Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states

Authors: PEREZ-MARTINEZ, PABLO - Reina Sofia University; CORELLA, DOLORES - University Of Valencia; SHEN, JIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ARNETT, DONNA - University Of Alabama; YIANNAKOURIS, NIKOS - Harokopio University Of Athens; TAI, E SHYONG - Singapore General Hospital; ORHO-MELANDER, MARJU - Lund University; TUCKER, KATHERINE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TSAI, MICHAEL - University Of Minnesota; STRAKA, ROBERT - University Of Minnesota; PROVINCE, MICHAEL - Washington University; KAI, CHEW SUOK - Ministry Of Health - Singapore; PEREZ-JIMENEZ, FRANCISCO - Reina Sofia University; Lai, Chao Qiang; LOPEZ-MIRANDA, JOSE - Reina Sofia University; GUILLEN, MARISA - University Of Valencia; Parnell, Laurence; BORECKI, INGRID - Washington University; KATHIRESAN, SEKAR - Massachusetts General Hospital; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/19/2008
Publication Date: 1/10/2009
Citation: Perez-Martinez, P., Corella, D., Shen, J., Arnett, D.K., Yiannakouris, N., Tai, E., Orho-Melander, M., Tucker, K.L., Tsai, M., Straka, R.J., Province, M., Kai, C., Perez-Jimenez, F., Lai, C., Lopez-Miranda, J., Guillen, M., Parnell, L.D., Borecki, I., Kathiresan, S., Ordovas, J.M. 2009. Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states. American Journal of Clinical Nutrition. 89:391-399.

Interpretive Summary: Elevated levels of triglycerides in the blood present an increased risk for cardiovascular disease. Genetic variants of the APOA5 and GCKR genes have been linked to fasting levels of blood triacylglycerols. We investigated the combined effects of one GCKR variant (rs780094C-->T) and two in APOA5 (-1131T-->C and APOA5 56C-->G) on fasting triacylglycerol in several independent populations and on the response to intake of a high-fat meal or fenofibrate, a lipid-lowering drug. In total eight populations in America, Asia and Europe were assessed (7730 persons) and two intervention studies in US Whites (1061 persons). We defined three genetic groups based on the versions of the APOA5 and GCKR genes the individuals carry: protective, intermediate, at risk. Subject in the "at risk" group had significantly higher levels of triacylglycerol after a short-term fast and a higher prevalence of elevated blood triglycerides than did subjects in the protective group across all eight populations. Moreover, subjects in the "at risk" group showed greater fluctuations in their triacylglycerol measures than did the other groups, especially among persons with elevated blood triglycerides: a greater rise in the after intake of a high-fat meal and a greater reduction after a short-term fast when taking fenofibrate. In conclusion, genetic variants at two genes, APOA5 and GCKR, produce an additive effect on triacylglycerol levels after both a short-term fast and a high-fat meal and contribute to the variability in response to a lipid-lowering drug, fenofibrate, that is observed between individuals.

Technical Abstract: Background: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol. Objective: We investigated the combined effects of the GCKR rs780094C-->T, APOA5 -1131T-->C, and APOA5 56C-->G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions. Design: We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7,730 men and women) and 2 intervention studies in US whites (n = 1,061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes). Results: Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend <0.001). Conclusions: SNPs in GCKR and APOA5 have an additive effect on both fasting and postprandial triacylglycerol and contribute to the interindividual variability in response to fenofibrate treatment.