Multi-locus approach in pharmacogenetics. Application in the cholesterol lowering and anti-inflammatory pathways of statins

Multi-locus approach in pharmacogenetics. Application in the cholesterol
lowering and anti-inflammatory pathways of statins

Pharmacogenetics aims to discover genetic determinants of drug response.
Statins reduce the risk of coronary artery disease by approximately 30% in
subjects with hypercholesterolemia and in high-risk normocholesterolemic
subjects. These reductions, however, are average effects for patients included
in trials; in subpopulations effects might differ. The risk reducing effect of
statins is both due to their cholesterol lowering effects and to other
pleiotropic effects such as anti-inflammatory effects. This project will
determine if genetic variation in genes that are involved in lipid lowering and
in anti-inflammatory effects of statins can predict inter-individual
differences in MI reduction.

The aim of this project is to study SNPs in genes involved in the cholesterol
lowering pathway and in the anti-inflammatory pathway of statins to explain
differences in the protective effect of statins against myocardial infarction
(MI). A second aim is to test and improve methods that can be used in
multi-locus approaches in (pharmaco-) genetics.

A nested case-control study in a hypercholesterolemic cohort (total
cholesterol >=5.0 mmol/l or use of cholesterol lowering drugs) will be performed
in the population-based Pharmaco Morbidity Record Linkage System (PHARMO:
www.pharmo.nl). In the PHARMO database pharmacy dispensing data (including type
of drug, dose, dispensing date, dose regimen, duration of use, and prescriber)
of a representable sample of all Dutch pharmacies is linked to a nationwide
registration of hospital discharge records (LMR), these data include diagnostic
information from ICD-9-CM and procedures during hospital stay (since 1985). At
this moment drug use of 2,000,000 subjects in 25 areas in the Netherlands is
monitored in PHARMO, additional clinical information is available, because
there is a link with general practitioner*s practice databases and clinical
laboratoria.
Potential participants will be invited to participate through their community
pharmacy, they will be asked to sign informed consent and to complete a
questionnaire on cardiovascular risk factors and disease history. Subjects will
be asked to perform a saliva sample to collect cells for DNA extraction.

Patients will be asked to perfom a saliva sample. Furthermore the patient will
be asked to fill out a questionnaire (this will take approximately 30 minutes).
Patients can perform the buccal swaps and the filling out the questionnaire at
home. Information obtained from DNA analyses might be a burden to the patient
because of the knowledge about future risk of disease, and problems with
insurance. This DNA information won't be shared with the patient.