Genetic susceptibility to adverse drug effects - Epidemiology ...

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Common NOS1AP variants potentiate digoxin induced QT-shortening and risk of sudden cardiac death follow-up time of 10.4 (SD 3.7) years. Of these, 871 subjects used digoxin at any time during the study period. Baseline characteristics of the QTc and SCD study populations and of SCD cases are shown in Table 1. Genotypes and digoxin exposure. Genotype assessment of rs10494366 T>G and rs10918594 C>G was successful in 96.4% and 97.6%, minor allele frequencies were 36.5% and 31.4% respectively. Both SNPs were in Hardy-Weinberg equilibrium (p= 0.53 for rs10494366 and p=0.78 for rs10918594). Genotype frequencies in digoxin users did not significantly differ from non-users (p= 0.93 and p= 0.71 respectively). Mean digoxin dose was 0.61 DDD (SD 0.27) and did not significantly differ between genotype groups of ECGs taken while using digoxin, of those ever using digoxin in the total SCD sample or of SCD cases using digoxin on the index date. Figure 2 QTc difference in msec using by NOS1AP genotype and digoxin use 15 10 5 0 QTc difference in msec -5 -10 -15 -20 No digoxin Digoxin -25 -30 -35 TT TG GG QTc change in msec compared to persons with rs10494366 TT genotype without digoxin use (reference) adjusted for: age, sex, heart failure, myocardial infarction and diabetes mellitus at time of ECG (repeated measures analyses). Age, sex, heart failure, myocardial infarction and diabetes mellitus adjusted mean QTc for the reference group is 426msec. Vertical bars indicate 95% confidence intervals. 95
Chapter 4.2 Table 2 NOS1AP genotype effect on QTc stratified on digoxin users QTc change in msec (95% CI) by genotype b Genotype N a Crude Adjusted c Adjusted + dose d No digoxin Allelic model e 7342 3.6 (2.9;4.3) 3.6 (2.9;4.3) NA Genotypic model TT 2973 Reference Reference NA TG 3379 3.4 (2.4;4.5) 3.5 (2.5;4.5) NA GG 990 7.3 (5.8;8.8) 7.3 (5.8;8.7) NA Digoxin Allelic model e 233 -3.4 (-10.2;3.3) -4.5 (-11.1;2.2) -4.3 (-10.8;2.3) Genotypic model TT 107 Reference Reference Reference TG 102 -1.7 (-11.1;7.6) -1.5 (-10.8;7.8) -1.8 (-11.0;7.3) GG 24 -8.8 (-24.2;6.5) -12.4 (-27.6;2.8) -11.3 (-26.4;3.8) P-value for multiplicative interaction Allelic model e 8.8*10 -4 8.7*10 -5 NA Genotypic model 0.0033 2.1*10 -4 NA Results for rs10494366 genotypes; NA= not applicable a Number of unique individuals b QTc change in msec with 95% confidence interval. Homozygous major allele group is the referent. c Adjusted for known QT-prolonging factors: age, sex, heart failure, myocardial infarction and diabetes mellitus at time of ECG. d (Users only) Additionally adjusted for digoxin dose at time of ECG e Additive genetic model, QTc change per additional minor allele QTc interval. In the total study population, ECGs taken while subjects were using digoxin showed QTc interval shortening of 9.5 (95%CI 6.9;12.1) msec compared to non-users. After adjustment for sex and time dependent age, heart failure, diabetes mellitus and myocardial infarction digoxin use was associated with 15.7 (95%CI 13.0;18.3) msec shortening. Within the stratum of digoxin users, the effect of digoxin dose was 11.1 (95%CI 3.2;18.9) msec shortening per 0.5 DDD increase. In non-digoxin users, QTc interval increased with approximately 5, 6, 30 3.5 msec per additional variant allele, similar to previous studies. Digoxin users with TT genotypes for rs10494366 had a 11.4 (95%CI 7.5;15.3) msec shorter QTc interval than TT subjects not using digoxin (reference group), whereas digoxin users homozygous for the G-allele showed 23.0 (95%CI 14.4;31.5) msec QTc shortening compared to the reference group (Figure 2). The interaction between digoxin exposure and NOS1AP genotypes in their effect on QTc interval exceeded multiplicative scale. Within the digoxin use stratum, the genotype effect on QTc interval was similar to that shown in Figure 2 and was not substantially changed by additional adjustment for digoxin dose (Table 2). We identified 80 persons starting on digoxin between ECGs, 24 persons discontinuing digoxin 96
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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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Page 111 and 112: Chapter 4.3 Table 2 Cardiovascular
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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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