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

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.

Figures

FIGURE 1

Comparison of fasting triacylglycerol (TG) across 3 combined genotype groups in the 8 studied populations. Values are means (±SEMs) and percentages. P1: P values for lineal trend of triacylglycerol means among genotypes (adjusted for age, sex, and BMI) in men and women. P2: P values obtained in chi-square test for percentages. The black bars represent the percentage of hypertriglyceridemic (triacylglycerol > 150 mg/dL) subjects within each genotype group. P, homozygous subjects for the wild-type alleles for each single nucleotide polymorphism (SNP; CC rs780094 at the GCKR gene and TT −1131T→C APOA5 + CC 56C→G APOA5), n = 1679; M, any mixed genotype not included in groups P and R, n = 4295; R, carriers of the variant allele for the GCKR rs780094 (CT or TT) and carriers of the variant alleles at one of the APOA5 SNPs (TC or CC at −1131T→C or CG or GG at 56C→G), n = 1756; EPIGEM, Epidemiología Genética y Molecular; PREDIMED, Prevención con Dieta Mediterránea; GOLDN, Genetics of Lipid Lowering Drugs and Diet Network; BPR CPHHD, Boston Puerto Rican Health Study–Centers on Population Health and Health Disparities; SNHS, Singapore National Health Survey.

FIGURE 2

Postprandial triacylglycerol (TG) response in the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study participants who underwent the oral fat-load test, according to the 3 GCKR-APOA5 combined genotype groups. P, homozygous subjects for the wild-type alleles for each single nucleotide polymorphism (SNP; CC rs780094 at the GCKR gene and TT −1131T→C APOA5 + CC 56C→G APOA5), n = 281; M, any mixed genotype not included in groups P and R, n = 583; and R, carriers of the variant allele for the GCKR rs780094 (CT or TT) and carriers of the variant alleles at one of the APOA5 SNPs (TC or CC at −1131T→C or CG or GG at 56C→G), n = 141. Adjusted TG means (for sex, age, and BMI) and SEMs, immediately before (time 0) and 3.5 and 6 h after the high-fat meal are compared. Adjusted P values for the effect of the genotype (PG), the time (PT), and the interaction of genotype and time (PGxT) obtained in the statistical model for repeated measures are shown.

FIGURE 3

Fasting means (±SEMs) of plasma triacylglycerol (TG) concentrations after (pretreatment) and before (posttreatment) the fenofibrate intervention (3 wk, 160 mg/d) in the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study participants (n = 844) according to the 3 GCKR-APOA5 combined genotype groups and hypertriglyceridemic (TG > 150 mg/dL) status. P, homozygous subjects for the wild-type alleles for each single-nucleotide polymorphism (SNP; CC rs780094 at the GCKR gene and TT −1131T→C APOA5 + CC 56C→G APOA5), n = 236; M, any mixed genotype not included in groups P and R, n = 490; and R, carriers of the variant allele for the GCKR rs780094 (CT or TT) and carriers of the variant alleles at one of the APOA5 SNPs (TC or CC at −1131T→C or CG or GG at 56C→G), n = 118. TG means were adjusted for sex, age, and BMI at pretreatment and additionally for baseline TG at the posttreatment analysis. P values indicate the global mean comparison among the 3 genotype groups in each category and time. NTG, normotriglyceridemia; HTG, hypertriglyceridemia.