International Congress on Abnominal Obesity
Am J Clin Nutr 89: 391-399, 2009. First published December 3, 2008; doi:10.3945/ajcn.2008.26363
 American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26363
Vol. 89, No. 1, 391-399, January 2009
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© 2009 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states1,2,3

Pablo Perez-Martinez, Dolores Corella, Jian Shen, Donna K Arnett, Nikos Yiannakouris, E Syong Tai, Marju Orho-Melander, Katherine L Tucker, Michael Tsai, Robert J Straka, Michael Province, Chew Suok Kai, Francisco Perez-Jimenez, Chao-Qiang Lai, Jose Lopez-Miranda, Marisa Guillen, Laurence D Parnell, Ingrid Borecki, Sekar Kathiresan and Jose M Ordovas

1 From the Nutrition and Genomics Laboratory (PP-M, DC, JS, C-QL, LDP, and JMO) and the Dietary Assessment and Epidemiology Research Program (KLT), Jean Mayer–US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA; the Reina Sofia University Hospital, Lipids and Atherosclerosis Research Unit and CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), University of Cordoba, Cordoba, Spain (PP-M, FP-J, and JL-M); the Genetic and Molecular Epidemiology Unit and CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), School of Medicine, University of Valencia, Valencia, Spain (DC and MG); the Department of Epidemiology, University of Alabama, Birmingham, AL (DKA); the Harokopio University of Athens, Athens, Greece (NY); the Department of Endocrinology, Singapore General Hospital, Singapore (EST); the Department of Clinical Sciences, University Hospital Malmö, Clinical Research Center, Lund University, Malmö, Sweden (MO-M); the Departments of Laboratory Medicine and Pathology (MT) and Experimental and Clinical Pharmacology (RJS), University of Minnesota, Minneapolis, MN; the Division of Biostatistics, Washington University School of Medicine, St Louis, MO (MP and IB); the Epidemiology and Disease Control Division, Ministry of Health, Singapore (CSK); and the Cardiovascular Disease Prevention Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA (SK).

2 Supported by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Agricultural Research Service; NIH Heart, Lung, and Blood Institute grant U 01 HL72524, Genetic and Environmental Determinants of Triglycerides; NIH, National Institute on Aging, grant 5P01AG023394-02; RD07/0067/0006 (ISCIII) and PR2008-0268 (MICIN); and CIBEROBN03/06 and PI070954 from the Instituto de Salud Carlos III, Spain.

3 Reprints not avalible. Address correspondence to P Perez-Martinez, Reina Sofia University Hospital, Lipids and Atherosclerosis Research Unit, Avda Menéndez Pidal, s/n 14004 Córdoba, Spain. E-mail: pablopermar{at}yahoo.es.

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 = 7730 men and women) and 2 intervention studies in US whites (n = 1061) 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.