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Research Project: Childhood Obesity Prevention

Location: Children's Nutrition Research Center

Title: 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
item Wojczynski, Mary - Washington University School Of Medicine
item Parnell, Laurence - Tufts University
item Pollin, Toni - University Of Maryland
item Lai, Chao - Tufts University
item Feitosa, Mary - Washington University School Of Medicine
item O'connell, Jeff - University Of Maryland
item Frazier-wood, Alexis - Children'S Nutrition Research Center (CNRC)
item Gibson, Quince - University Of Maryland
item Askubekyan, Stella - University Of Alabama
item Ryan, Kathy - University Of Maryland
item Province, Michael - Washington University School Of Medicine
item Tiwari, Hemant - University Of Alabama
item Ordovas, Jose - Tufts University
item Shuldiner, Alan - University Of Maryland
item Arnett, Donna - University Of Alabama
item Borecki, Ingrid - Washington University School Of Medicine

Submitted to: Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/1/2015
Publication Date: 10/1/2015
Citation: Wojczynski, M.K., Parnell, L.D., Pollin, T.I., Lai, C.Q., Feitosa, M.F., O'Connell, J.R., Frazier-Wood, A.C., Gibson, Q., Askubekyan, S., Ryan, K.A., Province, M.A., Tiwari, H.K., Ordovas, J.M., Shuldiner, A.R., Arnett, D.K., Borecki, I.B. 2015. 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). Metabolism. 64(10):1359-1371.

Interpretive Summary: Triglycerides (TG) are produced, in part, after eating dietary fat. High TGs in the blood are a strong cardiovascular disease risk factor, and so how much TG an individual has in their blood after eating a high fat meal indicates their cardiovascular disease risk. While some genetic variants have been identified which predict how much TG someone has in their blood after eating dietary fat, the problem is that this does not explain all the differences between people in their TG response to fat. Therefore, we sought to identify new genetic variants which associate with TG levels in the blood after eating fat, by looking at variants across the whole genome. We identified one genes where variation was associated with how much TG was in someone's blood after a high fat meal: ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This study is important because it contributes information to a growing body of research which will help us identify for whom it is particularly important to follow a low-fat diet in the quest for disease prevention.

Technical Abstract: 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). 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. 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. 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.