Genetic susceptibility to adverse drug effects - Epidemiology ...

General Introduction
cells where it was over expressed, 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,
distribution and clearance of many drugs. 16-21 Since its first discovery, as many as 647 single
nucleotide polymorphisms (SNPs) -with an established frequency- have been identified in
the ABCB1 gene. 22 Among the first SNPs to be identified was the C3435T polymorphism,
which was found to be associated with decreased ABCB1 expression and increased digoxin
concentration. 23 Since then, many more studies on the association between ABCB1 SNPs
-mostly C1236T, G2677T/A and C3435T- and kinetics of digoxin, 24-29 a very old cardiovascular
drug still in use today, as well as many other drugs 30-34 have been performed with varying
results. 35-37
NOS1AP. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene can be seen as an
exponent of both pharmacogenomics and classical pharmacogenetics. Common genetic variants
of NOS1AP were recently discovered to be associated with QT-interval prolongation in a
genome wide association study. 38 The electrocardiographic QT interval is a non-invasive measure
of ventricular repolarization. Mendelian congenital long- and short QT syndromes (LQTS,
SQTS) are both characterized by sudden cardiac death (SCD) from ventricular arrhythmias. 39
Moreover, non-syndromal long 40-43 and short 44 QT interval are associated with an increased
risk of SCD in unselected populations. In addition, many drugs are known to prolong QT-interval
duration, 45, 46 and medication-induced prolonged QT interval and ventricular arrhythmias
have led to the withdrawal of many non-cardiac medications. 47, 48 NOS1AP was not previously
known to play a role in cardiac repolarization and, so far, not much is known about the mechanism
by which NOS1AP influences QT duration. Since QT-altering drugs may interact with
genetic variants in QT-duration associated genes, 39, 49, 50 this makes NOS1AP an interesting
candidate for pharmacogenetic studies with QT-altering drugs.
Aim and outline of this thesis. In this thesis we explore the effect of interaction of common
variants in the ABCB1 and NOS1AP genes with drugs on drug response and adverse effects
of drugs in a number of epidemiological studies. We mainly focus on digoxin and on other cardiovascular
drugs as drugs of interest. In chapter 2 we will quantify the risk of digoxin intoxication,
to give a perspective of the possible impact of these interactions on drug safety. Chapter
3 will focus on variations in the ABCB1 gene and their interaction with the commonly used
drugs digoxin and mefloquine. In chapter 4 we study the effect of NOS1AP variants on QTduration
and their interaction with QT-altering drugs such as digoxin and cardiovascular drugs
and with anti-diabetic medication. Chapter 5 describes the effect of the interaction of ABCB1
and NOS1AP genotypes with digoxin on cardiac function as assessed with echocardiography.
In the general discussion (Chapter 6) the main findings of this thesis are placed in the broader
context of potential clinical implications of pharmacogenetics and we address methodological
considerations. Finally, we discuss the direction and methods of future research in the field,
especially the possibilities of genome wide association studies in pharmacogenomics.
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