Pharmacogenetics of antihypertensive drug treatment - design and conduct of an observational study

Abstract

Hypertension is a major public health hazard, because of its high prevalence and strong positive association with cardiovascular diseases. Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients, and responsible for a large proportion of the burden of stroke and myocardial infarction (MI) in the population. The aim of this thesis was to assess the feasibility of setting up a large retrospective population based pharmacogenetic study and to gain more insight into the interactions between antihypertensive drugs and candidate gene polymorphisms on the risk of MI. Firstly, we focused on methodological issues in a pharmacogenetic study. Our study shows that it is feasible to set up a large retrospective study by collecting information through community pharmacies and patients themselves and to build a large DNA data bank. Furthermore, we found that fear for genetic screening does not seem to have a large impact on the willingness to participate. The main reason mentioned for non participation was health problems. Females were less willing to participate just like older patients. DNA samples from men yielded more DNA than those from women whereas DNA purity was the same for both men and women. Diuretic drug use, older age and laboratory personnel were associated with lower DNA purity. Secondly, we examined different drug-gene interactions. Among subjects with the ?-adducin G460W variant the risk of MI was similar among thiazide users compared to users of other antihypertensives, whereas among wild type carriers this risk was significantly lower. However, the interaction between current use of diuretics and the ?-adducin polymorphism was not statistically significantly increased on the multiplicative scale. The interaction between the eNOS G894T polymorphism and the use of calcium antagonists on the risk of MI was studied in a Dutch study population and in a US replication study population. Homozygous T-allele carriers using dihyropyridines had a higher risk of MI in the Dutch study population, but not in the US study population. Homozygous G-allele carriers did not have an increased risk in the Dutch study population, but did have in the US study population. We found a statistically significant interaction in the Dutch study but not in a US replication study. In both populations no significant interactions between the eNOS variant and diltiazem or verapamil was found. Finally, we examined the effects of renin-angiotensin-system polymorphisms on the risk of MI among users of renin-angiotensin-system inhibitors. In the patients treated with ACE-inhibitors the largest risk reduction was found in patients carrying the ACE 4656 G-allele (GC and GG) compared to patients with the CC genotype. The risk of MI was significantly reduced in current users of ACE-inhibitors, who used dosages lower than the equivalent of 1 defined daily dose, with the AGTR1 1166AC or AA genotype compared to users of ACE-inhibitors with the AGTR1 1166CC genotype. The ACE G4656C polymorphism did not modify the effectiveness of AT II antagonists on the risk of MI. No interaction was found with the ACE T3892C and the AGT C235T polymorphism. This may affect treatment of hypertension in the future when other studies confirmed these findings.