Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups.
Genetic variation in UDP-glucuronosyltransferase 1A1 (UGT1A1)expression has several important clinical implications. UGT1A1 basal transcription is affected by a polymorphic (TA)n repeat, and another important regulatory element is the phenobarbital-responsive enhancer module (PBREM) which might contain variants affecting inducible gene expression. We assessed the extent of linkage disequilibrium between the (TA)n polymorphism and variants in the PBREM and UGT1A1 promoter. We also investigated the relationship between PBREM-(TA)n haplotypes and the glucuronidation rate of the UGT1A1 substrate SN-38. DNAs from 83 human livers were genotyped for the (TA)n polymorphism and microsomes from the same livers were phenotyped for SN-38 glucuronidation. The (TA)n polymorphism was genotyped in 24 additional African-Americans included in the Human Variation Panel (Coriell Institute). A 606-bp region spanning the PBREM was sequenced in 81 liver and a subset of 22 Human Variation Panel DNAs and six variants were found. The -3279G T and -3156G A variants are common (0.39 and 0.30, respectively). -3279G T is more common in Caucasians than African-Americans (P = 0.001). In Caucasians, linkage disequilibrium was highly significant between sites -3279, -3156, and the (TA)n polymorphism (P < 0.0001). In contrast, in African-Americans, only marginal levels of significance were observed between (TA)n and -3279 (P = 0.02) and between -3279 and -3156 (P = 0.04). Ten promoter haplotypes were identified. Haplotype I is the most common (0.39), from which haplotype II (0.15) differs at position -3279. SN-38G formation rates were correlated with (TA)n genotypes. This study showed that (i) common promoter variants are in linkage disequilibrium and (ii) the haplotype structure of promoter is probably different between Caucasians and African-Americans.
Innocenti
Federico
F
Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, Cancer Research Center, The University of Chicago, Chicago, IL 60637, USA.
Grimsley
Carrie
C
Das
Soma
S
Ramírez
Jacqueline
J
Cheng
Cheng
C
Kuttab-Boulos
Hala
H
Ratain
Mark J
MJ
Di Rienzo
Anna
A
D001741:Black or African American; D001483:Base Sequence; D001663:Bilirubin / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D015810:Linkage Disequilibrium; D008862:Microsomes, Liver / Q000201:enzymology*; D008969:Molecular Sequence Data; D010634:Phenobarbital / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D059004:Topoisomerase I Inhibitors; D044465:White People; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D010634:Phenobarbital; D059004:Topoisomerase I Inhibitors; D000099148:UGT1A1 Enzyme