Genetic susceptibility to adverse drug effects - Epidemiology ...

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Common ABCB1 variants are associated with increased digoxin serum concentration The main strength of our study compared to earlier studies on ABCB1 SNPs and digoxin serum concentrations resides in the large number of digoxin users from a population based cohort. Selection bias is unlikely since SNPs were in HWE and the distribution of genotypes did not differ between the study population and the whole Rotterdam Study cohort or digoxin users without a serum concentration assessment. Furthermore, digoxin prescribing and serum concentration assessment were blinded for genotype. The influence of confounding, which was probably limited, was further minimized by applying a multivariate regression model including the most relevant determinants of digoxin serum concentration. One limitation is that the present study does not allow an estimation of the influence of ABCB1 SNPs on treatment efficacy. Another limitation involves measurement inaccuracies. Digoxin concentration sampling under everyday circumstances is often, incorrectly, performed without regarding the time interval since last digoxin dose in clinical practice. 27 We could not verify the influence of such inaccuracy since the time of the last dose of digoxin and the time of drawing the blood sample had not been registered consistently. Any measurement errors (misclassification of the outcome) were most likely random and would have led to a conservative estimate of the actual effect. We limited the effect of dose titration based on serum concentrations by using only the first serum assessment of each subject. Furthermore, the sensitivity analyses, limited to subjects who had their first prescription of digoxin after the laboratory they were referred to started contributing data, showed similar effect estimates. Finally, this study was performed in a European population. The effect of ABCB1 SNPs on serum digoxin concentrations may not automatically be valid for other populations since haplotype allele variation might differ and variation in expression of other transporter proteins might play a role. For instance, the 2677A variant is more frequent in certain Asian populations, 19, 28 but it was too rare in our study population to investigate its effect. In conclusion, we found that the ABCB1 C1236T, G2677T and C3435T variants were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population. The association was strongest for the 1236-2677-3435 TTT haplotype, suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. The findings in this study might provide a starting point for strategies toward improving the efficacy and safety of digoxin therapy. As an efflux transporter, ABCB1 influences pharmacokinetics of many drugs. 7 Therefore, these variants could have important implications for individual variation in drug concentrations and susceptibility to toxic effects. 29-32 41
Chapter 3.1 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455(1):152-62. Ueda K, Cardarelli C, Gottesman MM, et al. Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci U S A 1987;84(9):3004-8. Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 1987;84(21):7735-8. Cordon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A 1989;86(2):695-8. Sugawara I, Kataoka I, Morishita Y, et al. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 1988;48(7):1926-9. Klimecki WT, Futscher BW, Grogan TM, et al. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 1994;83(9):2451-8. Marzolini C, Paus E, Buclin T, et al. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004;75(1):13-33. http://www.ncbi.nlm.nih.gov/SNP/snp. NCBI. (Accessed Juli 11, 2007, at http://www.ncbi.nlm.nih.gov/SNP/snp_ref. cgi?locusId=5243&chooseRs=het.) Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 2000;97(7):3473-8. Chowbay B, Li H, David M, et al. Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol 2005;60(2):159-71. Hofman A, Grobbee DE, de Jong PT, et al. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991;7(4):403-22. Fang Y, van Meurs JB, d’Alesio A, et al. Promoter and 3’-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study. Am J Hum Genet 2005;77(5):807-23. Abecasis GR, Cookson WO. GOLD--graphical overview of linkage disequilibrium. Bioinformatics 2000;16(2):182-3. Stram DO, Leigh Pearce C, Bretsky P, et al. Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals. Hum Hered 2003;55(4):179-90. Schaid DJ. Evaluating associations of haplotypes with traits. Genet Epidemiol 2004;27(4):348-64. Aarnoudse AL, Dieleman JP, Stricker BHC. Age- and gender-specific incidence of hospitalisation for digoxin intoxication. Drug Saf 2007;30(5):431-6. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347(18):1403-11. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995;275(2):1011-8. Kroetz DL, Pauli-Magnus C, Hodges LM, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003;13(8):481-94. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001;69(3):169-74. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001;70(2):189-99. Tang K, Wong LP, Lee EJ, et al. Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum Mol Genet 2004;13(8):783-97. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A “Silent” Polymorphism in the MDR1 Gene Changes Substrate Specificity. Science 2006;315(5811):525-8. Kurzawski M, Bartnicka L, Florczak M, et al. Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients. Pharmacol Rep 2007;59(1):107-11. 42
Page 1 and 2: Genetic susceptibility to adverse d
Page 3 and 4: The work presented in this thesis w
Page 5: Promotiecommissie Promotoren: Prof.
Page 10: 1 General Introduction
Page 13 and 14: Chapter 1 genome. Every SNP represe
Page 15 and 16: Chapter 1 References 1. 2. 3. 4. 5.
Page 18: 2 Quantifying the risk of adverse d
Page 21 and 22: Chapter 2 Introduction The cardiac
Page 23 and 24: Chapter 2 Table 1 Characteristics o
Page 25 and 26: Chapter 2 digoxin treatment appears
Page 27 and 28: Chapter 2 References 1. 2. 3. 4. 5.
Page 30: 3 Common variants in the ABCB1 gene
Page 33 and 34: Chapter 3.1 Introduction The ATP-Bi
Page 35 and 36: Chapter 3.1 Co-variables. Covariate
Page 37 and 38: Chapter 3.1 Table 3 Frequencies of
Page 39 and 40: Chapter 3.1 Table 5 Risk of serum d
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Page 61 and 62: Chapter 3.3 Introduction The quinol
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Common NOS1AP variants potentiate d
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Chapter 4.3 Introduction In the pas
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Chapter 4.3 Figure 1 Flowdiagram of
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Chapter 4.3 Table 1 Characteristics
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Chapter 4.3 Table 2 Cardiovascular
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Chapter 4.3 Table 3 Drugs, NOS1AP a
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Chapter 4.3 found indication that t
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Chapter 4.3 References 1. 2. 3. 4.
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4.4 Common variation in the NOS1AP
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Common variants in the NOS1AP gene
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5 Effect of ABCB1 and NOS1AP genoty
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Effect of ABCB1 and NOS1AP genotype
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6 General discussion Despite all re
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General discussion ening properties
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General discussion or the excess [C
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General discussion continuously mon
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General discussion cardiovascular d
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General discussion for non-cardiova
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General discussion 25. 26. 27. 28.
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General discussion QTc interval in
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General discussion 169
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7.1 Summary Despite all research ef
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Summary reduced mortality in patien
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Chapter 7.2 steeds aanzienlijk is e
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8 Dankwoord Een proefschrift schrij
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Dankwoord Bijzondere dank aan alle
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10 Bibliography Manuscripts based o
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Bibliography Van der Hooft CS, Diel
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