Genetic susceptibility to adverse drug effects - Epidemiology ...

More documents

Recommendations

Info

3.2 Common ABCB1 variants increase QTc shortening and risk of SCD in digoxin users Abstract Background and objective. Digoxin is one of the oldest cardiovascular drugs still in use today, but its use has always been associated with the risk of intoxication and life threatening arrhythmias. Digoxin is a known substrate of ATP-Binding Cassette B1 (ABCB1/MDR1). Therefore, we hypothesized that these ABCB1 variants might also increase digoxin toxicity associated sudden cardiac death (SCD). In addition, to further evaluate the association with cardiac effects of digoxin, we studied the association of ABCB1 variants with QTc interval duration in digoxin- and non-digoxin users. Methods. We used the Rotterdam Study, a population-based, prospective cohort study of individuals ≥55 Years of age. ABCB1 SNPs C1236T, G2677T/A and C3435T were assessed on peripheral blood DNA using Taqman assays. Hazard ratios (HRs) for time to SCD among ABCB1 genotypes with and without digoxin were estimated by Cox proportional hazards modeling with time-dependent exposures. Heart rate corrected QT (QTc) interval duration was measured in prospectively collected ECGs and digoxin exposure was determined at the time of each ECG. Results. There were 229 SCD cases, 40 of whom were exposed to digoxin at time of death. In digoxin users, homozygotes for 1236 or 2677 T-alleles and TTT-haplotype alleles had a two-fold increased risk of SCD (HR homozygous TTT: 2.36, 95%CI 1.02;5.45) in a recessive genetic model. No effect of ABCB1 variants on SCD risk was observed within non-digoxin users. We included 13,694 ECGs from 5535 individuals (294 ECGs from 222 individuals on digoxin). In digoxin users, ABCB1 T-allele or TTT-haplotype allele carriers increased QTc shortening compared to subjects homozygous for the reference allele. Conclusion: ABCB1 C1236T, G2677T/A and C3435T T-alleles and the associated TTThaplotype allele increase the risk of SCD to digoxin and show increased QTc shortening to digoxin. 45
Chapter 3.2 Introduction Digoxin is one of the oldest cardiovascular drugs still in use today. Although digoxin therapy is relatively safe nowadays, 1 its use has often been associated in the past with considerable risks of intoxication, frequently resulting in of arrhythmias and death. 2-4 Toxic concentrations may occur at therapeutic doses. Moreover, toxic effects of digoxin can appear within the accepted therapeutic serum concentration range. 5 Digoxin is a known substrate of P-glycoprotein, a multi-drug efflux transporter encoded by the ATP-Binding Cassette B1 (ABCB1) also known as the Multidrug Resistance 1 (MDR1) gene, a 200kb gene on chromosome 7p21. It was first discovered in chemotherapy resistant tumor cells but is also widely expressed in normal tissues such as the duodenum, kidneys, liver and the blood-brain barrier where it plays a role in the uptake and clearance of many drugs. 6-11 P-glycoprotein is suggested to play a role in digoxin concentration management. Many studies on single nucleotide polymorphisms (SNPs) of ABCB1 and digoxin kinetics have been performed. However, most studies were small and the results were ambiguous. 12 In a recent study, we showed that common variants in ABCB1 were associated with increased serum digoxin concentrations and risk of supra-therapeutic concentrations in a group of 195 chronic digoxin users from the Rotterdam Study. 13 Therefore, we hypothesized that common ABCB1 variants might also be involved in digoxin toxicity associated fatal arrhythmia in the form of sudden cardiac death (SCD) to digoxin therapy. In addition, to further evaluate the association of ABCB1 SNPs with cardiac effects of digoxin, we studied the association of ABCB1 variants with QTc interval duration in users and non-users of digoxin. Methods Setting and study population. The Rotterdam Study is a prospective population-based cohort study of chronic diseases in the elderly. All inhabitants of Ommoord, a Rotterdam suburb, aged 55 years and older (10,278), were ascertained from the municipal register and invited to participate. Of them, 78% (7983, 58% female and 98% white) took part in the baseline examination from March 1990 through July 1993. Second and third examinations were conducted from September 1993 to August 1996 and from April 1997 to December 1999. Objectives and methods of the Rotterdam Study have been described in detail. 14, 15 The medical ethics committee of Erasmus Medical Center (Rotterdam, The Netherlands) approved the study and all participants provided signed informed consent for participation, including retrieval of medical records, use of blood and DNA for scientific purposes and publication of data. Apart from extensive structured interview rounds, clinical characteristics including smoking, body mass index (BMI), hypertension, diabetes mellitus, heart failure and myocardial infarction are ascertained as previously described. 16-21 Active surveillance for incident diabetes mellitus, heart failure and myocardial infarction is conducted continuously between exams. DNA for genotyping is available for 6571 (82%) participants from the baseline visit. Exposure of 46
Page 1 and 2: Genetic susceptibility to adverse d
Page 3 and 4: The work presented in this thesis w
Page 5: Promotiecommissie Promotoren: Prof.
Page 10: 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.
Page 18: 2 Quantifying the risk of adverse d
Page 21 and 22: Chapter 2 Introduction The cardiac
Page 23 and 24: Chapter 2 Table 1 Characteristics o
Page 25 and 26: Chapter 2 digoxin treatment appears
Page 27 and 28: Chapter 2 References 1. 2. 3. 4. 5.
Page 30: 3 Common variants in the ABCB1 gene
Page 33 and 34: Chapter 3.1 Introduction The ATP-Bi
Page 35 and 36: Chapter 3.1 Co-variables. Covariate
Page 37 and 38: Chapter 3.1 Table 3 Frequencies of
Page 39 and 40: Chapter 3.1 Table 5 Risk of serum d
Page 41 and 42: Chapter 3.1 Table 6 Other studies o
Page 43 and 44: Chapter 3.1 References 1. 2. 3. 4.
Page 48 and 49: Common ABCB1 variants increase QTc
Page 58: Common ABCB1 variants increase QTc
Page 61 and 62: Chapter 3.3 Introduction The quinol
Page 63 and 64: Chapter 3.3 In addition to the diar
Page 65 and 66: Chapter 3.3 Table 1 General charact
Page 67 and 68: Chapter 3.3 confounding by contrain
Page 69 and 70: Chapter 3.3 adverse effects of mefl
Page 74: 4 Common variants in the NOS1AP gen
Page 77 and 78: Chapter 4.1 Introduction Sudden car
Page 79 and 80: Chapter 4.1 Assessment of QTc inter
Page 81 and 82: Chapter 4.1 Table 1 Baseline charac
Page 83 and 84: Chapter 4.1 Table 3 Number of indiv
Page 85 and 86: Chapter 4.1 ditional GG haplotype c
Page 90 and 91: 4.2 Common NOS1AP variants potentia
Page 92 and 93: Common NOS1AP variants potentiate d
Page 94 and 95: Common NOS1AP variants potentiate d
Page 96 and 97:
Common NOS1AP variants potentiate d
Page 98 and 99:
Page 100 and 101:
Page 102:
Page 105 and 106:
Chapter 4.3 Introduction In the pas
Page 107 and 108:
Chapter 4.3 Figure 1 Flowdiagram of
Page 109 and 110:
Chapter 4.3 Table 1 Characteristics
Page 111 and 112:
Chapter 4.3 Table 2 Cardiovascular
Page 113 and 114:
Chapter 4.3 Table 3 Drugs, NOS1AP a
Page 115 and 116:
Chapter 4.3 found indication that t
Page 117 and 118:
Chapter 4.3 References 1. 2. 3. 4.
Page 120 and 121:
4.4 Common variation in the NOS1AP
Page 122 and 123:
Common variants in the NOS1AP gene
Page 124 and 125:
Page 126 and 127:
Page 128 and 129:
Page 130 and 131:
Page 132:
Page 136 and 137:
5 Effect of ABCB1 and NOS1AP genoty
Page 138 and 139:
Effect of ABCB1 and NOS1AP genotype
Page 140 and 141:
Page 142 and 143:
Page 144 and 145:
Page 146 and 147:
Page 148 and 149:
Page 150:
Page 154 and 155:
6 General discussion Despite all re
Page 156 and 157:
General discussion ening properties
Page 158 and 159:
General discussion or the excess [C
Page 160 and 161:
General discussion continuously mon
Page 162 and 163:
General discussion cardiovascular d
Page 164 and 165:
General discussion for non-cardiova
Page 166 and 167:
General discussion 25. 26. 27. 28.
Page 168 and 169:
General discussion QTc interval in
Page 170:
General discussion 169
Page 174 and 175:
7.1 Summary Despite all research ef
Page 176:
Summary reduced mortality in patien
Page 179 and 180:
Chapter 7.2 steeds aanzienlijk is e
Page 182 and 183:
8 Dankwoord Een proefschrift schrij
Page 184:
Dankwoord Bijzondere dank aan alle
Page 188 and 189:
10 Bibliography Manuscripts based o
Page 190:
Bibliography Van der Hooft CS, Diel
show all

Genetic susceptibility to adverse drug effects - Epidemiology ...

Create successful ePaper yourself

Delete template?

Save as template?