0000000000012233
AUTHOR
Laurence D. Parnell
Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.
Objective— Apolipoprotein A5 ( APOA5 ) is a key determinant of plasma triglyceride (TG) concentrations. Genetic variation at the APOA5 locus could be responsible for some of the observed differences in response to fenofibrate therapy. Methods and Results— We examined the association between tag SNPs (−1131T>C and 56C>G) at APOA5 and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women participating in the GOLDN study. After 3-week drug treatment, APOA5 56G carriers displayed significant decrease in TG ( P =0.006), and increase in HDL-C ( P =0.002) levels relative to their basal values in the fasting state when compared with noncarriers (a TG re…
Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study
Several polymorphisms in the APOA5 gene have been associated with increased plasma triglyceride (TG) concentrations. However, associations between APOA5 and lipoprotein subclasses, remnant-like particles (RLPs), and cardiovascular disease (CVD) risk have been less explored. We investigated associations of five APOA5 single-nucleotide polymorphisms (SNPs; −1131T>C, −3A>G, 56C>G IVS3+ 476G>A, and 1259T>C) with lipoprotein subfractions and CVD risk in 1,129 men and 1,262 women participating in the Framingham Heart Study. Except for the 56C>G SNP, the other SNPs were in significant linkage disequilibria, resulting in three haplotypes (11111, 22122, and 11211) representing 98% of the population.…
Apolipoprotein A2 Polymorphism Interacts with Intakes of Dairy Foods to Influence Body Weight in 2 U.S. Populations
The interaction between a functional apolipoprotein A2 gene (APOA2) variant and saturated fatty acids (SFAs) for the outcome of body mass index (BMI) is among the most widely replicated gene-nutrient interactions. Whether this interaction can be extrapolated to food-based sources of SFAs, specifically dairy foods, is unexplored. Cross-sectional analyses were performed in 2 U.S. population–based samples. We evaluated interactions between dairy foods and APOA2 −265T > C (rs5082) for BMI in the Boston Puerto Rican Health Study (n = 955) and tested for replication in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1116). Dairy products were evaluated as total dairy, hig…
Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval. RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the …
A High Intake of Saturated Fatty Acids Strengthens the Association between the Fat Mass and Obesity-Associated Gene and BMI123
Evidence that physical activity (PA) modulates the association between the fat mass and obesity-associated gene (FTO) and BMI is emerging; however, information about dietary factors modulating this association is scarce. We investigated whether fat and carbohydrate intake modified the association of FTO gene variation with BMI in two populations, including participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1069) and in the Boston Puerto Rican Health (BPRHS) study (n = 1094). We assessed energy, nutrient intake, and PA using validated questionnaires. Genetic variability at the FTO locus was characterized by polymorphisms rs9939609 (in the GOLDN) and rs11…
Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states.
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…
Dietary Intake of n-6 Fatty Acids Modulates Effect of Apolipoprotein A5 Gene on Plasma Fasting Triglycerides, Remnant Lipoprotein Concentrations, and Lipoprotein Particle Size
Background— Apolipoprotein A5 gene (APOA5) variation is associated with plasma triglycerides (TGs). However, little is known about whether dietary fat modulates this association. Methods and Results— We investigated the interaction between APOA5 gene variation and dietary fat in determining plasma fasting TGs, remnant-like particle (RLP) concentrations, and lipoprotein particle size in 1001 men and 1147 women who were Framingham Heart Study participants. Polymorphisms –1131T>C and 56C>G, representing 2 independent haplotypes, were analyzed. Significant gene–diet interactions between the –1131T>C polymorphism and polyunsaturated fatty acid (PUFA) intake were found (PG polymorphism. The –1131…
Epigenomics and metabolomics reveal the mechanism of the APOA2-saturated fat intake interaction affecting obesity
BACKGROUND: The putative functional variant −265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. OBJECTIVE: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. DESIGN: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible ge…
Perilipin polymorphism interacts with saturated fat and carbohydrates to modulate insulin resistance
Macronutrient intakes and genetic variants have been shown to interact to alter the risk of insulin resistance, but replication of gene-nutrient interactions across independent populations may be difficult to achieve. Saturated fat and carbohydrate were previously shown to interact with genotype for insulin resistance for a variant of perilipin (PLIN), the major adipocyte-associated protein and a regulator of adipocyte metabolism. We investigated the same interaction for PLIN 11482G>A (rs894160) on insulin resistance in US men(n=462) and women(n=508) (mean ±SD, 49±16 years). In multivariate linear regression models, we found a significant (PA for HOMA-IR (homeostasis model assessment of ins…