|FEITOSA, MARY F. - Washington University|
|AN, PING - Washington University|
|ORDOVAS, JOSE M. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|KETKAR, SHAMIKA - Washington University|
|HOPKINS, PAUL N. - University Of Utah|
|STRAKA, ROBERT J. - University Of Minnesota|
|ARNETT, DONNA K. - University Of Alabama|
|BORECKI, INGRID B. - Washington University|
Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/13/2011
Publication Date: 4/1/2011
Citation: Feitosa, M., An, P., Ordovas, J., Ketkar, S., Hopkins, P., Straka, R., Arnett, D., Borecki, I. 2011. Association of gene variants with lipid levels in response to fenofibrate is influenced by metabolic syndrome status. Atherosclerosis. 215(2):435-439.
Interpretive Summary: Abnormal amounts of lipids in the blood that lead to hardening of the arteries consisting of elevated serum triglycerides (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) concentrations are one of the hallmarks of the metabolic syndrome (MetS). Fenofibrate therapy is being used to address these abnormal lipid concentrations; however, there are dramatic differences in response among individuals with and without MetS that could be due, in part, to genetic factors. Therefore, we investigated the association in 25 candidate genes with lipid responses to a 3-week trial on fenofibrate in subjects with and without MetS. Our results support that variants of APOA5 and APOE genes were associated with HDL-C and LDL-C responses in MetS subjects, while APOA4 was associated with TG response in non-MetS subjects. Therefore, genetic effects that contributed to the variability of lipid responses to fenofibrate may differ in subjects with and without MetS. These findings may provide guidance for more personalized and effective therapies to prevent cardiovascular disease.
Technical Abstract: Fenofibrate therapy reduces serum triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C) and thus addresses the atherogenic dyslipidemia associated with metabolic syndrome (MetS). Our hypothesis is that genetic factors contribute to the variability of lipid response to fenofibrate differently in subjects with MetS and without MetS. We investigated the association in 25 candidate genes with lipid responses to a 3-weeks trial on fenofibrate in subjects with and without MetS. We employed growth curve mixed models to generate the response phenotypes to fenofibrate in TG, HDL-C, and low-density lipoprotein-cholesterol (LDL-C) and examined the genetic associations accounting for family dependencies. After correcting for multiple testing (p less than 0.05) and accounting for significant differences in the association effect sizes between subjects with and without MetS (p less than 0.05), variants of APOA5 (rs662799) and APOE (rs429358) were associated with HDL-C and LDL-C responses in MetS subjects, while APOA4 (rs675) was associated with TG response in non-MetS subjects. There was also suggestive evidence that MetS may interact with APOA4 (p=0.017), APOA5 (p=0.06), and APOE (p=0.09) to the variation to lipid responses. Genetic effects that contributed to the variability of lipid responses to fenofibrate may differ in subjects with and without MetS. This research may provide guidance for more personalized and effective therapies.