UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females.
OBJECTIVE
The objective of this study was to investigate the prevalence of different polymorphisms and haplotypes associated with individual variations in pharmacokinetics and drug toxicity in the uridine-diphosphate glucuronosyl transferase (UGT) 1A gene in a Swedish cohort (248 healthy volunteers) and in 14 different ethnic groups. We also estimated UGT1A genotype-dependent glucuronidation efficiency using the endogenous substrate bilirubin as an indicator.


METHODS
Pyrosequencing-based genotyping assays were used to determine the different polymorphisms and haplotypes.


RESULTS
Haplotype analysis of the UGT1A1 (*1*28), UGT1A6 (*1*2), and UGT1A7(*1*2*3*4) allelic variants showed that three major haplotypes constituted 84% of the allelic variants in the cohort. We identified 15 haplotypes altogether from all groups, including previously undescribed haplotypes. Testing for the association of genotype and total bilirubin levels (nonfasting) in plasma disclosed that homozygous carriers of the TA allele, irrespective of haplotype combinations, had increased levels of bilirubin compared with noncarriers, but a gender-associated difference was observed.


CONCLUSIONS
In a Swedish cohort, several genetic variants in the UGT1A gene are common, but prevalence in a population may differ because of ethnicity. A phenotype based on bilirubin levels has limitations in serving as an indicator of pharmacogenetic differences in glucuronidation due to the influence of gender. Because of possible substrate overlap regarding different UGT1A isoforms, determination of haplotypes of potential cis-acting polymorphisms in the UGT1A gene should be considered in pharmacogenetic association studies regarding drugs that undergo glucuronidation.
Mercke Odeberg
J
J
Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
Andrade
J
J
Holmberg
K
K
Hoglund
P
P
Malmqvist
U
U
Odeberg
J
J
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001663:Bilirubin / Q000097:blood*; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D010802:Phylogeny; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D013548:Sweden; D044465:White People / Q000235:genetics; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D000099148:UGT1A1 Enzyme; C524630:UGT1A7 protein, human