s equilibrium (HWE) tests were performed on the control group using chi-square test, while the evaluation index was represented by odds ratio (OR) and 95% confidence interval (CI). Egger’s test and sensitivity analysis were used to evaluate the publication bias and reliability, repetitively. Results Totally, four studies with high overall quality were enrolled in this study. No association was observed between UGT1A1*28 gene polymorphisms and NHBI in allele model (TA7 versus TA6, OR (95% CI) = 2.13 (0.81–5.62), p = .13), codominance models (TA7/6 versus TA6/6, OR (95% CI) = 2.94 (0.90–9.57), p = .07; TA7/7 versus TA6/6, OR (95% CI) = 2.08 (0.37–11.52), p = .40), recessive model (TA7/7 versus TA6/6 + TA7/6, OR (95% CI) = 1.44 (0.41–5.14), p = .57), and dominant model (TA7/7 + TA7/6 versus TA6/6, OR (95% CI) = 2.92 (0.84–10.12), p = .09). Furthermore, there was no publication bias found in current meta-analysis. Conclusions Gene polymorphism of UGT1A1*28 might not be associated with the risk of NHBI.

ABCC2 c.-24 C>T single-nucleotide polymorphism was associated with the pharmacokinetic variability of deferasirox in Chinese subjects.

Our aim was to evaluate the influence of genetic polymorphisms involved in the metabolism and transportation of deferasirox on deferasirox pharmacokinetics in the Chinese population. Thirty-eight healthy Chinese subjects were administered with a single dose of 20 mg kg-1 deferasirox. Allelic discriminations for eight single-nucleotide polymorphisms (SNPs) in UDP-glucuronosyltransferase 1A1, 1A3 (UGT1A1, UGT1A3), multidrug resistance protein 2 (MRP2, ABCC2), and breast cancer resistance protein (BCRP, ABCG2) were performed. The concentrations of deferasirox in the plasma were determined by UPLC-MS/MS. Subjects carrying ABCC2 c.-24 T allele had a 65% higher clearance (CL/F) and 42% lower area under the concentration-time curve from 0 to 72 h (AUC0-72h) as compared with non-carriers (P = 0.008, P = 0.011, respectively). ABCC2 c.-24 T was also associated with 59% shorter half-life (T1/2) and 17% shorter mean residence time (MRT) (P = 0.030, P = 0.014, respectively). ABCC2 1249A was associated with a marginal increase in deferasirox Cmax (P = 0.07). Genetic polymorphisms of UGT1A1, UGT1A3, and ABCG2 did not significantly influence the pharmacokinetics of deferasirox. Subjects with UGT1A1 211GG-(-1352)CC-(-3156)GG haplotype had higher AUC0-72h than others. Since only two subjects were recruited in the GG-CC-GG group, further confirmative studies were warranted. ABCC2 c.-24 C>T was associated with the pharmacokinetic variability of deferasirox in Chinese subjects. This study revealed an important role of MRP2 in the pharmacokinetics of deferasirox and drew attention to drug combination with MRP2 inhibitors like cyclosporine and methotrexate in deferasirox therapy.

Uridine diphosphate glucuronosyl transferase 1A (UGT1A1) promoter polymorphism in young patients with sickle cell anaemia: report of the first cohort study from Nigeria

Background(TA) n repeat sequence (rs8175347) of UGT1A1 gene promoter polymorphism is associated with serum bilirubin levels and gallstones among different sickle cell anaemia (SCA) populations. There are no data on UGT1A1 polymorphisms and their impact on Nigerian SCA patients. In this study, we determined the distribution of the UGT1A1 (TA) n genotypes among a group of young Nigerian SCA patients and healthy controls. In addition, the influence of UGT1A1 (TA) n genotypes on the laboratory and clinical events among the patients was determined.MethodsThe distribution of the UGT1A1 (TA) n genotypes among 101 young Nigerian SCA patients and 64 normal appropriate controls were determined and studied. The UGT1A1 (TA) n genotypes were further classified into subgroups and used to differentiate the clinical events and laboratory parameters of the patients.ResultsFour (TA) n alleles:(TA)5, 6, 7, and 8 were found. These were associated with 10 genotypes: TA5/5, 5/6, 5/7, 5/8, 6/6, 6/7, 6/8, 7/7, 7/8, 8/8. The normal (wild-type)-(TA) 6/6), low- (TA) 7/7, 7/8, 8/8), intermediate- (TA) 5/7, 5/8, 6/7, 6/8), and high-activity (TA) 5/5, 5/6,) genotypes were found in 24.8, 24.8, 41.5, and 8.9% patients and 20.3, 15.6, 61, and 3.1% controls respectively. The general genotype distribution of the patients and control group were not significantly different. There were significant differences in serum bilirubin and lactate dehydrogenase (LDH) of the patients when differentiated by the UGT1A1 (TA) n genotypes (p<0.05). Asymptomatic gallstones were found in 5.9% of patients and were significantly of the low-activity genotypes sub-group 5 (20%) vs 1(1.3%) p = 0.0033. Although, bilirubin and fetal hemoglobin (HbF) of patients with gallstones were significantly different from those without gallstone, only the serum bilirubin was associated with UGT1A1 (TA) n genotypes on multivariate analysis (p < 0.0001).ConclusionThis study highlights the contribution of UGT1A1 polymorphisms, a non-globin genetic factor, to the laboratory and clinical manifestations of young Nigerian SCA patients for the first time. It also shows that children with co-inheritance of low UGT1A1 (TA) n affinity genotypes may be at risk of gallstone, hence the need to follow them up.

The efficacy and safety of FOLFIRI+BEV/mXELIRI+BEV by UGT1A1 polymorphisms in metastatic colorectal cancer AXEPT trial

Abstract Background Irinotecan have been well known to correlate between UGT1A1 polymorphisms (UGT1A1) and adverse events. Modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1 to14 every 3 weeks) has shown non inferiority of overall survival compared with FOLFIRI based on Asian XELIRI ProjecT (AXEPT) as second line chemotherapy for patients with mCRC. In this preplanned analysis of the AXEPT trial, we evaluated the relationship between UGT1A1 and the efficacy and safety of irinotecan-based chemotherapy. Methods Patients were randomized FOLFIRI ± bevacizumab (BV) or modified XELIRI ± BV based on UGT1A1 results (wild type, heterozygosity, and homozygosity). With regard to irinotecan dosage in both treatment arms, the reduced dosage (150mg/m2) were administered in case of homozygosity. Assessed endpoints were overall survival (OS), progression free survival (PFS), overall response rate (ORR), relative dose intensity (RDI) and safety. Result UGT1A1 was available for all 650 randomized patients (wild type, 309 (47.5%) heterozygosity, 291 (44.8%) and homozygosity, 50 (7.7%)). Median OS was of patients with a wild/hetero/homo was 14.3, 18.3 and 9.1 months in FOLFIRI arm and 18.1, 16.3 and 13.0 months in mXELIRI arm, respectively. Median PFS of patients with a wild/hetero/homo was 6.8, 8.8 and 4.8 months in FOLFIRI arm and was 8.3, 8.7 and 6.5 months in mXELIRI arm, respectively. Grade 3, 4 toxicities of special interests (wild/hetero/homo) were neutropenia (35.9%/50.4%/45.8% in FOLFIRI arm and 17.0%/15.7%/21.7% in mXELIRI arm), febrile neutropenia (5.9%/2.3%/4.2% in FOLFIRI arm and 1.4%/4.3%/8.7% in XELIRI arm), and diarrhea (1.3%/6.0%/0% in FOLFIRI arm and 4.8%/10.7%/0% in mXELIRI arm). Conclusions mXELIRI±BV was showed the good efficacy and well tolerated in patients with all UGT1A1 polymorphisms. mXELIRI+BV could be an alternative to FOLFIRI as a standard second line backbone treatment for mCRC.

Glomerular Filtration Rate Is a Major Predictor of Clearance of Oxcarbazepine Active Metabolite in Adult Chinese Epileptic Patients: A Population Pharmacokinetic Analysis.

Oxcarbazepine (OXC) is almost completely metabolized to its10-monohydroxy derivative (MHD), which is responsible for the pharmacological effects of the drug. Several studies have described the population pharmacokinetics (PPK) of MHD in pediatric patients, but little is known about its pharmacokinetics in adult patients. In addition, no study to date has proposed a model to investigate the influence of genetic polymorphisms on MHD pharmacokinetics. The aim of this study was to establish a PPK model of MHD to investigate the effects of genetic polymorphisms in UGT2B7, UGT1A9, ABCB1, and ABCB2 in adult Chinese patients with epilepsy and to develop a new dosage guideline for OXC. Data were prospectively collected from 187 adult patients with epilepsy who were taking OXC. MHD trough concentrations were detected by enzyme-multiplied immunoassay. Patients were genotyped for 4 single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Other covariates included sex, age, body weight (BW), hepato-renal function, and concomitant medications. Data were analyzed using the nonlinear mixed effects modelling software. The apparent clearance (CL) of MHD was significantly influenced by glomerular filtration rate and BW, and was unrelated to other covariates such as genetic polymorphisms and coadministration with levetiracetam, lamotrigine, and topiramate. Moreover, a new dosage guideline was proposed based on the final model to individualize OXC regimens for adult patients with varying BW and renal function. Glomerular filtration rate was first found as an important covariate influencing MHD CL. A PPK model was established to estimate the individual MHD CL for adult patients taking OXC and may be applied for individualizing doses in the target population.

Interethnic Variations of UGT1A1 and UGT1A7 Polymorphisms in the Jordanian Population.

Glucuronidation is one of the most important phase II metabolic pathways. It is catalyzed by a family of UDP-glucuronosyltransferase enzymes (UGTs). UGT1A1 and UGT1A7 catalyze the glucuronidation of a diverse range of medications, environmental chemicals and endogenous compounds. Polymorphisms in the UGT1A gene could potentially be significant for the pharmacological, toxicological and physiological effects of the enzymes. The UGT1A gene is polymorphic among ethnic groups and the aim of this study was to investigate the different UGT1A1 and UGT1A7 polymorphisms in Circassians, Chechens and Jordanian-Arabs. A total of 168 healthy Jordanian-Arabs, 56 Circassians and 54 Chechens were included in this study. Genotyping of 20 different Single-nucleotide polymorphism (SNPs) was done by using polymerase chain reaction- DNA sequencing. We found that Circassians and Chechens have significantly higher allele frequencies of UGT1A7*2, UGT1A7*3 and UGT1A7*4 than the Jordanian-Arab population, but all three populations have similar frequencies of UGT1A1*28. Therefore, Circassians and Chechens are expected to have significantly lower levels of the UGT1A7 enzyme with almost 90% of these populations having genes that encode low or intermediate enzyme activity. This inter-ethnic variation in the UGT1A alleles frequencies may affect drug response and susceptibility to cancers among different subethnic groups in Jordan. Our results can also provide useful information for the Jordanian population and for future genotyping of Circassian and Chechen populations in general.

Molecular biomarkers and precision medicine in colorectal cancer: a systematic review of health economic analyses.

An increased understanding of the biology of colorectal cancer (CRC) has fuelled identification of biomarkers with potential to drive a stratified precision medicine care approach in this common malignancy.We conducted a systematic review of health economic assessments of molecular biomarkers (MBMs) and their employment in patient stratification in CRC. Our analysis revealed scenarios where health economic analyses have been applied to evaluate the cost effectiveness of MBM-guided clinical interventions: (i) evaluation of Dihydropyrimidine dehydrogenase gene (DPYD) status to identify patients susceptible to 5-Fluouracil toxicity; (ii) determination of Uridine 5′-diphospho- glucuronosyltransferase family 1 member A1 gene (UGT1A1) polymorphism status to help guide irinotecan treatment; (iii) assessment of RAS/RAF mutational status to stratify patients for chemotherapy or Epidermal Growth Factor Receptor (EGFR) therapy and (iv) multigene expression analysis (Oncotype Dx) to identify and spare non-responders the debilitating effects of particular chemotherapy interventions.Our findings indicate that Oncotype Dx is cost-effective in high income settings within specific price points, by limiting treatment toxicity in CRC patients. DPYD status testing may also be cost effective in certain settings to avoid specific 5-FU toxicities post treatment. In contrast, current research does not support UGT1A1 polymorphism status as a cost-effective guide to irinotecan dosing, while the health economic evidence to support testing of KRAS/NRAS mutational status and chemo/EGFR therapy choice was inconclusive, despite its widespread adoption in CRC treatment management. However, we also show that there is a paucity of high-quality cost-effectiveness studies to support clinical application of precision medicine approaches in CRC.

Study of Gilbert's Syndrome-Associated UGT1A1 Polymorphism in Jaundiced Neonates of ABO Incompatibility Hemolysis Disease.

This study aimed to assess the probable relationship between icter in neonates with ABO incompatibility hemolysis and UGT1A1 gene polymorphism. There were 65 ABO hemolytic disease of the newborn (HDN) neonates of full term in the study group and 82 non-ABO HDN neonates of full term in the compared group. We tested the UGT1A1 gene mutation of neonates of ABO HDN and non-ABO HDN. We compared the incidence of hyperbilirubinemia between neonates with and without UGT1A1 mutations in the ABO HDN and non-ABO HDN, to determine the relationship between icter in neonates with ABO HDN and UGT1A1 gene polymorphism. SPSS 13.0 were used to analyze those two groups' data. There was statistically significant difference of the serum bilirubin level between the Gly71Arg homozygous and no mutation group in the ABO HDN patients (p < 0.05). When hyperbilirubinemia was defined as serum bilirubin concentration >342 μmol/L, the incidence of hyperbilirubinemia between patients of UGT1A1 and non-UGT1A1 mutations in the ABO HDN group was significantly different (p < 0.05). But in the non-ABO HDN group, no significant difference was found. Individuals with Gly71Arg homozygous contributed to their hyperbilirubinemia in ABO HDN patients.

A meta-analysis of the influence of UGT1A6 genetic polymorphisms on valproic acid pharmacokinetics .

Genetic polymorphisms in UGT1A6 might contribute to interindividual variability in the pharmacokinetics of valproic acid (VPA). However, whether the 541A>G and 552A>C variants decrease VPA concentration remains controversial. Herein, we performed a meta-analysis to evaluate the influence of UGT1A6 genetic polymorphisms on VPA pharmacokinetics. Searches, two-step selection, data extraction, and quality assessment were performed using a conventional protocol, and the influence of UGT1A6 genetic polymorphisms on concentration-to-dose ratio was quantitatively assessed by pooled analysis using the Comprehensive Meta-Analysis program. Six studies using monotherapy were included in the quantitative analysis. Concentration-to-dose ratio of 541A>G and 552A>C homozygous variant were significantly lower than that of the wild-type (WT; standardized difference in means (SDM) = -0.771, 95% confidence interval (CI) = -1.123 to -0.419; SDM = -0.879, 95% CI = -1.257 to -0.500, respectively). Differences were also significant in both child and adult subgroups analysis. For heterozygous variants, there was no significant difference in concentration-to-dose ratio between 541A>G and 552A>C heterozygous variant and WT (SDM = -0.183, 95% CI = -0.449 to 0.084; SDM = -0.275, 95% CI = -0.647 to 0.097, respectively). In conclusion, concentration-to-dose ratio for VPA monotherapy were significantly lower for UGT1A6 homozygous variants 541A>G and 552A>C than for the WT. .

Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.

While uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme in the metabolism of irinotecan, relationship between UGT1A1 genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer is not clarified. Efficacy and safety in advanced gastric cancer patients, who were tested for UGT1A1*6 and *28 genotype and treated with irinotecan monotherapy as third-line treatment from 2009 to 2014, were evaluated according to the UGT1A1*6 and *28 genotypes. Among 74 patients of the subjects, the genotypes of UGT1A1 were wild-type (WT) in 37 patients (50%), single heterozygosity (SH) in 27 (36.5%) and double heterozygosity or homozygosity (Homo/DH) in 10 (13.5%). The initial dose of irinotecan was reduced in 10 patients (27%) with WT, in 9 (33%) with SH, and in 7 (70%) with Homo/DH. Median overall survival was 6.9 months, 6.3 months, and 2.8 months in the WT, SH and Homo/DH genotypes, associated with median time to treatment failure of 2.4 months, 2.3 months, and 1.3 months, respectively. Among 36 patients with measurable lesion, disease control rates were 47.6%, 41.7% and 33.3% in the WT, SH and Homo/DH genotypes. Grade 3 or higher adverse events of special interest were neutropenia (13%, 22%, and 64% for the WT, SH and Homo/DH genotypes), febrile neutropenia (2%, 7%, and 50%) and diarrhea (6%, 5%, and 21%). The UGT1A1 polymorphism may be related to the clinical outcomes of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.

UGT1A1 polimorfizmi kao prediktivni farmakogenetički biljezi irinotekanske toksičnosti u bolesnika s metastatskim kolorektalnim karcinomom

UGT1A1 polimorfizmi kao prediktivni farmakogenetički biljezi irinotekanske toksičnosti u bolesnika s metastatskim kolorektalnim karcinomom

Study of polymorphisms of UGT1A1 and DPYD genes in chemotherapy for colorectal cancer

Background. The personalized approach implies an individual choice of medicines and their doses for the patient, providing the most effective and safe pharmacotherapy. Objective: analysis of the frequencies of UGT1A1 and DPYD polymorphisms and comparison of genotyping data with irinotecan and 5-fluorouracil-induced toxicity, respectively.Materials and Methods. Venous blood of 94 Caucasian patients (46 men and 48 women, median age 61 years). The *6 and *28 UGT1A1 alleles were identified by pyrosequencing, and the *2А DPYD allele was identified by Real-time PCR.Results. The genotyping of 94 patients with colon cancer did not reveal the *2A SNP in the DPYD gene. The frequency rate of the *6 and *28 alleles of the UGT1A1 gene was 0.346 and 0.016, respectively. 24 % of patients receiving chemotherapy with 5-fluorouracil developed side effects associated with the circulatory system and the gastrointestinal tract. Hematological and nonhematological toxic reactions were noted in 48 % and 50 % of patients receiving irinotecan. Severe bilirubinemia was associated with the *28/*28 UGT1A1 genotype. The presence of a high-risk genotype (*28/*1, *28/*28 UGT1A1) correlated with the development of side effects (p=0.040).Conclusion. The absence of carriers of the *2А DPYD allele in the sample with a significant proportion of pronounced adverse toxic reactions to 5-fluorouracil causes the need for the inclusion of new polymorphisms of the DPYD gene in pharmacogenetic testing. The inclusion of genotyping of UGT1A1 polymorphisms into a complex of preliminary examination is advisable when planning treatment with irinotecan.

The Effect of Polymorphism in UGT1A4 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Patients With Breast Cancer in China

IntroductionUGT1A4 is a major enzyme responsible for the glucuronidation of tamoxifen (TAM) and its metabolites. Genetic variations in the UGT1A4 gene could have a significant impact on the clinical efficacy of TAM. This study was performed to validate the association between UGT1A4 polymorphisms and the clinical outcomes for patients with breast cancer who received adjuvant TAM. Patients and MethodsA total of 773 patients with breast cancer who received adjuvant TAM (n = 321) or aromatase inhibitors (n = 452) at the National Cancer Center in China were analyzed. Through a series of screenings, the single nucleotide polymorphism rs869283 (c.-1180G>A) in the promoter region of the UGT1A4 gene was selected. The associations of rs869283 genotype with disease-free survival (DFS) and clinicopathologic characteristics were analyzed. ResultsA total of 608 (78.7%) patients were wild-type G/G genotype, 154 (19.9%) patients were G/A genotype, and 11 (1.4%) patients were A/A genotype. In the TAM treatment group, patients with A/A or G/A genotype had a lower 5-year DFS rate than those with the wild-type G/G genotype (69.3% vs. 83.7%; P = .031). The rs869283 genotype remained an independent prognostic marker for DFS in multivariate analysis (hazard ratio, 1.74; P = .014). No association between the rs869283 genotype and DFS was found in patients who received AIs (P = .772). ConclusionsOur findings showed that patients with the UGT1A4 rs869283 G/A or A/A genotype received less benefit from adjuvant TAM treatment than those with the G/G genotype. Further studies are warranted to confirm our findings.