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

Xin Geng, Marguerite R. Irvin, Bertha Hidalgo, Stella Aslibekyan, Vinodh Srinivasasainagendra, Ping An, Alexis C. Frazier-Wood, Hemant K. Tiwari, Tushar Dave, Kathleen Ryan, Jose M. Ordovas, Robert J. Straka, Mary F. Feitosa, Paul N. Hopkins, Ingrid Borecki, Michael A. Province, Braxton D. Mitchell, Donna K. Arnett, Degui Zhi

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4 Scopus citations

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.—Geng, X., M. R. Irvin, B. Hidalgo, S. Aslibekyan, V. Srinivasasainagendra, P. An, A. C. Frazier-Wood, H. K. Tiwari, T. Dave, K. Ryan, J. M. Ordovas, R. J. Straka, M. F. Feitosa, P. N. Hopkins, I. Borecki, M. A. Province, B. D. Mitchell, D. K. Arnett, and D. Zhi. An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort.

Original languageEnglish (US)
Pages (from-to)722-729
Number of pages8
JournalJournal of lipid research
Volume59
Issue number4
DOIs
StatePublished - 2018

Bibliographical note

Funding Information:
The work on the GOLDN study has been funded by National Institutes of Health Grants U01HL072524 and R01HL091357. The HAPI Heart Study was supported by National Institutes of Health Grants U01 HL072515 and P30 DK072488. Whole-genome sequencing (WGS) of Amish subjects was provided by the Trans-Omics for Precision Medicine (TOPMed) program through the National Heart, Lung, and Blood Institute. WGS for TOPMed Genetics of Cardio-metabolic Health in the Amish (phs000956.v2.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). Analysis of the HAPI Heart Study data was supported by P30 DK072488. X.G. and D.Z. are partially supported by National Institute of Food and Agriculture Agriculture and Food Research Initiative Competitive Grant 2015-67015-22975 and US Department of Agriculture Aquaculture Research Program Competitive Grant 2014-70007-22395. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The work on the GOLDN study has been funded by National Institutes of Health Grants U01HL072524 and R01HL091357. The HAPI Heart Study was supported by National Institutes of Health Grants U01 HL072515 and P30 DK072488. Whole-genome sequencing (WGS) of Amish subjects was provided by the Trans-Omics for Precision Medicine (TOPMed) program through the National Heart, Lung, and Blood Institute. WGS for TOPMed Genetics of Cardio-metabolic Health in the Amish (phs000956.v2.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). Analysis of the HAPI Heart Study data was supported by P30 DK072488. X.G. and D.Z. are partially supported by National Institute of Food and Agriculture Agriculture and Food Research Initiative Competitive Grant 2015-67015-22975 and US Department of Agriculture Aquaculture Research Program Competitive Grant 2014-70007-22395. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Manuscript received 6 September 2017 and in revised form 4 February 2018. Published, JLR Papers in Press, February 20, 2018 DOI https://doi.org/10.1194/jlr.P080333

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