Genetic susceptibility to adverse drug effects - Epidemiology ...

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General discussion ening properties of digoxin on ECG. Apart from the influence on QTc-shortening to digoxin, we found echocardiographic indications that the ABCB1 TTT-haplotype allele was associated with decreased diastolic function in digoxin users, driving their echocardiographic parameters towards impaired relaxation. The TTT-haplotype allele was also associated with an increased systolic function in digoxin users without prevalent heart disease, but with a decreased function in those with prevalent heart failure or myocardial infarction (Chapter 5). Although the latter associations were not statistically significant, probably due to low numbers, these observations (apart from the decreased systolic function in those with prevalent heart disease) are in line with the findings of increased digoxin concentrations in TTT-haplotype allele carriers and the known effects of digoxin on cardiac function. 37, 38 Unfortunately, the number of digoxin users with eligible echocardiograms available was too low to draw solid conclusions from this study. The quinolone derivative mefloquine is widely used in the treatment and prophylaxis of malaria in travellers to areas with chloroquine resistant falciparum malaria but its use is associated with, sometimes severe, neuropsychiatric adverse effects. 39-41 Risk factors for adverse effects of mefloquine identified so far include history of seizures or psychiatric disorders, female gender and low body mass index (BMI). 42, 43 It has been suggested that the distribution volume or blood concentration of mefloquine plays a role, although no clear association between mefloquine blood level and neuropsychiatric adverse effects could be demonstrated. 43, 44 Mefloquine is able to cross the blood brain barrier 45 and ABCB1 is not only expressed in the intestine and in the liver, where it may influence the uptake in the blood and excretion in the bile of mefloquine, but also in the blood-brain barrier. 22 Therefore, even at similar serum concentrations, ABCB1 function may influence the risk of neuropsychiatric adverse effects by affecting the brain tissue concentration. We studied a cohort of mefloquine users followed during the three weeks preceding their travel, as was previously studied for neuropsychiatric effects of mefloquine (Chapter 3.3). 40, 42 We found that ABCB1 C1236T, G2677T and C3435T variants and the associated 1236-2677-3435 TTT haplotype were associated with an increased risk of neuropsychiatric adverse effects during the study period (relative risk (RR) for homozygous TTT subjects versus all other haplotype carriers 2.5, 95%CI 1.3-4.6). The effect was stronger in women (RR 3.2, 95%CI 2.0-5.2) in whom the frequency of adverse effects was much higher. In men, the effect was smaller and no longer statistically significant (RR 1.7, 95%CI 0.4-6.5). We found no association between ABCB1 SNPs or haplotypes and serum concentration of mefloquine. Furthermore, consistent with literature, 43, 44 we found no association of mefloquine serum concentration and the occurrence of neuropsychiatric adverse effects. This suggests that the association of ABCB1 variants with neuropsychiatric adverse effects of mefloquine is driven by differences in brain tissue concentration rather than in serum concentration. A lower expression of ABCB1 will result in lower mefloquine efflux from the brain, thus exposing it to higher tissue concentrations. Similar effects of ABCB1 polymorphisms have 46, 47 recently been shown for other drugs. NOS1AP variants and drug effects. Recently, common genetic variants of NOS1AP were discovered to be associated with QT-interval prolongation in a genome wide association study. 48 The NOS1AP gene, encoding the Nitric Oxide Synthase 1 Adaptor protein, was not previously known to be involved in myo- 155
Chapter 6 cardial repolarization. Both syndromal 49 and non-syndromal 50-53 long- and short 54 QT-interval increase the risk of SCD, making QT-interval and QT-altering factors important to study. Many drugs are known to prolong QT-interval duration, 55, 56 and medication-induced prolonged QT interval and ventricular arrhythmias, 57, 58 which may result in SCD, have led to the withdrawal of many non-cardiac medications. Since the impact of NOS1AP variants on QT interval duration in older populations, in whom non-genetic factors might play a stronger role than heritable factors, is unknown, we sought to replicate this finding in the Rotterdam Study, comprising participants of 55 years and older (Chapter 4.1). We also tested for association of NOS1AP variants with SCD. In the Rotterdam Study, we strongly confirmed the association of NOS1AP variants with a 3.8 (95%CI 3.0-4.6) msec increase in QT interval duration per additional minor variant allele. With the limited number of SCD cases in our cohort, it was not possible to demonstrate that this association translates into an influence on risk of SCD although the point estimates suggest that such a risk increase may truly exist. Additional larger studies will be required to determine whether NOS1AP genotype is associated with SCD. Since QT-altering drugs may interact with genetic variants in QT-duration associated genes, 49, 59, 60 this makes NOS1AP an interesting candidate for pharmacogenetic studies with QT-altering drugs. One of these QT-altering drugs is digoxin. Digoxin exerts its action, in part, by increasing intracellular Ca ++ concentration ([Ca ++ ] i ) through an increase of intracellular Na + by inhibition of the Na/K ATPase. 61, 62 This leads to higher contractile force and to QT-shortening. 38 Therefore, we hypothesized that subjects carrying the minor variants of two NOS1AP SNPs known to prolong the QT interval might be less sensitive to the QT shortening effects and pro-arrhythmogenic effects of digoxin. 54, 63, 64 In contrast with our expectations, in the Rotterdam Study, comprising both digoxin users and non-users of digoxin, we found that NOS1AP minor allele carriers had a significantly increased QT shortening on digoxin compared to major allele homozygotes, in contrast to the effect observed in non-digoxin users (Chapter 4.2). Participants homozygous for the NOS1AP major allele using digoxin had a 11.4 (95%CI 7.5;15.3) msec shorter QTc interval than major allele homozygotes not using digoxin (reference group), whereas digoxin users homozygous for the minor allele showed 23.0 (95%CI 14.4;31.5) msec QTc shortening compared to the reference group. Apparently, the QTc-shortening effect of digoxin is significantly worsened in those with a variant allele. Furthermore, minor alleles were associated with an increased risk of SCD to digoxin up to three-fold. Although the mechanism by which NOS1AP influences QT interval duration and interacts with digoxin is not known, it may involve calcium handling in the cardiomyocyte. 65-68 NOS1AP has been found to activate NOS1. 69 NOS1 knockout cardiomyocytes have increased contractility through increased [Ca ++ ] i and a slower decay of the [Ca ++ ] i transient. 65-68, 70 This slower decay of the [Ca ++ ] i transient is at contrast with normal [Ca ++ ] i kinetics, 38 but does explain the QT-prolonging effects of NOS1AP gene variants if these variants result in less activation of NOS1. Furthermore, NOS1 is able to interact with the L-type Ca ++ channel, 71 which is known to be associated with both Short- and Long QT Syndrome and SCD. 72, 73 This suggests a model in which both digoxin and NOS1AP minor alleles lead to increased [Ca ++ ] i , resulting in excess [Ca ++ ] i . Cardiac calcium overload could in turn increase risk of ventricular arrhythmias. 61 This would explain the increased risk of SCD in digoxin users with the minor NOS1AP alleles. If either digoxin 156
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Genetic susceptibility to adverse d
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The work presented in this thesis w
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Promotiecommissie Promotoren: Prof.
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1 General Introduction
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Chapter 1 genome. Every SNP represe
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Chapter 1 References 1. 2. 3. 4. 5.
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2 Quantifying the risk of adverse d
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Chapter 2 Introduction The cardiac
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Chapter 2 Table 1 Characteristics o
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Chapter 2 digoxin treatment appears
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Chapter 2 References 1. 2. 3. 4. 5.
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3 Common variants in the ABCB1 gene
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Chapter 3.1 Introduction The ATP-Bi
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Chapter 3.1 Co-variables. Covariate
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Chapter 3.1 Table 3 Frequencies of
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Chapter 3.1 Table 5 Risk of serum d
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Chapter 3.1 Table 6 Other studies o
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Chapter 3.1 References 1. 2. 3. 4.
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3.2 Common ABCB1 variants increase
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Common ABCB1 variants increase QTc
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Chapter 3.3 Introduction The quinol
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Chapter 3.3 In addition to the diar
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Chapter 3.3 Table 1 General charact
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Chapter 3.3 confounding by contrain
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Chapter 3.3 adverse effects of mefl
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4 Common variants in the NOS1AP gen
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Chapter 4.1 Introduction Sudden car
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Chapter 4.1 Assessment of QTc inter
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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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4.2 Common NOS1AP variants potentia
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Common NOS1AP variants potentiate d
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Page 105 and 106: Chapter 4.3 Introduction In the pas
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Page 111 and 112: Chapter 4.3 Table 2 Cardiovascular
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Page 115 and 116: Chapter 4.3 found indication that t
Page 117 and 118: Chapter 4.3 References 1. 2. 3. 4.
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Page 158 and 159: General discussion or the excess [C
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Page 162 and 163: General discussion cardiovascular d
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Page 168 and 169: General discussion QTc interval in
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Page 182 and 183: 8 Dankwoord Een proefschrift schrij
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Page 188 and 189: 10 Bibliography Manuscripts based o
Page 190: Bibliography Van der Hooft CS, Diel
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