Genetic susceptibility to adverse drug effects - Epidemiology ...

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3.1 Common ABCB1 variants are associated with increased digoxin serum concentration Abstract Background and objective. Digoxin is a known substrate of ATP-Binding Cassette B1 (AB- CB1/MDR1). However, the results of studies on the association between ABCB1 polymorphisms and digoxin kinetics remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population. Methods. Digoxin users were identified in the Rotterdam Study, a prospective populationbased cohort study of individuals aged 55 years and older. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 SNPs C1236T, G2677T/A and C3435T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes and digoxin blood levels using linear regression models adjusting for potential confounders. Results. Digoxin serum levels and DNA were available for 195 subjects (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18 to 0.21 μg/l per additional T-allele). The association was even stronger for the 1236-2677-3435 TTT-haplotype allele (0.26 μg/l (95%CI 0.14;0.38)) but absent for other haplotypes (CGC-allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. Conclusion. We found that the common ABCB1 C1236T, G2677T and C3435T variants and the associated TTT-haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population. 31
Chapter 3.1 Introduction The ATP-Binding Cassette B1 (ABCB1) or Multidrug Resistance 1 (MDR1) gene is a 200kb gene on chromosome 7p21. It was first discovered in chemotherapy resistant tumor cells but ABCB1 is also widely expressed in normal tissues such as the duodenum, kidneys, liver and the blood-brain barrier. 1-6 There, ABCB1 is known to play an important role in the uptake, distribution and excretion of many drugs. 7 Since its first discovery, as many as 647 single nucleotide polymorphisms (SNPs) -with an established frequency- have been identified in the ABCB1 gene. 8 Among the first SNPs to be identified was the C3435T polymorphism, which was found to be associated with decreased ABCB1 function, resulting in increased digoxin concentration. 9 Since then, many more studies on the association between ABCB1 SNPs –mostly C1236T, G2677T/A and C3435T- and kinetics of digoxin and many other drugs have been performed with varying results. In a recent meta-analysis combining all studies of the C3435T SNP and digoxin , an association with serum digoxin kinetics could not be confirmed. However, all these studies consisted of small groups of healthy volunteers, the largest study encompassing 50 subjects. Furthermore, all but one of these studies concerned single dose kinetics. In the only multiple dose study, subjects received digoxin for no more than five consecutive days. 10 The aim of our study was to investigate the association of the ABCB1 SNPs C1236T, G2677T/A and C3435T and their haplotypes with digoxin serum concentrations in a large population based cohort of digoxin users. Methods Setting and study population. A cohort of digoxin users was identified from the Rotterdam Study, a prospective population-based cohort study of chronic diseases in the elderly. Objectives and methods of the Rotterdam Study have been described in detail elsewhere. 11 The medical ethics committee of the Erasmus Medical Center (Rotterdam, The Netherlands) approved the study and all participants provided signed, informed consent for participation, retrieval of medical records, use of blood and DNA for scientific purposes and publication of obtained results. Baseline examinations took place from March 1990 through July 1993. In addition to the follow-up examinations that take place approximately every four years, all drug prescriptions dispensed to participants by automated pharmacies are routinely stored in the database since January 1, 1991. DNA for genotyping was available for 6571 (82%) participants from the baseline visit. For the present study, the study population comprised all subjects from the baseline cohort who were dispensed digoxin and who had a digoxin serum concentration assessment at any point during the study period. We excluded persons for whom DNA for genotyping was unavailable or information on dose was lacking. Follow-up started on January 1, 1991 or first digoxin prescription, whichever was latest, and lasted until the end of the study period on 32
Page 1 and 2: Genetic susceptibility to adverse d
Page 3 and 4: The work presented in this thesis w
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Page 10: 1 General Introduction
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Chapter 4.1 Table 1 Baseline charac
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Chapter 4.1 Table 3 Number of indiv
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Chapter 4.1 ditional GG haplotype c
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Chapter 4.1 References 1. 2. 3. 4.
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4.2 Common NOS1AP variants potentia
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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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