Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate

Authors: ASLIBEKYAN, STELLA - University Of Alabama; GOODARZI, MARK - Cedars-Sinai Medical Center; FRAZIER-WOOD, ALEXIS - University Of Alabama; YAN, XIAOFEI - Cedars-Sinai Medical Center; IRVIN, MARGUERITE - University Of Alabama; KIM, ERIC - Cedars-Sinai Medical Center; TIWARI, HEMANT - University Of Alabama; GUO, XIUQING - Cedars-Sinai Medical Center; STRAKA, ROBERT - University Of Minnesota; TAYLOR, KENT - Cedars-Sinai Medical Center; TSAI, MICHAEL - University Of Minnesota; HOPKINS, PAUL - University Of Utah; KORENMAN, STANLEY - University Of California; BORECKI, INGRID - Washington University; CHEN, YII-DER - Cedars-Sinai Medical Center; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ROTTER, JEROME - Cedars-Sinai Medical Center; ARNETT, DONNA - University Of Alabama

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/28/2012
Publication Date: 10/31/2012
Citation: Aslibekyan, S., Goodarzi, M.O., Frazier-Wood, A.C., Yan, X., Irvin, M.R., Kim, E., Tiwari, H.K., Guo, X., Straka, R.J., Taylor, K.D., Tsai, M.Y., Hopkins, P.N., Korenman, S.G., Borecki, I.B., Chen, Y.I., Ordovas, J.M., Rotter, J.I., Arnett, D.K. 2012. Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate. PLoS One. 7(10):e48663.

Interpretive Summary: Lipoproteins are spherical particles that carry lipids, particularly cholesterol and triglyceride, in the plasma. There is a well-established association between dyslipidemias, or disorders of lipoprotein metabolism, and coronary heart disease (CHD). Elevated levels of blood cholesterol, especially low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for CHD. Blood levels of these lipids are determined by both genetic and environmental factors. We recently performed a large-scale meta-analysis of genome-wide studies and identified 95 regions in the genome, 59 of them novel, which are significant predictors of blood lipid traits. In this work, we tested whether the same regions explain the observed heterogeneity in response to lipid-lowering therapy with the drug fenofibrate, which resembles the effects of dietary omega-3 fatty acids. For this purpose we used data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study which had 861 participants. We observed statistically significant associations between a polymorphism (variants of a particular DNA sequence) near the APOA1 gene (known as rs964184) and fenofibrate response for HDL-C and triglycerides. This gene codes the APOA1 protein, which is found on HDL particles. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG) which had 267 participants. Suggestive associations with fenofibrate response were observed for markers in or near other genes such as PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. In addition, we found strong evidence for epistasis (gene-gene interaction) between the CILP2 gene and the APOE-APOC1-APOC4-APOC2 gene cluster that define the cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate d and potentially in response to dietary components (i.e., omega-3 fatty acids).

Technical Abstract: A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n'='861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value=0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n'='267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction'=' 0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.