An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort

Authors: GENG, XIN - University Of Texas Health Science Center; IRVIN, MARGUERITE - University Of Alabama; HIDALGO, BERTHA - University Of Alabama; ASLIBEKYAN, STELLA - University Of Alabama; SRINIVASASAINAGENDRA, VINODH - University Of Alabama; AN, PING - Washington University School Of Medicine; FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); TIWARI, HEMANT - University Of Alabama; DAVE, TUSHAR - University Of Maryland School Of Medicine; RYAN, KATHLEEN - University Of Maryland School Of Medicine; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STRAKA, ROBERT - University Of Minnesota; FEITOSA, MARY - Washington University School Of Medicine; HOPKINS, PAUL - University Of Utah; BORECKI, INGRID - University Of Washington; PROVINCE, MICHAEL - Washington University School Of Medicine; MITCHELL, BRAXTON - University Of Maryland School Of Medicine; ARNETT, DONNA - University Of Kentucky; ZHI, DEGUI - University Of Texas Health Science Center

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2018
Publication Date: 2/20/2018
Citation: Geng, X., Irvin, M.R., Hidalgo, B., Aslibekyan, S., Srinivasasainagendra, V., An, P., Frazier-Wood, A.C., Tiwari, H.K., Dave, T., Ryan, K., Ordovas, J.M., Straka, R.J., Feitosa, M.F., Hopkins, P.N., Borecki, I., Province, M.A., Mitchell, B.D., Arnett, D.K., Zhi, D. 2018. An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort. Journal of Lipid Research. http://dx.doi.org/10.1194/jlr.P080333.

Interpretive Summary: Triglyceride levels in the blood increase when a diet high in saturated- or trans- fats are eaten. Hypertriglyceridemia (high levels of triglycerides in the blood), is a risk factor for cardiovascular disease (CVD). In this study, we looked at rare variation (places in the genome where less than 1% of the population show genetic differences), and whether places in the genome with rare variants predict the extent to which an individual produces less triglyceride levels after consuming fat. We found 4 places where rare variation influenced the extent to which triglycerides were lowered after eating fat. This information is useful for researchers who wish to follow up on these genetic loci to better understand how they influence the interaction between potential treatments and dietary fat on triglycerides, and may eventually help physicians be more able to select the most effective triglyceride lowering drugs for individuals.

Technical Abstract: Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7, SIPA1L2, and CEP72 are significantly associated with fasting low-density lipoprotein cholesterol (LDL-C) response to FFB (P=1.24E-07), triglyceride postprandial area under the increase (AUI) (P=2.31E-06), and triglyceride postprandial AUI response to FFB (P=1.88E-06) respectively. We sought to replicate the association for SIPA1L2 in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study and thus the gene-based result was not replicated. For functional validation, we found gene transcript level of SIPA1L2 is associated with triglyceride postprandial AUI (P<=0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.