Genetic susceptibility to adverse drug effects - Epidemiology ...

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Effect of ABCB1 and NOS1AP genotypes on cardiac function in digoxin users Table 2 Echocardiographic characteristics Echocardiographic parameter NOS1AP ABCB1 Digoxin users genotyped genotyped Number 4827 2753 59 Structural parameters Left ventricular end systolic dimension, 31.0 (28.0-35.0) 32.0 (28.0-35.0) 34.0 (28.0-43.0) mm (median (IQR)) Left ventricular end diastolic dimension, 51.2 (5.6) 50.6 (5.9) 53.1 (8.5) mm (mean (SD)) Systolic parameters Ejection fraction, % (median (IQR)) 78.0 (71.3-82.1) 73.7 (68.6-80.6) 71.1 (61.3-78.9) Fractional shortening, % (mean (SD)) 38.5 (7.1) 36.9 (7.5) 33.2 (10.1) Left ventricular function, % a Normal 56.1 44.8 25.9 Fair 38.1 47.9 43.1 Moderate 4.1 5.1 19.0 Poor 1.7 2.3 12.1 Diastolic parameters Mitral valve inflow peak E, m/s 0.65 (0.16) 0.64 (0.17) 0.68 (0.23) (mean (SD)) Mitral valve inflow peak A, m/s 0.77 (0.18) 0.78 (0.18) 0.75 (0.20) (mean (SD)) E/A ratio (median (IQR)) 0.83 (0.71-1.00) 0.80 (0.67-1.00) 0.75 ( (0.65- 1.00) Mitral valve inflow deceleration time, 215.3 (47.9) 219.3 (51.3) 223.5 (66.7) msec (mean (SD)) Diastolic function, % b Normal 51.3 45.0 35.4 Impaired relaxation 12.2 15.1 14.6 Restrictive 0.5 0.5 2.1 Indeterminate 36.0 39.4 47.9 The group of NOS1AP genotyped consists of all genotyped subjects from both the baseline and the extension cohort, the ABCB1 group comprises only genotyped participants from the baseline cohort, the digoxin group consists of all genotyped digoxin users from both cohorts. For normally distributed variables, mean (SD) is displayed. If a variable was not normally distributed, median (inter quartile range (IQR)) is shown. a Qualitative assessment of ventricular systolic function b Normal diastolic function: E/A ratio between 0.75 and 1.50 and deceleration time between 150 ms and 240 ms, impaired relaxation: E/A ratio < 0.75 and deceleration time > 240 ms, restrictive diastolic dysfunction: E/A ratio > 1.50 and deceleration time < 150 ms. 141
Chapter 5 Table 3 Association between digoxin use and systolic or diastolic properties on echocardiography B (95% CI) Variable No prevalent heart failure or myocardial infarction (22 users of digoxin) Prevalent heart failure or myocardial infarction (37 users of digoxin) Systolic function Ejection fraction (%) -1.5 (-4.8;1.7) -3.7 (-7.9;0.4) Fractional shortening (%) -0.2 (-2.8;2.5) -2.7 (-5.6;0.3) Diastolic function Mitral valve inflow peak E (m/s) 0.00 (-0.06;0.06) 0.06 (-0.01;0.13) Mitral valve inflow peak A (m/s) -0.10 (-0.17;-0.02) -0.03 (-0.10;0.04) Ln E/A ratio a 0.08 (-0.03;0.20) 0.06 (-0.06;0.18) Mitral valve inflow deceleration time -17.6 (-37.7;2.6) 11.6 (-10.0;33.3) All NOS1AP genotyped subjects, adjusted for age, sex and ultrasonography system. a Log-transformed because E/A ratio and residuals were not normally distributed, after log-transformation residuals were normally distributed. prevalent heart disease (Table 4). Results were less equivocal for mitral valve inflow deceleration time, but digoxin users homozygous for the TTT haplotype seemed to have increased deceleration time, also driving towards impaired relaxation. For the individual SNPs we found similar effects (results not shown). In table 6, the results for an allelic model are displayed stratified on digoxin use and prevalent heart disease. NOS1AP and digoxin. The NOS1AP cohort was larger, with extra participants from the second inception cohort. Since this cohort was younger at the time of echocardiography, the extension resulted in only few extra digoxin users. Also, the NOS1AP variants were less frequent, resulting in little or no extra power compared to the ABCB1 study population. Therefore, still no robust effect estimates could be obtained. Similar to our observations for the ABCB1 TTT-haplotype, in the stratum of participants without prevalent heart disease, digoxin users carrying the rs10494366 minor allele haplotype showed improved ejection fraction and fractional shortening compared to those not carrying this haplotype. Again, the effect of the minor allele seemed opposite in the prevalent heart disease stratum (Table 5). In diastole, digoxin users carrying the minor allele seemed to have an increased E/A ratio. Deceleration time seemed increased in digoxin using minor allele carriers in the prevalent heart disease stratum, but the results might be opposite for the non-heart disease stratum. Similar results were observed for rs10918594 minor allele carriers. We observed no effect of NOS1AP genotype on systolic or diastolic function in non-users of digoxin. In table 6, the results for an allelic model are displayed (where applicable) stratified on digoxin use and prevalent heart disease, but none of the results showed a significant association. 142
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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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Page 156 and 157: General discussion ening properties
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Page 190: Bibliography Van der Hooft CS, Diel
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