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UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females

  • Pharmacogenetics
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Abstract

Objectives

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.

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Acknowledgements

We thank Gertrud Lundkvist, Åsa Håkansson, and Kerstin Weber, Department of Clinical Chemistry and Pharmacology, Lund University Hospital, for assisting with the clinical part, and Agneta Kristensen, Department of Clinical and Experimental Pharmacology, Lund University Hospital, for assisting with DNA preparation. The KTH DNA typing facility is financed by a grant from the Wallenberg Consortium North Foundation.

We declare that the study was performed in accordance with ICH GCP guidelines according to the EU directive 2001/20 and Swedish law. The study was approved by the ethics committee at Lund University, Sweden.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden

    J. Mercke Odeberg, P. Hoglund & U. Malmqvist

  2. Department of Biotechnology, Royal Institute of Technology (KTH), Stockholm, Sweden

    J. Andrade, K. Holmberg & J. Odeberg

  3. Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden

    J. Odeberg

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  1. J. Mercke Odeberg
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  2. J. Andrade
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  3. K. Holmberg
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  4. P. Hoglund
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Correspondence to J. Odeberg.

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Mercke Odeberg, J., Andrade, J., Holmberg, K. et al. UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females. Eur J Clin Pharmacol 62, 829–837 (2006). https://doi.org/10.1007/s00228-006-0166-3

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  • DOI: https://doi.org/10.1007/s00228-006-0166-3

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