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1.  Nontraditional risk factors for cardiovascular disease and visceral adiposity index among different body size phenotypes 
Du, T | Zhang, J | Yuan, G | Zhang, M | Zhou, X | Liu, Z | Sun, X | Yu, X
Background and Aims
Increased cardiovascular disease and mortality risk in metabolically healthy obese (MHO) individuals remain highly controversial. Several studies suggested risk while others do not. The traditional cardiovascular risk factors may be insufficient to demonstrate the complete range of metabolic abnormalities in MHO individuals. Hence, we aimed to compare the prevalence of elevated lipoprotein (a), apolipoprotein B, and uric acid (UA) levels, apolipoprotein B/apolipoprotein A1 ratio, and visceral adiposity index (VAI) scores, and low apolipoprotein A1 levels among 6 body size phenotypes (normal weight with and without metabolic abnormalities, overweight with and without metabolic abnormalities, and obese with or without metabolic abnormalities).
Methods and Results
We conducted a cross-sectional analysis of 7765 Chinese adults using data from the nationwide China Health and Nutrition Survey 2009. MHO persons had intermediate prevalence of elevated apolipoprotein B and UA levels, apolipoprotein B/apolipoprotein A1 ratio and VAI scores, and low apolipoprotein A1 levels between metabolically healthy normal-weight (MHNW) and metabolically abnormal obese individuals (P < 0.001 for all comparisons). Elevated apolipoprotein B and UA concentrations, apolipoprotein B/apolipoprotein A1 ratio, and VAI scores were all strongly associated with the MHO phenotype (all P < 0.01).
Prevalence of elevated apolipoprotein B and UA levels, apolipoprotein B/apolipoprotein A1 ratio and VAI scores, and low levels of apolipoprotein A1 was higher among MHO persons than among MHNW individuals. The elevated levels of the nontraditional risk factors and VAI scores in MHO persons could contribute to the increased cardiovascular disease risk observed in long-term studies.
PMCID: PMC4302064  PMID: 25159728
Apolipoprotein A1; apolipoprotein B; metabolically abnormal and obese; metabolically healthy but obese
2.  Does serum uric acid predict incident metabolic syndrome in a population with high prevalence of obesity? 
To evaluate whether uric acid (UA) predicts 4-yr incidence of metabolic syndrome (MetS) in non-diabetic participants of the Strong Heart Study (SHS) cohort.
Design and Methods
In this population-based prospective study we analyzed 1499 American Indians (890 women), without diabetes or MetS, controlled during the 4th SHS exam and reexamined 4 years later during the 5th SHS exam. Participants were divided into sex-specific tertiles of UA and the first two tertiles (group N) were compared with the third tertile (group H).
Body mass index (BMI =28.3±7 vs. 31.1±7 kg/m2), fat-free mass (FFM = 52.0±14 vs. 54.9±11 kg), waist-to-hip ratio, HOMA-IR (3.66 vs. 4.26), BP and indices of inflammation were significantly higher in group H than in group N (all p<0.001). Incident MetS at the time of the 5th exam was more frequent in group H than group N (35 vs. 28%, OR 1.44 (95% CI=1.10-1.91; p< 0.01). This association was still significant (OR= 1.13, p=0.04) independently of family relatedness, sex, history of hypertension, HOMA-IR, central adiposity and renal function, but disappeared when fat-free mass was included in the model.
In the SHS, UA levels are associated to parameters of insulin resistance and to indices of inflammation. UA levels, however, do not predict incident MetS independently of the initial obesity-related increased FFM.
PMCID: PMC4250289  PMID: 25063537
Uric Acid; Metabolic Syndrome; Obesity; Fat Free Mass; Strong Heart Study
3.  Lipoprotein lipase variants interact with polyunsaturated fatty acids for obesity traits in women: Replication in two populations 
Background and aims
Lipoprotein lipase (LPL) is a candidate gene for obesity based on its role in triglyceride hydrolysis and the partitioning of fatty acids towards storage or oxidation. Whether dietary fatty acids modify LPL associated obesity risk is unknown.
Methods and results
We examined five single nucleotide polymorphisms (SNPs) (rs320, rs2083637, rs17411031, rs13702, rs2197089) for potential interaction with dietary fatty acids for obesity traits in 1171 participants (333 men and 838 women, aged 45–75 y) of the Boston Puerto Rican Health Study (BPRHS). In women, SNP rs320 interacted with dietary polyunsaturated fatty acids (PUFA) for body mass index (BMI) (P = 0.002) and waist circumference (WC) (P = 0.001) respectively. Higher intake of PUFA was associated with lower BMI and WC in homozygotes of the major allele (TT) (P = 0.01 and 0.005) but not in minor allele carriers (TG and GG). These interactions were replicated in an independent population, African American women of the Atherosclerosis Risk in Communities (ARIC) study (n = 1334).
Dietary PUFA modulated the association of LPL rs320 with obesity traits in two independent populations. These interactions may be relevant to the dietary management of obesity, particularly in women.
PMCID: PMC4356006  PMID: 25156894
Gene-diet interaction; Lipoprotein lipase; Polyunsaturated fatty acids; Obesity
4.  Age- and gender-specific awareness, treatment, and control of cardiovascular risk factors and subclinical vascular lesions in a founder population: The SardiNIA Study 
We investigated the gender-specific control of cardiovascular (CV) risk factors and subclinical vascular lesions in a founder population in Italy.
Methods and Results
6148 subjects were enrolled (aged 14—102 years) from four towns. Hypertension (HT), diabetes mellitus (DM) and dyslipidemia (LIP) were defined in accordance with guidelines. A self-reported diagnosis defined awareness of these conditions, and the current use of specific medications as treatment.
Prevalence was HT 29.2%, DM 4.8%, LIP 44.1% and was higher in men than in women. Disease prevalence increased with age for every CV risk factor. Men were less likely than women to take anti-HT drugs and to reach BP control (9.9% vs. 16%). Only 17.6% of HT >65 years had a BP ≤140/90 mmHg, though 48.5% were treated. The use of statins was very low (<1/3 of eligible subjects >65 years, those with the highest treatment rate). The ratio of control-to-treated HT was lower in subjects with, than in those without, thicker carotid arteries (31.5% vs. 38.8%, p < 0.05) or stiffer aortas (26.0% vs. 40.0%, p < 0.05) or carotid plaques (26.3% vs. 41.1%, p < 0.05).
A large number of subjects at high CV risk are not treated and the management of subclinical vascular lesions is far from optimal.
PMCID: PMC4658660  PMID: 19321325
Hypertension; Diabetes; Hypercholesterolemia; Subclincal vascular disease; Treatment; Control; Population
5.  Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers 
Background and Aims
Consumption of foods that modulate inflammatory stress in genetically-prone individuals may influence development of cardiometabolic diseases. Isoflavones in soy-derived foods function as phytoestrogens, have antioxidant and anti-inflammatory activity, inhibit protein-tyrosine kinase activity, and may be atheroprotective. We examined the relationship between soy food consumption and inflammatory responses to endotoxemia, postprandial responses to oral lipid tolerance test (OLTT), and insulin sensitivity from frequently sampled intravenous tolerance tests (FSIGTT).
Methods and Results
We administered low-dose endotoxin (LPS 1 ng/kg) to induce transient endotoxemia in young, healthy volunteers (N=215) of African (AA), and European (EA) ancestry as part of the GENE Study. We further supported these findings in two independent samples: the MECHE Study and NHANES. Soy food consumption was a significant predictor of peak cytokine response following LPS. Individuals with moderate-high (>1.48mg/day, N=65) vs. low-no (<1.48mg/day, N=150) isoflavone consumption had significantly higher tumor necrosis factor alpha (TNFα) post-LPS (AUC, P=0.009). Further, high-isoflavone consumers were protected against inflammation-induced decline in insulin sensitivity (SI) in GENE. We observed significant differences by soy consumption in the interferon gamma (IFNγ) response to OLTT, and the insulin response to OGTT in MECHE, as well as significantly lower fasting insulin, and 2-hour glucose post-OGTT in EA NHANES subjects.
We demonstrate that soy consumption may influence inflammatory and metabolic responses. In research of nutritional exposures, measuring evoked phenotypes may be more informative than describing resting characteristics.
Clinical Trial Registry
The GENE Study was registered under NCT00953667 and the MECHE Study under NCT01172951, both at
PMCID: PMC4130742  PMID: 24875672
Cardiometabolic disease; endotoxemia; LPS; isoflavone; soy; inflammation; insulin sensitivity
6.  Body adiposity index and incident hypertension: The Aerobics Center Longitudinal Study 
Background and Aim
The body adiposity index (BAI) has been recently proposed as a new method to estimate the percentage of body fat. The association between BAI and hypertension risk has not been investigated yet. The aim of our study was to evaluate the ability of BAI to predict hypertension in males and females compared with traditional body adiposity measures.
Methods and Results
The present follow-up analysis comprised 10 309 individuals (2259 females) free of hypertension from the Aerobics Center Longitudinal Study, who completed a baseline examination during 1988–2003. Body adiposity measures included BAI, body mass index (BMI), waist circumference, hip circumference, percentage of body fat and waist to hip ratio (WHR). Incident hypertension was ascertained from responses to mail-back surveys between 1990 and 2004. During an average of 9.1 years of follow-up, 872 subjects (107 females) became hypertensive. Hazard ratios (HRs) and 95% confidence intervals (95% CI) showed that males in the highest categories of all body adiposity measures showed a higher incident risk of hypertension (HRs ranged from 1.37 to 2.09). Females showed a higher incident risk of hypertension only in the highest categories of BAI, BMI and WHR (HRs ranged from 1.84 to 3.36).
Our results suggest that in order to predict incident hypertension BAI could be considered as an alternative to traditional body adiposity measures.
PMCID: PMC4130745  PMID: 24974319
Obesity; blood pressure; adiposity; body composition; adults
Background and Aims
Dietary sodium loading has been shown to adversely impact endothelial function independently of blood pressure (BP). However, it is unknown whether dietary sodium loading impacts endothelial function differently in men as compared to women. The aim of this study was to test the hypothesis that endothelial-dependent dilation (EDD) would be lower in men as compared to women in response to a high sodium diet.
Methods and Results
Thirty subjects (14F, 31±2y; 16M, 29±2y) underwent a randomized, crossover, controlled diet study consisting of 7 days of low sodium (LS; 20 mmol/day) and 7 days of high sodium (HS; 300–350 mmol/day). Salt-resistance was determined by a change in 24-hr mean arterial pressure (MAP)≤ 5 mmHg between HS and LS as assessed on day 7 of each diet. Blood and 24-hr urine were also collected and EDD was assessed by brachial artery flow-mediated dilation(FMD). By design, MAP was not different between LS and HS conditions and urinary sodium excretion increased on HS diet (p<0.01). FMD did not differ between men and women on the LS diet (10.2±0.65 vs. 10.7±0.83; p>0.05) and declined in both men and women on HS (p<0.001). However, FMD was lower in men as compared to women on HS (5.7±0.5 vs. 8.6±0.86; p<0.01).
HS reduced FMD in both men and women. In response to a HS diet, FMD was lower in men compared to women suggesting a greater sensitivity of the vasculature to high sodium in men.
PMCID: PMC4195435  PMID: 24989702
sex; sodium; flow-mediated dilation
8.  Fatty and lean red meat consumption in China: differential association with Chinese abdominal obesity 
We examined the longitudinal association between red meat (RM) consumption and the risk of abdominal obesity in Chinese adults.
Methods and results
Our data are from 16,822 adults aged 18 to 75 in the China Health and Nutrition Survey from 1993 to 2011. We assessed RM intake with three 24-hour dietary recalls. We defined abdominal obesity as a waist circumference (WC) ≥ 85 centimeters (cm) for men and ≥ 80 cm for women. Multilevel mixed-effect regression models showed that men experienced WC increases of 0.74 cm (95% confidence interval [CI]: 0.39–1.09) from a higher total intake of fresh RM and 0.59 cm (95% CI: 0.24–0. 95) from a higher intake of fatty fresh RM but 0.14 cm (95% CI: −0.39–0.66) from a higher intake of lean fresh RM in the top versus the bottom quartile when adjusted for potential confounders. In contrast, after additional adjustment for baseline WC, the odds ratios of abdominal obesity in men were attenuated for total fresh RM (1.25 [95% CI: 1.06–1.47]) and fatty fresh RM (1.22 [95% CI: 1.03–1.44]) but were still not affected by lean fresh RM (0.95 [95% CI: 0.75–1.22]). Women also showed a positive association of fatty fresh RM intake with abdominal obesity.
Greater intake of fatty fresh RM was significantly associated with higher WC (men only) and abdominal obesity risk in Chinese adults. The gender-specific differential association of fatty versus lean fresh RM warrants further study.
PMCID: PMC4112159  PMID: 24795160
fatty fresh red meat; abdominal obesity; waist circumference; Chinese
9.  PPARA gene polymorphisms modulate the association between physical activity and cardiometabolic risk 
Background and Aims
Habitual physical activity is understood to help prevent type 2 diabetes and atherosclerotic cardiovascular disease via beneficial effects on both metabolism and the vascular system. However, individuals do not have uniform cardiometabolic responses to physical activity. Here we explore the extent to which variation in the proliferator-activated receptor-alpha (PPARA) gene, which modulates carbohydrate and lipid metabolism, vascular function, and inflammation, predicts the overall cardiometabolic risk (CMR) profile of individuals engaging in various levels of physical activity.
Methods and results
917 unrelated, community volunteers (52% female, of Non-Hispanic European ancestry) aged 30–54 years, participated in the cross-sectional study. Subjects were genotyped for 5 single nucleotide polymorphisms in the PPARA gene, from which common haplotypes were defined. A continuous measure of CMR was calculated as an aggregate of 5 traditional risk factors: waist circumference, resting blood pressure, fasting serum triglycerides, HDL-cholesterol and glucose. Regression models were used to examine the main and interactive effects of physical activity and genetic variation on CMR. One common PPARA haplotype (H-23) was associated with a higher CMR. This association was moderated by daily physical activity (B= −0.11, SE=0.053, t=−2.05, P=0.04). Increased physical activity was associated with a steeper reduction of CMR in persons carrying the otherwise detrimental H-23 haplotype.
Variations in the PPARA gene appear to magnify the cardiometabolic benefits of habitual physical activity.
PMCID: PMC4050124  PMID: 24675006
Metabolic syndrome; cardiometabolic risk; physical activity; gene-by-physical activity interaction
10.  Identification of a dietary pattern associated with greater cardiometabolic risk in adolescence 
Background and aims
Energy dense, high fat, low fibre diets may contribute to obesity in young people, however their relationships with other cardiometabolic risk factors are unclear. We examined associations between an ‘energy-dense, high-fat and low-fibre’ dietary pattern (DP) and cardiometabolic risk factors, and the tracking of this DP in adolescence.
Methods and results
Data was sourced from participants in the Western Australian Pregnancy (Raine) Cohort Study. At 14 and 17 y, dietary intake, anthropometric and biochemical data were measured and z-scores for an ‘energy dense, high fat and low fibre’ DP were estimated using reduced rank regression (RRR). Associations between DP z-scores and cardiometabolic risk factors were examined using regression models. Tracking of DP z-scores was assessed using Pearson's correlation coefficient.
A 1 SD unit increase in DP z-score between 14 and 17 y was associated with a 20% greater odds of high metabolic risk (95% CI: 1.01, 1.41) and a 0.04 mmol/L higher fasting glucose in boys (95% CI: 0.01, 0.08); a 28% greater odds of a high-waist circumference (95% CI: 1.00, 1.63) in girls. An increase of 3% and 4% was observed for insulin and HOMA (95% CI: 1%, 7%), respectively, in boys and girls, for every 1 SD increase in DP z-score and independently of BMI. The DP showed moderate tracking between 14 and 17 y of age (r = 0.51 for boys, r = 0.45 for girls).
An ‘energy dense, high fat, low fibre’ DP is positively associated with cardiometabolic risk factors and tends to persist throughout adolescence.
•Relatively little is known about diet and the early development of cardiometabolic risk factors in young people.•Few studies have examined how dietary patterns track during childhood.•An energy-dense, high fat, low fibre dietary pattern is associated with poorer cardiometabolic health in adolescence.•This type of dietary pattern tracks moderately during adolescence.•The early establishment of healthy eating habits appears important for reducing later cardiometabolic risk.
PMCID: PMC4510146  PMID: 26026208
Dietary patterns; Energy density; Fibre; Fat; Cardiometabolic risk factors; Adolescents; Raine study; CVD, cardiovascular diseases; RRR, reduced rank regression; DP, dietary pattern; Raine, Western Australian Pregnancy (Raine) Cohort; FFQ, food frequency questionnaire; BMI, body mass index; WC, waist circumference; HOMA, insulin resistance; y, years; CSIRO, Commonwealth Scientific and Industrial Research Organisation; CDC, Center for Disease Control; IOTF, International Obesity Task Force; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; PWC-170, physical working capacity 170; PCA, principal component analysis
11.  HDL lipid composition is profoundly altered in patients with type 2 Diabetes and Atherosclerotic Vascular Disease 
Background and Aims
We have previously shown that the anti-inflammatory and anti-oxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD).
Methods and Results
HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (D+CVD−) and 38 T2D with known history of CVD (D+CVD+). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC).
Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from D+CVD+ when compared to D+CVD− and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100.
Patients with D+CVD− and D+CVD+ are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. In the present study, a loss of HDL function (as estimated by the HDL oxidant index) is observed only in patients with more advanced atherosclerosis.
PMCID: PMC4037341  PMID: 24594086
12.  Diet quality and markers of endothelial function: the CARDIA study 
Dietary patterns are associated cross-sectionally with cellular adhesion molecules (CAMs).
We studied prospective associations of three dietary patterns with CAMs.
In the Coronary Artery Risk Development in Young Adults (CARDIA) study, diet was assessed at years 0 (1985-86) and 7 (1992-93) examinations. Four circulating CAMs (E-selectin, P-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and vascular cellular adhesion molecule (VCAM)) were assayed at years 7 and 15 (2000-01). We created one index score “A Priori Diet Quality Score” and derived dietary patterns using principal components analysis (PCA). Multivariable linear regression models predicted year 15 CAMs from averaged (year 0/7) dietary patterns.
The A Priori Diet Quality Score rated 46 food groups beneficial, neutral or adverse based on hypothesized health effects. We derived two PCA dietary patterns: “fruit and vegetables (FV)” (high intakes of fruit, vegetables, and whole grains) and “meat” (high intakes of red meat, refined grain, and butter). All dietary patterns were related to E-selectin and sICAM-1. P-selectin was not related to the FV dietary pattern. VCAM was only related to the A Priori Diet Quality Score. Strongest associations were for the meat dietary pattern with E-selectin (effect size 28% of an SD (+3.9/13.7 ng/mL) and P-selectin (effect size 37% of an SD (+4.1/11.2 ng/mL) and the A Priori Diet Quality Score with sICAM-1 (effect size 34% of an SD (−15.1/44.7 ng/mL) and VCAM (effect size of 26% of an SD (−45.1/170.3 ng/mL).
This prospective analysis suggests that dietary patterns are associated with CAMs.
PMCID: PMC4037360  PMID: 24534074
Cohort; Epidemiology; Diet; Endothelial function; Cellular Adhesion Molecules (CAMs)
13.  Dietary intake, plasma homocysteine, and repetitive element DNA methylation in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background and Aims
DNA methylation of repetitive elements may explain the relations among dietary intake, hyperhomocysteinemia, and cardiovascular disease risk. We investigated associations of methyl micronutrient intake and plasma total homocysteine with LINE-1 and Alu methylation in a cross-sectional study of 987 adults aged 45–84 y who participated in the Multi-Ethnic Study of Atherosclerosis (MESA) Stress Study.
Methods and Results
DNA methylation was estimated using pyrosequencing technology. A 120-item food frequency questionnaire was used to ascertain daily intake of folate, vitamin B12, vitamin B6, zinc, and methionine. Plasma total homocysteine was quantified using a fluorescence polarization immunoassay. Associations of micronutrient intake and homocysteine with LINE-1 and Alu methylation were examined using linear regression. Adjusted differences in %5-methylated cytosines (%5mC) were examined by categories of predictors using multivariable linear regression models. Intake of methyl-donor micronutrients was not associated with DNA methylation. After adjustment for covariates, each 3 μmol/L increment of homocysteine corresponded with 0.06 (−0.01, 0.13) %5mC higher LINE-1 methylation. Additionally, BMI was positively associated with LINE-1 methylation (P trend=0.03). Participants with BMI ≥40 kg/m2 had 0.35 (0.03, 0.67) %5mC higher LINE-1 than those with normal BMI. We also observed a 0.10 (0.02, 0.19) %5mC difference in Alu methylation per 10 cm of height. These associations did not differ by sex.
Dietary intake of methyl-donor micronutrients was not associated with measures of DNA methylation in our sample. However, higher BMI was related to higher LINE-1 methylation, and height was positively associated with Alu methylation.
PMCID: PMC4037331  PMID: 24477006
14.  Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: Effects of fat composition and gender 
Background and aims
We have reported that adverse effects on flow-mediated dilation of an acute elevation of non-esterified fatty acids rich in saturated fat (SFA) are reversed following addition of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA), and hypothesised that these effects may be mediated through alterations in insulin signalling pathways. In a subgroup, we explored the effects of raised NEFA enriched with SFA, with or without LC n-3 PUFA, on whole body insulin sensitivity (SI) and responsiveness of the endothelium to insulin infusion.
Methods and results
Thirty adults (mean age 27.8 y, BMI 23.2 kg/m2) consumed oral fat loads on separate occasions with continuous heparin infusion to elevate NEFA between 60 and 390 min. For the final 150 min, a hyperinsulinaemic-euglycaemic clamp was performed, whilst FMD and circulating markers of endothelial function were measured at baseline, pre-clamp (240 min) and post-clamp (390 min). NEFA elevation during the SFA-rich drinks was associated with impaired FMD (P = 0.027) whilst SFA + LC n-3 PUFA improved FMD at 240 min (P = 0.003). In males, insulin infusion attenuated the increase in FMD with SFA + LC n-3 PUFA (P = 0.049), with SI 10% greater with SFA + LC n-3 PUFA than SFA (P = 0.041).
This study provides evidence that NEFA composition during acute elevation influences both FMD and SI, with some indication of a difference by gender. However our findings are not consistent with the hypothesis that the effects of fatty acids on endothelial function and SI operate through a common pathway.
This trial was registered at clinical as NCT01351324 on 6th May 2011.
•The impact of raised NEFA on endothelial function and insulin sensitivity was studied.•NEFA elevation during the SFA drink reduced FMD while SFA + LC n-3 PUFA improved FMD.•Men had a 10% higher SI with SFA + LC n-3 PUFA than SFA, with SI similar in women.•Changes in FMD were not mirrored by changes in circulating NOx.•Gender mediated the effect of NEFA composition on both endothelial function and SI.
PMCID: PMC4456421  PMID: 25921849
Flow-mediated dilatation; Insulin signalling; Nitric oxide; Hyperinsulinaemic-euglycaemic clamp; Fatty acids; bw, body weight; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; FAME, fatty acid methyl ester; FFM, fat-free mass; FMD, flow-mediated dilatation; iAUC, incremental AUC; LC, long-chain; NEFA, non-esterified fatty acid; NO, nitric oxide; NOx, total nitrites; PI3K, phosphoinositide 3 kinase; SFA, saturated fatty acid; SI, insulin sensitivity; TG, triglyceride
15.  Education modulates the association of the FTO rs9939609 polymorphism with body mass index and obesity risk in the Mediterranean population 
To define whether the rs9939609 FTO (fat mass and obesity associated) single nucleotide polymorphism (SNP) is associated with anthropometric measurements and its modulation by educational level in a Mediterranean population.
We studied 3 independent adult samples: a random sample (n = 1580) from the general population (GP), obese hospital patients (OHP) (n = 203) and elderly subjects (n = 1027) with high cardiovascular risk (HCR). Weight and height were directly measured. Education and physical activity (PA) were measured using questionnaires.
The rs9939609 presented heterogeneous associations with BMI. In the GP, the minor A-allele was significantly associated with greater BMI, following a co-dominant pattern (P = 0.009), whereas in the OHP this association was recessive (P = 0.004). Conversely, we did not find a significant association with BMI in the HCR group (P < 0.596). In the GP we found a significant interaction between the FTO SNP and education (P = 0.048). In the stratified analysis, no association of the FTO SNP with greater BMI in university subjects was detected (P = 0.786), whereas the association was observed in non-university subjects (P = 0.001). The FTO × education interaction (P = 0.020) was also observed in determining obesity risk in the GP. A-allele carriers had a greater risk of being obese only if they had no university education (OR: 1.56; 95%CI: 1.09–2.23 for TA and OR: 2.01; 95%CI: 1.27–3.26 for AA subjects). The interaction of the FTO with education remained significant even after adjustment for PA.
The association of the FTO SNP with greater BMI and obesity risk in the GP was strongly modulated by education.
PMCID: PMC4446979  PMID: 21186106
Obesity; FTO; Educational level; Physical activity; Mediterranean
16.  Fatty acids and TxA2 generation, in the absence of platelet-COX-1 activity 
Background and aims
Omega-3 fatty acids suppress Thromboxane A2 (TxA2) generation via mechanisms independent to that of aspirin therapy. We sought to evaluate whether baseline omega-3 fatty acid levels influence arachidonic acid proven platelet-cyclooxygenase-1 (COX-1) independent TxA2 generation (TxA2 generation despite adequate aspirin use).
Methods and results
Subjects with acute myocardial infarction, stable CVD or at high risk for CVD, on adequate aspirin therapy were included in this study. Adequate aspirin action was defined as complete inhibition of platelet-COX-1 activity as assessed by <10% change in light transmission aggregometry to ≥1 mmol/L arachidonic acid. TxA2 production was measured via liquid chromatography–tandem mass spectrometry for the stable TxA2 metabolite 11-dehydro-thromboxane B2 (UTxB2) in urine. The relationship between baseline fatty acids, demographics and UTxB2 were evaluated. Baseline omega-3 fatty acid levels were not associated with UTxB2 concentration. However, smoking was associated with UTxB2 in this study.
Baseline omega-3 fatty acid levels do not influence TxA2 generation inpatients with or at high risk for CVD receiving adequate aspirin therapy. The association of smoking and TxA2 generation, in the absence of platelet COX-1 activity, among aspirin treated patients warrants further study.
PMCID: PMC4409424  PMID: 24370448
Omega-3 fatty acids; Thromboxane; Aspirin resistance; Platelet activation; Smoking
17.  Long-Term Dietary Sodium Restriction Increases Adiponectin Expression and Ameliorates the Proinflammatory Adipokine Profile in Obesity 
Obesity is associated with changes in adiponectin and pro-inflammatory adipokines. Sodium intake can affect adipokine secretion suggesting a role in cardiovascular dysfunction. We tested if long-term dietary sodium restriction modifies the expression of adiponectin and ameliorates the pro-inflammatory profile of obese, diabetic
Db/db mice were randomized to high sodium (HS 1.6% Na+, n=6) or low sodium (LS 0.03% Na+, n=8) diet for 16 weeks and compared with lean, db/+ mice on HS diet (n=8). Insulin levels were 50% lower in the db/db mice on LS diet when compared with HS db/db (p <0.05). LS diet increased cardiac adiponectin mRNA levels in db/db mice by 5-fold when compared with db/db mice on HS diet and by 2-fold when compared with HS lean mice (both p < 0.01). LS diet increased adiponectin in adipose tissue compared with db/db mice on HS diet, achieving levels similar to those of lean mice. MCP-1, IL-6 and TNF-α expression were reduced more than 50% in adipose tissue of db/db mice on LS diet when compared with HS db/db mice (all p < 0.05), to levels observed in the HS lean mice. Further, LS db/db mice had significantly reduced circulating MCP-1 and IL-6 levels when compared with HS db/db mice (both p < 0.01).
In obese-diabetic mice, long-term LS diet increases adiponectin in heart and adipose tissue and reduces pro-inflammatory factors in adipose tissue and plasma. These additive mechanisms may contribute to the potential cardioprotective benefits of LS diet in obesity-related metabolic disorders.
PMCID: PMC4405158  PMID: 24418377
sodium intake; obesity; inflammation; adiponectin; diabetes; insulin resistance
18.  Effects of Equol on Gene Expression in Female Cynomolgus Monkey Iliac Arteries 
Background and Aims
To examine effects of equol, the soy phytoestrogen metabolite, on gene expression in the monkey iliac artery.
Methods and Results
A high fat/high cholesterol diet was fed to eight ovariectomized cynomolgus monkeys for 6.5 years. After biopsy of the left iliac artery, the animals were randomized to two treatment groups for 8 months; the treatment groups were equol (23.7 mg/100 g diet, n=4) and vehicle (n=4). The right iliac artery was removed at necropsy. Gene expression in the iliac arteries in response to equol was determined by DNA microarray. Comparison of atherosclerotic lesions and plasma lipids at pre- versus post-equol treatment time points and in vehicle versus equol treatment groups did not identify any significant differences. Despite the lack of effect of equol on these parameters, 59 genes were down-regulated and 279 were up-regulated in response to equol. Comparison of these data to previous work identified 10 genes regulated in opposite directions by equol compared to presence of atherosclerosis plaque (Menopause 2011;18:1087–1095) and 55 genes differentially expressed in the same direction in response to both equol and estradiol (Eyster et al., Menopause 2013; in press).
Similar responses of genes to both equol and estradiol may reflect the extent to which equol serves as a natural selective estrogen receptor modulator in the arteries. Opposite responses of 10 genes to equol versus the presence of atherosclerosis implicates those genes in the potential protective effects of equol in arteries.
PMCID: PMC3972297  PMID: 24525253
equol; soy; gene expression; DNA microarray; atherosclerosis; artery
19.  ADAM17_i33708A>G polymorphism interacts with dietary n-6 polyunsaturated fatty acids to modulate obesity risk in the Genetics of Lipid Lowering Drugs and Diet Network study 
Background and aims
The disintegrin and metalloproteinase ADAM17, also known as tumor necrosis factor alpha converting enzyme, is expressed in adipocytes. Importantly, elevated levels of ADAM17 expression have been linked to obesity and insulin resistance. Therefore, the aim of this study was to evaluate the association of six ADAM17 single nucleotide polymorphisms (SNPs) (m1254A>G, i14121C>A, i33708A>G, i48827A>C, i53440C>T, and i62781G>T) with insulin-resistance phenotypes and obesity risk, and their potential interactions with dietary polyunsaturated fatty acids (PUFA).
Methods and results
ADAM17 SNPs were genotyped in 936 subjects (448 men/488 women) who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Anthropometrical and biochemical measurements were determined by standard procedures. PUFA intake was estimated using a validated questionnaire. G allele carriers at the ADAM17_m1254A>G polymorphism exhibited significantly higher risk of obesity (P=0.003), were shorter (P=0.017), had higher insulin (P=0.016), and lower HDL-C concentrations (P=0.027) than AA subjects. For the ADAM17_i33708A>G SNP, homozygotes for the A allele displayed higher risk of obesity (P=0.001), were heavier (P=0.011), had higher BMI (P=0.005), and higher waist measurements (P=0.023) than GG subjects. A significant gene-diet interaction was found (P=0.030), in which the deleterious association of the i33708A allele with obesity was observed in subjects with low intakes from (n-6) PUFA (P<0.001), whereas no differences in obesity risk were seen among subjects with high (n-6) PUFA intake (P>0.5)
These findings support that ADAM17 (m1254A>G and i33708A>G) SNPs may contribute to obesity risk. For the ADAM17_i33708A>G SNP, this risk may be further modulated by (n-6) PUFA intake.
PMCID: PMC4361226  PMID: 19819120
gene-diet interaction; obesity; BMI; HDL-cholesterol; insulin concentrations
20.  The low-carbohydrate diet and cardiovascular risk factors: Evidence from epidemiologic studies 
Obesity is an important public health issue because of its high prevalence and concomitant increase in risk of cardiovascular diseases. Low carbohydrate diets are popular for weight loss and weight management but are not recommended in leading guidelines due to the perception that increases in dietary fat intake may lead to an adverse cardiovascular risk profile. To clarify the effects of a low-carbohydrate diet for weight loss on cardiovascular disease risk factors as compared to a low fat diet for weight loss, we systematically reviewed data from randomized controlled clinical trials and large observational studies.
Data synthesis
We searched the MEDLINE database (Jan 1966–Nov 2013) to identify studies that examined a low-carbohydrate diet as compared to a low-fat diet for weight loss or the improvement of cardiovascular disease risk factors.
Recent randomized controlled trials document that low-carbohydrate diets not only decrease body weight but also improve cardiovascular risk factors. In light of this evidence from randomized controlled trials, dietary guidelines should be re-visited advocating a healthy low carbohydrate dietary pattern as an alternative dietary strategy for the prevention of obesity and cardiovascular disease risk factors.
PMCID: PMC4351995  PMID: 24613757
Low carbohydrate diet; Cardiovascular disease; Risk factors; Weight loss
21.  Cardiometabolic risk in overweight subjects with or without relative fat-free mass deficiency: the Strong Heart Study 
Sarcopenia is a condition mainly due to loss of fat-free mass (FFM) in elderly individuals. RFFMD, however, is also frequent in obese subjects due to abnormal body composition. Objective of this study was to evaluate the impact of relative fat-free mass deficiency (RFFMD) on cardiometabolic (CM) risk in obese normoglycemic individuals.
Overweight/obese American Indians from the Strong Heart Study population, without diabetes and with FBG ≤ 110 mg/dL and with GFR>60 mg/mL/1.73 m2 were selected for this analysis (n=742). RFFMD was defined on the basis of a multivariable equation previously reported. Fasting glucose and 2hr -OGTT were measured together with urine albumin/creatinine excretion, laboratory and anthropometric parameters.
In addition to lower FFM and greater adipose mass, participants with RFFMD had higher body mass index, waist circumference, C-reactive protein, fibrinogen, insulin resistance and urinary albumin/creatinine than participants with normal FFM (all p<0.001); they also had a greater prevalence of hypertension, impaired glucose tolerance (IGT) or OGTT-diabetes than participants with normal FFM (all p<0.003) and a near 2-fold greater probability of significant proteinuria (p<0.01). RFFMD was more frequent in women than in men: significant sex-RFFMD interactions were found for BMI and waist circumference (both p<0.0001).
RFFMD in overweight/obese normoglycemic individuals is associated with greater probability of hypertension, abnormalities of glucose tolerance and proteinuria. Assessment of RFFRMD might, therefore, help stratifying cardiometabolic risk among normoglycemic individuals with overweight/obesity.
PMCID: PMC3959567  PMID: 24360764
fat-free mass deficiency; cardiometabolic risk; overweight/obesity; normoglycemia; proteinuria
22.  Determinants of intrathoracic adipose tissue volume and associations with cardiovascular disease risk factors in Amish 
Hypothesizing that intrathoracic fat might exert local effects on the coronary vasculature, we assessed the association of intrathoracic fat volume and its two subcomponents with coronary artery calcification (CAC) in 909 relatively healthy Amish adults.
Design and Methods
Intrathoracic fat, which is comprised of fat between the surface of the heart and the visceral epicardium (epicardial fat) and fat around the heart but outside of the fibrous pericardium (pericardial fat), was measured from electron beam CT scans. We examined the association between intrathoracic fat volume and cardiovascular disease risk factors in multivariate regression model.
Fat volume in the epicardial and pericardial compartments were highly correlated with each other and with body mass index. Neither CAC extent nor CAC presence (Agatston score>0) was associated with increased intrathoracic fat volume in sex-stratified models adjusting for age (p>0.10). Intrathoracic fat volume was significantly correlated with higher systolic/diastolic blood pressure, pulse pressure, fasting glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol in sex-stratified models adjusting for age (p<0.05). However, associations were attenuated after further adjustment for body mass index.
These data do not provide support for a significant role for intrathoracic fat in the development of CAC.
PMCID: PMC4109402  PMID: 24477004
Ectopic fat; Intrathoracic fat; Epicardial fat; Obesity; Coronary artery calcification; Cardiovascular diseases
23.  [No title available] 
PMCID: PMC3943940  PMID: 24361073
24.  Reduction in Dietary Trans Fat Intake is Associated with Decreased LDL Particle Number in a Primary Prevention Population 
Background and Aims
Increased trans fat intake has been associated with an increased risk of cardiovascular disease (CVD). While the affect of trans fat on traditional lipids is known, it’s association with LDL particle number (LDL-P), a novel marker of CVD risk, has not been established. The purpose of this study was to determine the association between trans fat intake and LDL-P over 1-year among individuals participating in a lifestyle intervention trial.
Methods and Results
Family members (n = 400, 33% male, mean age 48 ± 13) of patients hospitalized with CVD who participated in a 1-year randomized controlled primary prevention lifestyle intervention trial and had complete dietary data and LDL-P measures at baseline and 1-year. Change in trans fat as a percentage of total diet and mean absolute change in LDL-P at 1-year was assessed using multivariate adjusted linear regression models. At baseline, there was a significant positive correlation between dietary trans fat intake and LDL-P (Beta = 37, p = 0.04). For every 1 percent change in trans fat intake there was a 27 nmol/L change in LDL-P (Beta = 27, p = 0.04) over 1-year which was independent of baseline predictors and confounders (age, sex, smoking, statin use, waist size and physical activity; Beta = 30, p = 0.03).
A reduction in trans fat intake over 1-year was significantly associated with a reduction in LDL-P independent of potential confounders. Healthcare providers should reinforce the beneficial impact of a healthy diet, and in particular modifications in trans fat intake on improving lipid profiles.
PMCID: PMC3943937  PMID: 24099723
Prevention; Cardiovascular Disease; Nutrition
25.  Assessment of Old and New Proteins 
Nutrition, metabolism, and cardiovascular diseases : NMCD  2012;23(0 1):10.1016/j.numecd.2012.05.006.
Protein modifications and the accumulation of those proteins are implicated in a host of diseases from Parkinson’s and Alzheimer’s to both insulin independent and insulin dependent diabetes mellitus. Accumulation of irreversibly modified proteins occurs when the degradation rate of proteins is reduced or the rate of modification increases. Although the synthesis rates of individual proteins in vivo have been extensively studied the methodology to measure degradation rates of individual proteins in vivo remains to be well developed. However, the ability to measure the relative age of a particular protein pool in relation to the quality of the pool (amount of damage) is a recent advance. This brief review describes a novel methodology to simultaneously measure the synthesis rate of individual proteins along with the accumulation of oxidative damage to those proteins in vivo. The results of a recent investigation on individuals with type 1 diabetes mellitus are described. Accelerated damage to de novo synthesized ApoA1 is shown during short-term insulin cessation, which has potential clinical implications. Future implications of the novel method in diabetes and aging are also discussed.
PMCID: PMC3537901  PMID: 22784971
protein; synthesis; turnover; isotope tracer; individual proteins

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