Genetic susceptibility to adverse drug effects - Epidemiology ...

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ABCB1 (MDR1) gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine the SNPs were calculated, we decided on the genetic model (recessive, dominant or doseeffect) based on the results. Multivariate analysis was performed using a binary logistic regression model. Logistic regression analysis was chosen because time played no role in this study. Confounders were defined as covariates associated with neuropsychiatric effects at a p-value of 0.1 and changing the point estimate by 10% or more. Mefloquine concentration was tested as an intermediate by including it into the model as a covariate. In a second step, we identified effect modification by age, gender, BMI and previous mefloquine use by introducing interaction terms and stratified on these factors when statistically significant. Because the cohort size is limited and the outcome is frequent, in contrast to traditional case-control studies, ORs cannot be interpreted as relative risks. Linear regression analysis was used to study the associations of the changes in scores on the neuropsychiatric tests and mefloquine concentrations with the genotypes, haplotypes and covariates. Time since last mefloquine dose was included in the model. Testing of confounders was similar to that for the logistic regression model. A trend test for an allele dose-effect relation of the SNP variants was obtained with the number of variant alleles entered as an ordered categorical variable. Haplotypes were constructed using the program PHASE version 2.0. 17, 18 Linkage disequilibrium was computed using the Haploview software version 3.11. 19 Results Of the 151 subjects available, 4 89 subjects (48 males and 41 females) with a mean age of 40 years, had blood samples available. The other 62 subjects refused to give a blood sample. All subjects included in the final cohort were white persons of European origin. General characteristics of the study population are presented in Table 1. Women had a significantly lower BMI compared with men (p= 0.02). Of all subjects, 37% had previously used mefloquine (Table 1). The concomitant use of drugs was higher in women than in men but this difference was mainly explained by 9 women who only used an oral contraceptive. One subject used a known P-gp inducer (acitretin, a synthetic retinoic acid analog) and one used a known P-gp inhibitor (atorvastatin). The prevalence of comorbidity was low (n=13) and included, among others, skin problems (n=2) and hypertension and other cardiovascular disease (n=5). The time interval since administration of the last mefloquine dose to follow-up ranged from 0 days (i.e., same day) to 7 days (i.e., just before fourth dose), with a median of 2 days. Prevalence of SNPs. Frequencies of all three SNPs were consistent with other studies in Caucasian populations. For the C1236T the frequencies were CC 29.8%, CT 50.0% and TT 20.2%, for the G2677T they were GG 31.8%, GT 51.1%, TT 17.0% and for the C3435T polymorphism CC 22.6%, CT 51.2%, TT 26.2%. 7, 20, 21 Genotyping failed in 5 subjects(5.6%), 1 subject (1.1%) and 5 subjects (5.6%) respectively. All SNPs were in Hardy-Weinberg equilibrium with p= 0.8 for C3435T, p= 0.7 for G2677T and p= 0.9 for C1236T. The C1236T, G2677T 63
Chapter 3.3 Table 1 General characteristics of the study population and comparisons between males and females Characteristic Males (n=48) Females (n=41) Age (years) mean, range 41.0 (21 – 68) 38.2 (18 – 59) BMI (kg/m 2 ) ab 24.7 (19.0 - 33.0) 23.1 (18.3 - 31.3) ≤ 25 28 (59.6 %) 31 (75.6 %) > 25 19 (40.4 %) 10 (24.4%) Smokers 13 (27.1 %) 13 (31.7 %) Concomitant drug 7 (14.6 %) 15 (36.6 %) Previous mefloquine users 21 (43.8 %) 12 (29.3%) Neuropsychiatric adverse events 9 (18.8 %) 16 (39.0 %) Delta TMD b -0.4 (-13 – 21) 5.3 (-16 – 48) Delta hand-eye coordination (log RMSE) b -0.19 (-0.64 – 1.04) -0.23 (-0.69 – 0.55) Mefloquine blood level (μg/ml) b 0.59 (0.31 - 1.14) 0.75 (0.37 - 1.51) Statistically significant differences between males and females are printed in bold (p ≤ 0.05), BMI: Body Mass Index, TMD: Total Mood Disturbance a Numbers do not add up due to missing data on weight and height. b Mean, range and C3435T SNPs were found to be in linkage disequilibrium. D’ for C3435T-G2677T was 0.87, for C3435T-C1236T and G2677T-C1236T it was 0.83 and 0.95 respectively. Construction of haplotypes, via estimation maximization, resulted in two frequent (1236-2677-3435 CGC and TTT) and four minor haplotypes; the other two theoretically possible haplotypes were not found in this population. Frequencies of the different haplotypes were: 1236-2677- 3435 CGC 45.5%, TTT 38.6%, TTC 2.8%, CGT 9.1%, TGT 2.8% and CTT 1.1%. Neuropsychiatric adverse effects. During the study period, 16 women (39.0%) and 9 men (18.8%) reported neuropsychiatric complaints. The most frequently reported adverse effects were insomnia or abnormal dreams (or both) (n= 10), fatigue (n= 8), headache (n= 8), dizziness (n= 5) and agitation, emotional instability or depression (n= 5). Women reported significantly more neuropsychiatric complaints then men (p = 0.03) and a higher change in TMD score (p =0.03) (Table 1). SNPs and neuropsychiatric adverse effects. On the basis of the genotype-specific results we decided to use a recessive model for further analyses. There was no significant association between any of the SNPs and neuropsychiatric adverse effects in the combined analyses. In the gender-stratified analyses, women homozygous for the TT-variant of any of the three SNPs had a significantly higher risk of adverse effects from mefloquine than the reference groups (i.e., the combined groups of CT and CC [for C1236T and C3435T] or GT and GG [for G2677T]), with ORs of 6.3, 10.5 and 5.4 for C1236T, G2677T and C3435T, respectively (Table 2). In men, no significant association with these SNPs was seen. Although the interaction term for previous use was not significant, we stratified on previous use to explore potential 64
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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
Page 13 and 14: Chapter 1 genome. Every SNP represe
Page 15 and 16: Chapter 1 References 1. 2. 3. 4. 5.
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Page 21 and 22: Chapter 2 Introduction The cardiac
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Page 25 and 26: Chapter 2 digoxin treatment appears
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Page 33 and 34: Chapter 3.1 Introduction The ATP-Bi
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Page 111 and 112: Chapter 4.3 Table 2 Cardiovascular
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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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