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Metabolism. 2015 Oct;64(10):1359-71. doi: 10.1016/j.metabol.2015.07.001. Epub 2015 Jul 3.

Genome-wide association study of triglyceride response to a high-fat meal among participants of the NHLBI Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).

Author information

1
Department of Genetics, Washington University School of Medicine, St. Louis, MO. Electronic address: mwojczynski@wustl.edu.
2
Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
3
Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.
4
Department of Genetics, Washington University School of Medicine, St. Louis, MO.
5
Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX.
6
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
7
Section on Statistical Genetics, Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
8
Program in Personalized and Genomic Medicine, and Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD.

Abstract

OBJECTIVE:

The triglyceride (TG) response to a high-fat meal (postprandial lipemia, PPL) affects cardiovascular disease risk and is influenced by genes and environment. Genes involved in lipid metabolism have dominated genetic studies of PPL TG response. We sought to elucidate common genetic variants through a genome-wide association (GWA) study in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).

METHODS:

The GOLDN GWAS discovery sample consisted of 872 participants within families of European ancestry. Genotypes for 2,543,887 variants were measured or imputed from HapMap. Replication of our top results was performed in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 843). PPL TG response phenotypes were constructed from plasma TG measured at baseline (fasting, 0 hour), 3.5 and 6 hours after a high-fat meal, using a random coefficient regression model. Association analyses were adjusted for covariates and principal components, as necessary, in a linear mixed model using the kinship matrix; additional models further adjusted for fasting TG were also performed. Meta-analysis of the discovery and replication studies (n = 1715) was performed on the top SNPs from GOLDN.

RESULTS:

GOLDN revealed 111 suggestive (p < 1E-05) associations, with two SNPs meeting GWA significance level (p < 5E-08). Of the two significant SNPs, rs964184 demonstrated evidence of replication (p = 1.20E-03) in the HAPI Heart Study and in a joint analysis, was GWA significant (p = 1.26E-09). Rs964184 has been associated with fasting lipids (TG and HDL) and is near ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This association was attenuated upon additional adjustment for fasting TG.

CONCLUSION:

This is the first report of a genome-wide significant association with replication for a novel phenotype, namely PPL TG response. Future investigation into response phenotypes is warranted using pathway analyses, or newer genetic technologies such as metabolomics.

KEYWORDS:

Genetics; Gwas; Postprandial lipemia; Triglyceride

PMID:
26256467
PMCID:
PMC4573277
DOI:
10.1016/j.metabol.2015.07.001
[Indexed for MEDLINE]
Free PMC Article

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