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)

Authors: WOJCZYNSKI, MARY - Washington University; Parnell, Laurence; POLLIN, TONI - University Of Maryland; Lai, Chao Qiang; FEITOSA, MARY - Washington University; O'CONNEL, JEFF - University Of Maryland; FRAZIER-WOOD, ALEXIS - Baylor College Of Medicine; GIBSON, QUINCE - University Of Maryland; ASLIBKEYAN, STELLA - University Of Alabama; RYAN, KATHY - University Of Maryland; PROVINCE, MICHAEL - Washington University; TIWARI, HEMANT - University Of Alabama; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SHULDINER, ALAN - University Of Maryland; ARNETT, DONNA - University Of Alabama; BORECKI, INGRID - Washington University

Submitted to: Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/1/2015
Publication Date: 7/3/2015
Citation: Wojczynski, M.K., Parnell, L.D., Pollin, T.I., Lai, C., Feitosa, M.F., O'Connel, J.R., Frazier-Wood, A.C., Gibson, Q., Aslibkeyan, 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. 64:1359-1371.

Interpretive Summary: After most meals, blood levels of triglycerides and other fats become elevated and remain so for several hours. These elevated levels of triglyceride in response to a meal have direct consequence on cardiovascular disease. But not all individuals show the same increases in triglycerides after a meal and genetic differences between individuals may influence the nature of this response. Thus, researchers used two different sets of people from the USA to identify common genetic differences that contribute to triglyceride increases after a meal. Employing standard genomic, genetic and statistical techniques, we found over 100 different genetic contributors to the differences in the after-meal triglyceride increases, with two of these showing especially strong effects. Of these two genetic contributors, one showed similar results in a second set of individuals, thus strengthening our findings. This is the first report ever to examine the genetic contributors to differences in the extent of the increase in blood triglycerides that naturally occurs after a meal. This research is significant in shedding light on the basis of an important diet-based metric of cardiovascular disease.

Technical 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. Meta-analysis of the discovery and replication studies (n=1,715) 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. 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.