UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females (original) (raw)
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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References
- Evans WE, McLeod HL (2003) Pharmacogenomics–drug disposition, drug targets, and side effects. N Engl J Med 348:538–549
Google Scholar - Meisel C, Gerloff T, Kirchheiner J, Mrozikiewicz PM, Niewinski P, Brockmoller J, Roots I (2003) Implications of pharmacogenetics for individualizing drug treatment and for study design. J Mol Med 81:154–167
PubMed Google Scholar - Miners JO, McKinnon RA, Mackenzie PI (2002) Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology 181–182:453–456
Google Scholar - Bosma PJ (2003) Inherited disorders of bilirubin metabolism. J Hepatol 38:107–117
Article PubMed CAS Google Scholar - Kiang TK, Ensom MH, Chang TK (2005) UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther 106:97–132
Article PubMed CAS Google Scholar - Chowdhury JR, Chowdhury NR, Jansen PLM (2003) Bilirubin metabolism and its disorders in hepatology. In: Zakim D, Boyer TD (eds) Hepatology: a textbook of liver disease, 4th edn. Saunders, Philadelphia, pp 233–270
- Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:1171–1175
Google Scholar - Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Hasegawa Y (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60:6921–6926
Google Scholar - Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
PubMed CAS Google Scholar - Holmberg K, Persson ML, Uhlen M, Odeberg J (2005) Pyrosequencing analysis of thrombosis-associated risk markers. Clin Chem 51:1549–1552
Article PubMed CAS Google Scholar - Odeberg J, Holmberg K, Eriksson P, Uhlen M (2002) Molecular haplotyping by pyrosequencing. Biotechniques 33:1104, 1106, 1108
PubMed CAS Google Scholar - Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989
Article PubMed CAS Google Scholar - Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927
PubMed CAS Google Scholar - Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29:311–322
Article PubMed CAS Google Scholar - Abecasis GR, Cookson WO (2000) GOLD–graphical overview of linkage disequilibrium. Bioinformatics 16:182–183
Article PubMed CAS Google Scholar - Fitch WM, Margoliash E (1967) Construction of phylogenetic trees. Science 155:279–284
PubMed CAS Google Scholar - Beutler E, Gelbart T, Demina A (1998) Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA 95:8170–8174
Article PubMed CAS Google Scholar - Kohle C, Mohrle B, Munzel PA, Schwab M, Wernet D, Badary OA Bock KW (2003) Frequent co-occurrence of the TATA box mutation associated with Gilbert’s syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Biochem Pharmacol 65:1521–1527
Article PubMed CAS Google Scholar - Lampe JW, Bigler J, Horner NK, Potter JD (1999) UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics 9:341–349
PubMed CAS Google Scholar - Ando Y, Chida M, Nakayama K, Saka H, Kamataki T (1998) The UGT1A1*28 allele is relatively rare in a Japanese population. Pharmacogenetics 8:357–360
PubMed CAS Google Scholar - Ciotti M, Marrone A, Potter C, Owens IS (1997) Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications. Pharmacogenetics 7:485–495
PubMed CAS Google Scholar - Peters WH, te Morsche RH, Roelofs HM (2003) Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert’s syndrome. J Hepatol 38:3–8
Article PubMed CAS Google Scholar - Burchell B, Hume R (1999) Molecular genetic basis of Gilbert’s syndrome. J Gastroenterol Hepatol 14:960–966
Article PubMed CAS Google Scholar - Fever JP, Blanckaert N (1991) Hyperbilirubinaemia. In: McIntyre N, Benhamou J, Bircher J et al. (eds) Oxford textbook of clinical hepatology. Oxford University Press, Oxford, pp 985–991
- Manolio TA, Burke GL, Savage PJ, Jacobs DR Jr, Sidney S, Wagenknecht LE, Allman RM, Tracy RP (1992) Sex- and race-related differences in liver-associated serum chemistry tests in young adults in the CARDIA study. Clin Chem 38:1853–1859
PubMed CAS Google Scholar - Rosenthal P, Pincus M, Fink D (1984) Sex- and age-related differences in bilirubin concentrations in serum. Clin Chem 30:1380–1382
Google Scholar - Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388
Article PubMed CAS Google Scholar - Strassburg CP, Oldhafer K, Manns MP, Tukey RH (1997) Differential expression of the UGT1A locus in human liver, biliary, and gastric tissue: identification of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue. Mol Pharmacol 52:212–220
PubMed CAS Google Scholar - Gagne JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C (2002) Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 62:608–617
Article PubMed CAS Google Scholar - Hanioka N, Ozawa S, Jinno H, Ando M, Saito Y, Sawada J (2001) Human liver UDP-glucuronosyltransferase isoforms involved in the glucuronidation of 7-ethyl-10-hydroxycamptothecin. Xenobiotica 31:687–699
Google Scholar
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
- Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden
J. Mercke Odeberg, P. Hoglund & U. Malmqvist - Department of Biotechnology, Royal Institute of Technology (KTH), Stockholm, Sweden
J. Andrade, K. Holmberg & J. Odeberg - Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden
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
- Received: 21 December 2005
- Accepted: 07 April 2006
- Published: 15 August 2006
- Issue Date: October 2006
- DOI: https://doi.org/10.1007/s00228-006-0166-3