UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: I. Identification of Polymorphisms in the 5′-Regulatory and Exon 1 Regions, and Association with Human Liver UGT1A6 Gene Expression and Glucuronidation

Krishnaswamy, Soundararajan; Qin, Hao; Alrohaimi, Abdulmohsen H; Hesse, Leah M.; Moltke, Lisa L. von; Greenblatt, David J.; Court, Michael H.

doi:10.1124/jpet.104.081950

Cited by 51 publications

(38 citation statements)

References 33 publications

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“…Glucuronidation by UGTs represents a minor detoxifying pathway for ethanol 28. Alcohol treatment up‐regulates UGT1A5 expression in hepatocytes29 and moderate to severe alcohol consumption is associated with increased levels of UGT1A6 in liver 30. Other alcohol metabolism‐related genes included cytochrome P450 family 2 subfamily J member 2 ( Cyp2J2 ), involved in the oxidation pathway of ethanol into acetaldehyde at elevated ethanol concentration,31 and adenosine triphosphate binding cassette subfamily B members 1 and 2 ( ABCB1 and ABCC2 ), involved in multidrug resistance and biliary transport.…”

Section: Discussionmentioning

confidence: 99%

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Jiao

Watt

Stevenson

et al. 2018

Hepatology Communications

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Telomerase reverse transcriptase (TERT) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether TERT mutations can be detected in circulating cell‐free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on TERT C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these TERT mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of TERT mutations in The Cancer Genome Atlas HCC specimens was 44.4%. TERT mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. TERT mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of TERT mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, TERT mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with TERT mutations, and vitamin K2 was identified as an upstream regulator. Conclusion: TERT mutations are detectable in plasma cfDNA. Long‐term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. (Hepatology Communications 2018;2:718‐731)

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Section: Discussionmentioning

confidence: 99%

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Jiao

Watt

Stevenson

et al. 2018

Hepatology Communications

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“…Methods for genotyping the UGT polymorphisms have been described previously elsewhere, including UGT1A1 -53(TA) Â 5, 6, 7, or 8 (Girard et al, 2005), UGT1A6 S7A (rs6759892), T181A (rs2070959), and R184S (rs1105879) (Krishnaswamy et al, 2005), UGT1A9 -275T.A (rs6714486) (Girard et al, 2004), UGT2B15*2 (rs1902023, D85Y) , and UGT1A-39UTR c.2042C.G (rs8330) (Court et al, 2013). Taqman allele discrimination assays were used to genotype DNA samples on a ABI 7300 (Applied Biosystems, Foster City, CA) real-time polymerase chain reaction (PCR) instrument for the CYP3A5*3 (rs776746; ABI assay C_26201809-30), CD44 I479T (rs1467558; ABI assay C_2143203_10), and BHMT1 R239Q (rs3733890; ABI assay C_11646606_20) single-nucleotide polymorphisms (SNPs).…”

Section: Methodsmentioning

confidence: 99%

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

et al. 2013

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Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a singletime-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophenmetabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients.This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminopheninduced ALF.

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“…14 The human UGT1A genes are regulated in a tissue-specific fashion, which is considered to represent the biochemical basis of organ-specific glucuronidation activity. [15][16][17] Glucuronidation is further influenced by induction, 18,19 phosphorylation, 20 the presence of genetic variants in the UGT coding regions leading to catalytically altered proteins, 21,22 by variants of the promoter regions leading to reduced UGT transcription, 4,13,23 as well as inhibitory effects of therapeutic drugs. Commonly administered drugs with inhibitory potential include amitriptyline, 24 protease inhibitors, 25 ketoconazole, 26 and acyl glucuronide adducts of ketoprofen.…”

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confidence: 99%

Gilbert's disease and atazanavir: From phenotype to UDP-glucuronosyltransferase haplotype

et al. 2006

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Gilbert's disease leads to intermittent non-hemolytic hyperbilirubinemia by a reduction of hepatic bilirubin glucuronidation associated with the presence of the UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism. It is considered benign because it does not result in hepatocellular damage. However, pharmacogenetic analyses have linked UGT1A1*28 to drug toxicity and cancer predisposition. The protease inhibitor atazanavir (ATV) is an inhibitor of hepatic UGT activity leading to hyperbilirubinemia in individual patients. Whether this is linked specifically to UGT1A1*28 or to more complex variants influencing glucuronidation is unclear. One hundred and six ATV-treated patients were characterized and genotyped for UGT1A1*28, the UGT1A3 (-66C) and UGT1A7 (-57G) promoter variants, and UGT1A7 129K/131K . ATV treatment increased median bilirubin levels from 10 to 41 mol/L (P ‫؍‬ .001) with hyperbilirubinemia exceeding 43 mol/L in 37%. Hyperbilirubinemia over 43 mol/L was significantly associated not only with UGT1A1*28 but also with UGT1A3-66C, UGT1A7-57G, and UGT1A7 129K/131K , although these variants do not naturally occur in linkage dysequilibrium in blood donors. Homozygous combinations of UGT1A1*28 with the other variants increased from 7.4% (normal bilirubin to 42 mol/L) to 41% to 46.1% (43 to >85 mol/L), and 100% (>85 mol/L). All six patients with hyperbilirubinemia greater than 85 mol/L were homozygous for all four variants identifying a haplotype inherited on a single allele. In conclusion, the genetic variant associated with Gilbert's disease is identified as part of a haplotype of four UGT1A variants spanning three genes at the UGT1A gene locus. This haplotype predisposes to hyperbilirubinemia in ATV treatment and may have an additional role as a pharmacogenomic risk factor for drug therapy. (HEPATOLOGY 2006;44:1324-1332

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UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: I. Identification of Polymorphisms in the 5′-Regulatory and Exon 1 Regions, and Association with Human Liver UGT1A6 Gene Expression and Glucuronidation

Cited by 51 publications

References 33 publications

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

Gilbert's disease and atazanavir: From phenotype to UDP-glucuronosyltransferase haplotype

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