Genetic Variation in the PPARA Gene is Associated with Simvastatin-Mediated Cholesterol Reduction in the Rotterdam Study

Abstract

Aim: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin. Materials & methods: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression. Results: The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism. Conclusion: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4.

Original submitted 13 February 2013; Revision submitted 8 May 2013

KEYWORDS::

• CYP3A4
• HMG-CoA reductase inhibitors
• pharmacogenetics
• PPARA
• rs4253728 G>A
• rs4823613 A>G
• statins

Financial & competing interests disclosure

This work was supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO; 050-060-810). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; and the European Commission and Municipality of Rotterdam. L Elens is a postdoctoral researcher with the Fonds National de la Recherche Scientifique (F.R.S.-FNRS), Belgium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO; 050-060-810). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; and the European Commission and Municipality of Rotterdam. L Elens is a postdoctoral researcher with the Fonds National de la Recherche Scientifique (F.R.S.-FNRS), Belgium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.