Genetics
Sex and BMI modify how much genetically lower CETP raises HDL-C and lowers LDL-C, though not cardiovascular outcomes (Genet Epidemiol 2023)
Original title: Study of effect modifiers of genetically predicted CETP reduction
Using UK Biobank participants, this study tested whether sex and body mass index (BMI) modify the association between genetically predicted lower CETP levels and lipid biomarkers and cardiovascular outcomes, extending the standard approach of using drug-target genetic variants to predict long-term on-target drug effects. Female sex and lower BMI were associated with a larger HDL-C rise and LDL-C fall for the same genetically predicted CETP reduction. In samples from the Montreal Heart Institute Biobank, sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity. These modifying effects on lipid biomarkers did not extend to sex differences in cardiovascular outcomes in this dataset. The authors present this as evidence relevant to precision-medicine use of CETP inhibitors and to assessing how representative clinical trial populations are of the wider population.
Original abstract
Genetic variants in drug targets can be used to predict the long-term, on-target effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes. We found sex and body mass index (BMI) to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher high-density lipoprotein cholesterol and lower low-density lipoprotein cholesterol for the same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex differences in cardiovascular outcomes in our data. Our results provide insight into the clinical effects of CETP inhibitors in the presence of effect modification based on genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.