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J Lipid Res. 2018 Apr;59(4):722-729. doi: 10.1194/jlr.P080333. Epub 2018 Feb 20.

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

Author information

1
School of Biomedical Informatics The University of Texas Health Science Center at Houston, Houston, TX 77030.
2
Departments of Epidemiology University of Alabama at Birmingham, Birmingham, AL 35233.
3
Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35233.
4
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
5
US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030.
6
Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201.
7
Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111.
8
Instituto Madrile├▒o de Estudios Avanzados en Alimentaci├│n, Madrid 28049, Spain.
9
Centro Nacional Investigaciones Cardiovasculares, Madrid 28029, Spain.
10
Department of Experimental and Clinical Pharmacology Minneapolis, University of Minnesota, MN 55455.
11
Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT 84112.
12
Genetic Analysis Center, Department of Biostatistics, University of Washington, Seattle, WA 98105.
13
College of Public Health, University of Kentucky, Lexington, KY 40506 donna.arnett@uky.edu Degui.Zhi@uth.tmc.edu.
14
School of Biomedical Informatics The University of Texas Health Science Center at Houston, Houston, TX 77030 donna.arnett@uky.edu Degui.Zhi@uth.tmc.edu.
15
School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030.

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 LDL cholesterol 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 that 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.

KEYWORDS:

cholesterol; epidemiology; genetics; high-density lipoprotein; low-density lipoprotein; postprandial lipemia; rare variant; triglyceride; whole-exome sequencing

PMID:
29463568
PMCID:
PMC5880495
[Available on 2019-04-01]
DOI:
10.1194/jlr.P080333

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