A frequent variant in the ABCA1 gene is associated with increased coronary heart disease risk and a better response to statin treatment in familial hypercholesterolemia patients
Aims: Statins are essential for the reduction of risk of coronary heart disease (CHD) in familial hypercholesterolemia (FH). One of many genes influenced by statin treatment is the ATP-binding cassette transporter A1 (ABCA1) gene, which plays an important role in metabolism of high-density lipoprotein (HDL). The present aim was to test if the ABCA1 C69T polymorphism influences CHD risk and response to statin treatment. Methods and results: In a large cohort of 1686 FH patients without a history of CHD before 1 January 1990, we analysed statin-ABCA1 C69T polymorphism interaction by comparing treated and untreated patients. We used a Cox proportional hazard model adjusted for sex, birth year, and smoking. In analyses restricted to untreated patients, the TT genotype was associated with 1.7 times higher CHD risk than the CC genotype (hazard ratio (HR) =1.65, 95% confidence interval (95% CI): 1.08=2.53; P = 0.02). Conversely, in statin-treated FH patients, CHD risk in TT individuals was not increased (HR: 0.65, 95% CI: 0.35=1.24; P = 0.2). Formal testing confirmed this interaction (P = 0.03). HDL-cholesterol levels were significantly more raised in statin-treated patients with the TT than with the CC genotype (two-way ANOVA, P = 0.045). Conclusion: In untreated FH patients, the TT genotype of the ABCA1 C69T polymorphism was associated with increased CHD risk. However, in statin-treated patients, CHD risk was no longer significantly different between genotypes, at least partially explained by a higher rise in HDL-cholesterol levels during statin treatment in TT individuals. Published on behalf of the European Society of Cardiology.
|Keywords||ABC transporter A1, ABCA1, Coronary disease, Familial hypercholesterolemia, Pharmacogenetics, Statin, adult, article, atorvastatin, cardiovascular risk, cohort analysis, controlled study, drug effect, drug response, familial hypercholesterolemia, female, gene frequency, gene interaction, genetic analysis, genetic association, genetic polymorphism, genetic variability, genotype, high density lipoprotein cholesterol, human, hydroxymethylglutaryl coenzyme A reductase inhibitor, ischemic heart disease, low density lipoprotein cholesterol, major clinical study, male, pravastatin, priority journal, proportional hazards model, risk assessment, simvastatin, triacylglycerol|
|Persistent URL||dx.doi.org/10.1093/eurheartj/ehq208, hdl.handle.net/1765/23556|
Versmissen, J., Oosterveer, D.M., Yazdanpanah, M., Mulder, M., Dehghan, A., Defesche, J.C., … Sijbrands, E.J.G.. (2011). A frequent variant in the ABCA1 gene is associated with increased coronary heart disease risk and a better response to statin treatment in familial hypercholesterolemia patients. European Heart Journal, 32(4), 469–475. doi:10.1093/eurheartj/ehq208