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352()6&+5,)7

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de
rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college
voor promoties in het openbaar te verdedigen op woensdag 30 maart 2011 des
middags te 12.45 uur

door

ÖZLEM BOZKURT

geboren op 17 augustus 1981 te Genk, België

 
 PROMOTOREN: Prof. dr. A. de Boer
Prof. dr. D.E. Grobbee

CO-PROMOTOR: Dr. O.H. Klungel

 
 Voor oma
Anneanneme

 
 
Contents

Chapter 1. General introduction 9

Chapter 2. Thiazide diuretics and diabetes 19

2.1 Use of thiazide diuretics and the risk of type 2 diabetes. 21

2.2 Variation in Renin-Angiotensin System and Salt-Sensitivity Genes

and the risk of diabetes Mellitus associated with the use of
thiazide diuretics. 33

Chapter 3. Genetic polymorphisms in RAAS genes, association between

use of ACE Inhibitors and ARB and the incidence of diabetes 51

3.1 Genetic variation in the Renin-Angiotensin-System modifies the

beneficial effects of ACE inhibitors on the risk of diabetes mellitus
among hypertensives. 53

3.2 Renin-angiotensin-system polymorphisms and the association

between use of angiotensin II receptor blockers or ACE inhibitors
and the risk of diabetes. 69

Chapter 4. Pharmacogenetic studies on glucose-lowering drugs 85

Pharmacogenetics of glucose lowering drug treatment:

a systematic review. 87

Chapter 5. General discussion 113

Chapter 6. Summary/Samenvatting 131

List of publications 143
Dankwoord 145

 
 
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1.3. CYP2C8 and SLCO1B1 polymorphisms and response to thiazolidinediones

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1.4. OCT polymorphisms and response to biguanides

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2. Candidate genes affecting pharmacodynamics

2.1. SUR-1 polymorphisms and response to sulfonylureas

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2.2. IRS-1 polymorphisms and response to sulfonylureas and biguanides

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2.3. PPAR-γ polymorphisms and response to thiazolidinediones and acarbose

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2.4. ACDC polymorphisms and response to thiazolidinediones and acarbose

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2.5. KCNJ11 polymorphisms and response to sulfonylurea and biguanides

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2.6. TCF7L2 polymorphisms and response to sulfonylureas and biguanides

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3. Candidate genes in the causal pathway

3.1. HNF-α polymorphisms and response to sulfonylureas and biguanides

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3.2. Lipoprotein lipase polymorphism and response to thiazolidinediones

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 Table 3FRQWLQXHG  

Drug/outcome Genes in the PK pathway Genes in the PD pathway Genes in the causal pathway
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 Table 3FRQWLQXHG  
Drug/outcome Genes in the PK pathway Genes in the PD pathway Genes in the causal pathway

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 Chapter 5

Table 1 Decision table for prescribing an appropriate treatment regimen for hypertensives with increased risk
of diabetes, taking into account polymorphisms in relevant genes

AGTR1 ACE AGT GNB3 ADD

Genotype
1166 4656// I/D 235 825 1460

GG//D C//I
A allele CC MM T allele CC T allele GG T allele
D allele
Treatment
Thiazides 1.76 0.97 3.17 1.35 1.66
1.69 2.01 1.36 1.48 1.81
(dd) (dd) (dd) (dd)

<1DDD/day 1.39* 0.84 1.61 1.22 1.04 1.46* 1.66* 1.07 1.34 1.16

≥1DDD/day 2.07* 0.57 3.07* 1.49* 2.25* 1.63* 2.22* 1.58* 1.56* 2.26*

ACEi
1.80 0.65 1.55 0.77 0.41 1.28
(AA) (C allele)

<1DDD/day 0.83 0.90 0.70 0.90 0.60 1

≥1DDD/day 0.24* 1.73* 0.71 0.59*

0.40 0.67
(AA) (C allele)

1.05 1.51* 1.99* 0.90 1.20 1.11

ARB
1.01 2.72 1.12 1.09 0.71 1.30
<1DDD/day

≥1DDD/day 0.67 24.8* 1.97 1.06 0.98 1.31

* p<0.05 =>our studies have found a significant association between antihypertensive treatment and risk of diabetes
(dd): depends on dose
Black box: use of medication should be avoided in order to avoid the increase in risk of diabetes
Light gray box/black letters: use of medication should be promoted in order to reduce the risk of diabetes
Dark gray box/white letters: until no harm has been shown, use of medication is possible
Blank box: no association has been found (neither positive nor negative), some caution needs to be taken when
prescribing

127
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 About the author

Özlem Bozkurt was born on 17 august 1981 in Genk, Belgium as the first daughter of a
Turkish coalmine worker. She studied Science and Math at the Onze-Lieve-Vrouwlyceum in
Genk and in 1999 she started her master Biomedical Sciences at the University of Hasselt and
University of Maastricht. For her graduation research she identified the effect of the scorpion
toxin BmBKTx1 on isolated metathoracic dorsal unpaired median (DUM) neurons of Locusta
migratoria using the whole cell patch clamp technique. The results were published in a peer
reviewed journal and this was also her first scientific publication.

After her graduation in 2003 she followed a one year advanced master in Nutrition and Health
at the Catholic University of Leuven where she wrote a paper on Cadmium in food.

In 2004 she started her PhD at the department of Pharmacoepidemiology and

Pharmacotherapy together with her advanced master in Epidemiology at the University of
Utrecht. In october 2007 she combined her PhD. with a position as Environmental Health
Care worker at the Flemisch Government in Brussels.

149