Population genetic structure of variable drug response

Abstract

Geographic patterns of genetic variation, including variation at drug metabolizing enzyme (DME) loci and drug targets, indicate that geographic structuring of inter-individual variation in drug response may occur frequently. This raises two questions: how to represent human population genetic structure in the evaluation of drug safety and efficacy, and how to relate this structure to drug response. We address these by (i) inferring the genetic structure present in a heterogeneous sample and (ii) comparing the distribution of DME variants across the inferred genetic clusters of individuals. We find that commonly used ethnic labels are both insufficient and inaccurate representations of the inferred genetic clusters, and that drug-metabolizing profiles, defined by the distribution of DME variants, differ significantly among the clusters. We note, however, that the complexity of human demographic history means that there is no obvious natural clustering scheme, nor an obvious appropriate degree of resolution. Our comparison of drug-metabolizing profiles across the inferred clusters establishes a framework for assessing the appropriate level of resolution in relating genetic structure to drug response.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Allele frequencies at each DME gene in the STRUCTURE-defined clusters.
Figure 2: Allele frequencies at each of the DME variants in the ethnically labeled groups.

References

  1. 1

    Weber, W.W. Pharmacogenetics (Oxford University Press, Oxford, 1997).

  2. 2

    Evans, W.E. & Relling, M.V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).

  3. 3

    Gough, A.C. et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347, 773–776 (1990).

  4. 4

    Kagimoto, M., Heim, M., Kagimoto, K., Zeugin, T. & Meyer, U.A. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J. Biol. Chem. 265, 17209–17214 (1990).

  5. 5

    Blum, M., Demierre, A., Grant, D.M., Heim, M. & Meyer, U.A. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc. Natl Acad. Sci. USA 88, 5237–5241 (1991).

  6. 6

    Bernal, M.L. et al. Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics 9, 657–660 (1999).

  7. 7

    Meyer, U.A. & Zanger, U.M. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu. Rev. Pharmacol. Toxicol. 37, 269–296 (1997).

  8. 8

    International Conference on Harmonisation. Ethnic Factors in the Acceptability of Foreign Clinical Data. (International Conference on Harmonisation, 1998).

  9. 9

    Wilson, J.F. & Goldstein, D.B. Consistent long-range linkage disequilibrium generated by admixture in a Bantu–Semitic hybrid population. Am. J. Hum. Genet. 67, 926–935 (2000).

  10. 10

    Pritchard, J.K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

  11. 11

    Seielstad, M.T., Minch, E. & Cavalli-Sforza, L.L. Genetic evidence for a higher female migration rate in humans. Nature Genet. 20, 278–280 (1998).

  12. 12

    Kohlmeier, L., DeMarini, D. & Piegorsch, W. Gene-nutrient interactions in nutritional epidemiology. in Design Concepts in Nutritional Epidemiology (eds. Margetts, B. & Nelson, M.) 312–337 (Oxford University Press, Oxford, 1997).

  13. 13

    Raymond, M. & Rousset, F. An exact test for population differentiation. Evolution 49, 1280–1283 (1995).

  14. 14

    Krajinovic, M., Labuda, D., Richer, C., Karimi, S. & Sinnett, D. Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 93, 1496–1501 (1999).

  15. 15

    Gaedigk, A. et al. NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations. Pharmacogenetics 8, 305–313 (1998).

  16. 16

    Goldstein, J.A. & Blaisdell, J. Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism. Methods Enzymol. 272, 210–218 (1996).

  17. 17

    Gaedigk, A. et al. Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data. Pharmacogenetics 9, 669–682 (1999).

  18. 18

    Basile, V.S. et al. A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. Mol. Psychiatry 5, 410–417 (2000).

  19. 19

    Ferguson, R.J. et al. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J. Pharmacol. Exp. Ther. 284, 356–361 (1998).

  20. 20

    Daly, A.K. et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6, 193–201 (1996).

  21. 21

    Sachse, C., Brockmoller, J., Bauer, S. & Roots, I. Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br. J. Clin. Pharmacol. 47, 445–449 (1999).

Download references

Acknowledgements

D.B.G. is a Royal Society/Wolfson Research Merit Award holder.

Author information

Correspondence to David B. Goldstein.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wilson, J., Weale, M., Smith, A. et al. Population genetic structure of variable drug response. Nat Genet 29, 265–269 (2001). https://doi.org/10.1038/ng761

Download citation

Further reading