Since cardiovascular diseases are a real public health problem, lipid lowering medication are widely used to decrease cholesterol and triglyceride levels in the general population. At present, it is estimated that approximately 200 million people are using statins worldwide. There is, however, a great interindividual variation in response to therapy which remains ununderstood and is not mastered. It is supposed that a part of this variability might be attributed to genetic factors. In 2014, we have conducted multiple studies in collaboration with the University of Athens (Greece) that allowed us demonstrating the importance of genetic polymorphisms in the metabolic pathway to explain difference in drug response. As a substantial number of patients are treated with that class of drugs, this could be of unprecedented importance as individualization of therapy can be of tangible health as well as cost benefits.
To pursue these investigations a step further, the group is now collaborating with Prof. Dr JL Balligand (FATH, IREC) to unravel the mystery of the pharmacogenetics of statins. In this context, a PhD student will join the PMGK team in September 2016. We will also work with Prof Giulio Muccioli (BPBL) for the analytical part of the project and with Prof Vincent Haufroid (LTAP, IREC) for the translational aspect. The main observation arising from our previous studies is the influence of the CYP3A4*22 allele on the lipid lowering response to Simvastatin. This highlights a potential important application of pharmacogenetics for statin therapy but is still in its infancy. Our collaborative project will try to decipher the potential of this promising observation but also to quantify and better characterize the importance of the patient genetic background in explaining differences in the statin response. In that way, the project will take several orientations (figure 5 and 6):
- The evaluation of the true pharmacokinetic impact of the CYP3A4*22 allele on the exposure to the drug.
- The estimation of the incidence of ADR in CYP3A4*22 carriers and other rare defective allele carriers (e.g. CYP3A4*20, SLCO1B1*5).
- Evaluation of the potential added value of taking into account other genetic variations.
- In vitro assessment of the mechanism of observed associations.
- In vivo animal studies characterizing the distribution of the drug while lightening on or repressing the expression of proteins.
Figure 5 : Workflow of the clinical study
Figure 6 : Workflow of the in vitro and in vivo animal studies