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Review
. 2011 Mar 24;364(12):1144-53.
doi: 10.1056/NEJMra1010600.

Genomics and drug response

Liewei Wang  1 , Howard L McLeod, Richard M Weinshilboum
Affiliations
Review

Genomics and drug response

Liewei Wang et al. N Engl J Med. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Warfarin Pharmacogenomics
Panels A and B show Manhattan plots of P values (negative log10) for the association between single-nucleotide-polymorphisms (SNPs) across the genome and the final warfarin dose. The horizontal line indicates a P value of 1.5×10−7, which is the level of genomewide statistical significance. In Panel A, the results of univariate regression analysis highlight SNP signals in or near CYP2C9 and VKORC1. In Panel B, the results of multivariate regression analysis with adjustment for the contributions of CYP2C9 and VKORC1 show the CYP4F2 signal on chromosome 19. (Data are from Takeuchi et al.) The label *2 indicates the nonsynonymous SNP rs1799853, *3 indicates the non-synonymous SNP rs1057910, and the *2*3 composite indicates the SNP rs4917639. M denotes mitochondrial SNPs. Panel C shows the sites of action of warfarin in the vitamin K cycle, as well as the roles of CYP2C9, CYP4F2, and VKORC1 in this process.
Figure 2
Figure 2. Risk of Hospitalization among Patients Who Underwent VKORC1 and CYP2C9 Genotyping, as Compared with a Historical Control Group, 6 Months after the Initiation of Warfarin Therapy
Shown are the rates of hospitalization for any cause (Panel A) and for bleeding or thromboembolism (Panel B). There was a significant benefit for patients who had undergone genotyping for the presence of VKORC1 and CYP2C9 variants that have been significantly associated with the risk of over-anticoagulation. Data are from Epstein et al.
Figure 3
Figure 3. Cancer Pharmacogenomics and Tumor and Germline Genomes
Both the tumor genome (e.g., in the case of gefitinib therapy) and the patient's germline genome (e.g., in the case of irinotecan therapy) can contribute to pharmacogenomic variation in response to antineoplastic drugs. The tumor genome plays a critical role in the response to gefitinib (Panel A), since the sensitivity of non–small-cell lung cancer to this drug is enhanced by activating mutations in the kinase domain of the gene encoding epidermal growth factor receptor (EGFR)., Tumor EGFR encoding activating mutations within the kinase domain results in enhanced tumor sensitivity to gefitinib. The rate of toxic effects associated with irinotecan (diarrhea and myelosuppression) is increased in patients with seven TA dinucleotide repeats rather than the more common six repeats in the promoter region of UGT1A1 encoding a UDP-glucuronosyltransferase in germline DNA, resulting in lower enzyme activity and a decreased rate of drug metabolism (Panel B).,
See this image and copyright information in PMC

References

    1. Weinshilboum RM, Wang L. Pharmacogenetics and pharmacogenomics: development, science, and translation. Annu Rev Genomics Hum Genet. 2006;7:223–45. - PubMed
    1. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363:166–76. - PubMed
    1. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364:1134–43. - PMC - PubMed
    1. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348:529–37. - PubMed
    1. Evans WE, McLeod HL. Pharmacogenomics — drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538–49. - PubMed

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