Lack of association between common polymorphisms in UGT1A9 and gene expression and activity.
Interindividual variability in the glucuronidation of xenobiotics metabolized by UDP-glucuronosyltransferase 1A9 (UGT1A9) suggests the presence of functional UGT1A9 variants. The aim of this study was to evaluate whether the putative functionality of the UGT1A9 variants-118T(9>10) (rs3832043), I399C>T (rs2741049), -275T>A (rs6714486), and-2152C>T (rs17868320) could be confirmed in an independent study. UGT1A9 genotypes and UGT1A9 activity (i.e., flavopiridol and mycophenolic acid glucuronidation) were determined in 46 Caucasian human livers. mRNA levels were quantitated by real-time polymerase chain reaction in 35 of these livers. In addition, samples from 60 unrelated Caucasians belonging to the HapMap Project were also genotyped to confirm the allele frequencies and linkage disequilibrium (LD) pattern observed in our Caucasian livers. The allele frequencies of the-118T(9>10), I399C>T, -275T>A, and-2152C>T variants were 0.39, 0.39, 0.02, and 0.02 in the livers, respectively. The I399C>T variant was in complete LD (r(2) = 1) with-118T(9>10) (linked alleles: C and T(9), respectively). Complete LD between these two variants was also found in the HapMap samples (frequencies of-118T(9>10) and I399C>T = 0.38). I399C>T and-118T(9>10) correlated with neither UGT1A9 activities nor mRNA levels. Because of the low frequencies of the-275T>A and-2152C>T variants, an effect on phenotype could not be evaluated. Our data demonstrate that the common I399C>T and-118T(9>10) polymorphisms do not explain interindividual variation in hepatic UGT1A9 activity and mRNA expression and are in complete LD in the donor liver samples we studied.
Ramírez
Jacqueline
J
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Liu
Wanqing
W
Mirkov
Snezana
S
Desai
Apurva A
AA
Chen
Peixian
P
Das
Soma
S
Innocenti
Federico
F
Ratain
Mark J
MJ
D002460:Cell Line; D015331:Cohort Studies; D005419:Flavonoids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D017930:Genes, Reporter; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000201:enzymology*; D049409:Luciferases, Firefly; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D010641:Phenotype; D010880:Piperidines / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013379:Substrate Specificity; D014162:Transfection; D000090264:UDP-Glucuronosyltransferase 1A9
D005419:Flavonoids; D020719:Glucuronides; D010880:Piperidines; D012333:RNA, Messenger; C000715591:UGT1A9 protein, human; C077990:alvocidib; C113145:mycophenolic acid glucuronide; D049409:Luciferases, Firefly; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D009173:Mycophenolic Acid