[show abstract][hide abstract] ABSTRACT: 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 rs1121980 (in the GOLDN and BPRHS). We found significant interactions between PA and FTO on BMI in the GOLDN but not in the BPRHS. We found a significant interaction between SFA intake and FTO on BMI, which was stronger than that of total fat and was present in both populations (P-interaction = 0.007 in the GOLDN and P-interaction = 0.014 in BPRHS for categorical; and P-interaction = 0.028 in the GOLDN and P-interaction = 0.041 in BPRHS for continuous SFA). Thus, homozygous participants for the FTO-risk allele had a higher mean BMI than the other genotypes only when they had a high-SFA intake (above the population mean: 29.7 ± 0.7 vs. 28.1 ± 0.5 kg/m²; P = 0.037 in the GOLDN and 33.6. ± 0.8 vs. 31.2 ± 0.4 kg/m²; P = 0.006 in BPRHS). No associations with BMI were found at lower SFA intakes. We found no significant interactions with carbohydrate intake. In conclusion, SFA intake modulates the association between FTO and BMI in American populations.
Journal of Nutrition 11/2011; 141(12):2219-25. · 4.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Experimental studies have suggested different effects of various fats on blood pressure. However, epidemiologic evidence of these relations remains limited and inconsistent. We therefore assessed the association of fatty acid (FA) composition in erythrocyte membranes with the risk of hypertension. We selected 516 cases of incident hypertension and 516 matched controls during 12.9 y of follow-up in the Women's Health Study. Erythrocyte FA was measured in baseline bloods using GC. After controlling matching factors and lifestyle factors, erythrocyte SFA showed a positive association, whereas total cis PUFA, cis (n-3) PUFA, and the ratio of PUFA:SFA (PS ratio) showed an inverse association with the risk of hypertension. The multivariable RR of hypertension across the increasing quartiles of erythrocyte FA subtypes were 1.00, 1.19, 1.44, and 1.76 for total SFA; 1.00, 0.84, 0.88, and 0.56 for total cis PUFA; 1.00, 0.87, 0.66, and 0.65 for cis (n-3) PUFA; and 1.00, 0.99, 0.70, and 0.51 for the PS ratio. After further adjusting for obesity-related metabolic factors, these associations were attenuated and remained significant only for the PS ratio. cis MUFA, cis (n-6) PUFA, and trans unsaturated FA in erythrocyte membranes were not associated with the risk of hypertension. Our study showed that FA composition in erythrocyte membranes is associated with the risk of hypertension in middle-aged and older women. However, after controlling for obesity-related metabolic factors, the associations remained significant only for the PS ratio.
Journal of Nutrition 09/2011; 141(9):1691-7. · 4.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although much is known about the effect of Apolipoprotein E (APOE) alleles on fasting lipid concentrations, less is known about the effect of APOE alleles on postprandial triglyceridemia or the triglyceride response to fenofibrate.
We evaluated the effects of the APOE locus on fasting and postprandial triglyceride concentrations as part of the Genetics of Lipid Lowering and Diet Network (GOLDN) study. Participants were evaluated after a high-fat meal challenge before (n=1072) and after 3 weeks of daily treatment with 160 mg of fenofibrate (n=738). Mixed models adjusted for sex, age, waist circumference, and family relationship were used to examine the association of the ε4 carrier and ε2 carrier status versus ε3 homozygotes with fasting triglycerides and the area under the curve (AUC) for triglycerides during the high-fat meal challenge. Compared with the ε3/ε3 genotype, ε2 carriers had on average higher fasting triglyceride concentrations (130.5 mg/dL versus 109.3 mg/dL, P<0.001). After fenofibrate treatment, the APOE genotype differences persisted in the fasting state (ε2 carriers: 85.1 mg/dL versus ε3/ε3: 75.9 mg/dL, P<0.05). Carriers of the ε4 allele had significantly higher fasting triglyceride concentrations only prefenofibrate (120.9 mg/dL versus 109.3 mg/dL, P=0.008). APOE alleles did not have an effect on response to fenofibrate. Postprandial triglycerides were significantly higher for ε2 carriers versus ε3 homozygotes (but not ε4 carriers) both before and after fenofibrate treatment (P=0.01 and P=0.005, respectively).
APOE polymorphisms are important determinants of triglyceride concentrations, especially in the fasting state.
[show abstract][hide abstract] ABSTRACT: Adiponectin is inversely associated with obesity, insulin resistance, and atherosclerosis, but little is known about the genetic pathways that regulate the plasma level of this protein. To find novel genes that influence circulating levels of adiponectin, a genome-wide linkage scan was performed on plasma adiponectin concentrations before and after 3 weeks of treatment with fenofibrate (160 mg daily) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. We studied Caucasian individuals (n = 1121) from 190 families in Utah and Minnesota. Of these, 859 individuals from 175 families had both baseline and post-fenofibrate treatment measurements for adiponectin. Plasma adiponectin concentrations were measured with an ELISA assay. All participants were typed for microsatellite markers included in the Marshfield Mammalian Genotyping Service marker set 12, which includes 407 markers spaced at approximately 10 cM regions across the genome. Variance components analysis was used to estimate heritability and to perform genome-wide scans. Adiponectin was adjusted for age, sex, and field center. Additional models also included BMI adjustment.
Baseline and post-fenofibrate adiponectin measurements were highly correlated (r = 0.95). Suggestive (LOD > 2) peaks were found on chromosomes 1p35.2 and 3q28 (near the location of the adiponectin gene).
Two candidate genes, IL22RA1 and IL28RA, lie under the chromosome 1 peak; further analyses are needed to identify the specific genetic variants in this region that influence circulating adiponectin concentrations.
BMC Medical Genetics 05/2009; 10:39. · 2.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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).
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).
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.
American Journal of Clinical Nutrition 01/2009; 89(1):391-9. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: The apolipoproteins (APOA1/C3/A4/A5) are key components in modulating lipoprotein metabolism. It is unknown whether variants at the APOA1/C3/A4/A5 gene cluster are associated with lipid response to pharmacologic intervention.
Plasma triglycerides (TGs) and high-density lipoprotein (HDL) levels were measured in 861 Genetics of Lipid-Lowering Drugs and Diet Network study participants who underwent a 3-week fenofibrate trial. We examined 18 common single nucleotide polymorphisms (SNPs) spanning the APOA1/C3/A4/A5 genes to investigate the effects of variants at the gene cluster on lipid response to fenofibrate treatment. We found that the minor alleles of the SNPs rs3135506 (APOA5_S19W), rs5104 (APOA4_N147S), rs4520 (APOC3_G34G), and rs5128 (APOC3_3U386) were associated with enhanced TG response to fenofibrate treatment (P= 0.0004-0.018). The minor allele of SNP rs2854117 (APOC3_M482) was associated with reduced rather than enhanced TG response (P= 0.026). The SNP rs3135506 (APOA5_S19W) was associated with HDL response, with minor allele related to reduced HDL response to fenofibrate (P= 0.002). Association analyses on haplotype provided corroborative evidence to single SNP association analyses. The common haplotypes H2, H3, and H5 were significantly associated with reduced TG response to fenofibrate.
The genetic variants at APOA1/C3/A4/A5 gene cluster may be useful markers to predict response of lipid-lowering therapy with fenofibrate. Further studies to replicate/confirm our findings are warranted.
Pharmacogenetics and Genomics 01/2009; 19(2):161-9. · 3.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: The scavenger receptor class B type 1 (SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggest that the SCARB1 gene may contribute to variation in plasma lipid levels at fasting; however, the results have been inconsistent, and it is unclear whether SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake, and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with postfenofibrate change for triglycerides (TG) (P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response, and response to fenofibrate intervention.
Journal of Human Genetics 07/2008; 53(8):709-17. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several perilipin (PLIN) polymorphic sites have been studied for their potential use as markers for obesity and the metabolic syndrome.
We aimed to examine whether the presence of polymorphisms at the perilipin (PLIN) locus (PLIN1, 6209T-->C; PLIN4, 11482G-->A; PLIN5, 13041A-->G; and PLIN6, 14995A-->T) influence postprandial lipoprotein metabolism in 2 white populations.
Eighty-eight healthy Spanish men and 271 healthy US subjects (men and women) underwent an oral-fat-load test in 2 independent studies. Blood samples were taken in the fasting state and during the postprandial phase at regular intervals. Total cholesterol and triacylglycerol and triacylglycerol in triacylglycerol-rich lipoproteins (TRL, large and small) were measured.
Carriers of the minor C allele at the PLIN1 variant displayed lower postprandial concentrations of large-TRL triacylglycerol (Spanish subjects: P = 0.024; US subjects: P = 0.005) than did subjects carrying the T/T genotype. The same pattern was observed in the Spanish population at the PLIN4 locus (P = 0.015), and both SNPs were in strong linkage disequilibrium. In both populations, subjects carrying the minor C and A alleles at PLIN1 and PLIN4, respectively, had significantly lower postprandial concentrations of plasma triacylglycerol (P < 0.05) and lower concentrations of small-TRL triacylglycerol than did those who were homozygous for the major alleles at PLIN1 and PLIN4 (Spanish subjects: P = 0.020 and 0.008, respectively; US subjects: P = 0.021 and 0.035, respectively).
These 2 studies suggest that the presence of the minor C and A alleles at PLIN1 and PLIN4, respectively, are associated with a lower postprandial response that may result in lower atherogenic risk for these persons.
American Journal of Clinical Nutrition 04/2008; 87(3):744-52. · 6.50 Impact Factor