High-density Lipoprotein Cholesterol Response Research Articles

PHOSPHO1 Gene DNA Methylations are Associated with a Change in HDL-C Response to Simvastatin Treatment.

Our aim was to detect the effects of DNA methylations in the phosphoethanolamine/ phosphocholine phosphatase (PHOSPHO1) gene on the therapeutic efficacy of simvastatin. We used an extreme sampling approach by selecting 211 individuals from approximately the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n=104 for the high response group and n=107 for the low response group) from a total of 734 subjects with hyperlipidemia. They received a daily oral dose of 20 mg simvastatin for eight consecutive weeks. DNA methylation loci at the PHOSPHO1 gene were measured using high-throughput next-generation sequencing-based sequencing technology. Fasting serum lipids were measured at baseline and after eight weeks of simvastatin treatment. Mean PHOSPHO1 DNA methylation had a significant negative correlation with high-density lipoprotein cholesterol (HDL-C) variation (β=-0.014, P=0.045) in the high response group. After stratifying by body mass index (BMI), the associations between the PHOSPHO1 DNA methylations and the change in HDL-C in response to simvastatin were more significant in obese subjects with a BMI of 25 kg/m2 or higher (β=-0.027, P=0.002). Mean PHOSPHO1 methylation and traditional predictors could explain up to 24.7% (adjusted R2) of the change in HDL-C response in obese patients. There was a statistically significant additive interaction term (P=0.028) between BMI and mean PHOSPHO1 methylation in the model of the change in HDL-C in response to simvastatin. Our findings suggest that PHOSPHO1 DNA methylations are associated with a change in HDL-C in response to simvastatin treatment, and this association is especially dependent on the extent of patient obesity.

Plasma high-density lipoprotein cholesterol responses to endurance exercise training: A meta-analysis of randomized controlled trials

Background: Endurance exercise improves lipid and lipoproteins levels, while low high-density lipoprotein cholesterol (HDL-C) levels are risk factors for cardiovascular disease. There is a lack of evidence for the exercise characteristics in increasing lipids level, irrespective of the fact that endurance exercise increases lipids and lipoproteins level. The aim of this study was to clarify the effect and characteristics of endurance exercise in increasing HDL-C in randomized controlled trials. Methods: A search was performed for published studies between 1999 and 2014. Studies that assessed endurance exercise for ≥8 weeks and also reported the HDL-C levels pre- and post-training were included. The random effects model was used to measure the association between exercise and net change of HDL-C. Univariate regression analyses investigated the correlation of exercise characteristics. Subgroup and sensitivity analyses were performed to explore the sources of heterogeneity and the effect of potential confounders. The influence of pre-exercise lipid profile was assessed by meta-regression. Data were analyzed using Stata SE (12.0). Results: Fourteen studies with a total of 777 subjects were included. The mean HDL-C was reported to be increased and was statistically significant (weighted mean difference: 4.41 mg/dL; 95% confidence interval [CI]: 2.16–6.66 mg/dL, P < 0.001; I2 = 87.4%, P < 0.001). Univariate analysis indicated that exercise length was significantly associated with a net change of HDL-C (r = 0.56, P = 0.01). Nevertheless, there was no significant association between exercise frequency, duration, and total minutes. By subgroup analysis, exercise increased HDL-C level in Asia, Europe, and Africa and among all body mass index groups (P < 0.05). None of the studies omitted, in turn, seemed to substantially influence the effect of exercise on HDL-C by sensitivity analysis. Meta-regression showed that pre-exercise total cholesterol (TC) negatively correlated with net change of HDL-C (95% CI: 0.127, −0.018, r = −0073, P = 0.012). However, pre-exercise triglycerides, low-density lipoprotein cholesterol, and HDL-C did not correlate with a net change of HDL-C. Conclusions: Regular endurance exercise increases HDL-C level in any weight population. Exercise length of more than 8 weeks was the most important element of an exercise prescription. Among all lipid profiles, only the initial lower TC level responded better to exercise training and was more effective in increasing HDL-C level.

Incorporating healthy dietary changes in addition to an increase in fruit and vegetable intake further improves the status of cardiovascular disease risk factors: A systematic review, meta-regression, and meta-analysis of randomized controlled trials.

Fruit and vegetable (FV) intake has been associated with a reduced risk of cardiovascular disease (CVD). Beyond increasing FV intake, the incorporation of other healthy dietary changes may help to further attenuate CVD risk. A systematic review and meta-analysis was conducted to determine the effect of increasing FV intake to > 3 servings daily as well as incorporating other healthy dietary changes on classical CVD risk factors through a systematic review, meta-regression, and meta-analysis of randomized controlled trials. The following databases were searched: PubMed, CINAHL Plus with Full Text, Medline (ProQuest), and Cochrane Library. 82, 24, and 10 articles were selected for the systematic review, meta-regression, and meta-analysis, respectively. Meta-regression analysis showed a dose-dependent response between the number of FV servings consumed in each intervention group and the blood triglyceride change value. Pooled weighted mean differences from the meta-analysis suggested that increasing FV intake to > 3 servings daily contributes to significant decreases in triglyceride (-0.10 mmol/L; 95%CI, -0.18 to -0.01) and diastolic blood pressure (-1.99 mmHg; 95%CI, -2.28 to -1.70) as well as marginal decreases in total cholesterol and low-density lipoprotein cholesterol. While improvements were observed in the triglyceride and high-density lipoprotein cholesterol response following the incorporation of other healthy dietary changes, no additional cardiovascular benefits were observed when FV intake was increased from > 3 to > 5 servings daily. Increasing FV intake to > 3 servings daily improves CVD risk factors, most distinctly triglyceride, especially when complemented with other healthy dietary changes.

Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia

Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional ∼20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.

Development of a Genetic Score to Predict an Increase in HDL Cholesterol Concentration After a Dietary Intervention in Adults with Metabolic Syndrome

Dietary intervention (DI) is a primary strategy to attenuate some of the metabolic abnormalities associated with metabolic syndrome (MetS), including low HDL cholesterol. There is no biomarker that can identify individuals who respond to DI by increasing HDL cholesterol. The aim of this study was to assess the predictive power of a genetic predisposition score (GPS) in Mexican adults with MetS to identify HDL cholesterol responders to DI. This study followed a prospective cohort design. Sixty-seven Mexican adults aged 20-60 y (21% men) with BMI ≥25 and ≤39.9 kg/m², who had at least 3 of 5 positive criteria for MetS, were included. Participants consumed a low saturated fat diet for 2.5 mo (<7% energy as saturated fat, <200 mg of cholesterol/d) and reduced their usual diet by ∼440 kcal/d, a reduction in total energy intake of about 25%. Anthropometry and serum biochemical markers, including HDL cholesterol, were measured before and after DI. A multilocus GPS was constructed using previously reported genetic variants associated with response to diet in subjects with MetS. GPS values, designed to predict the response of HDL cholesterol to the DI, were computed for each individual as the sum of the number of effect alleles across 14 SNPs. Individuals were dichotomized as high and low GPS according to median GPS (-2.12) and we observed a difference in HDL cholesterol changes on DI of +3 mg/dL (6.3%) in subjects with low GPS, whereas those with high GPS had HDL cholesterol decreases of -3 mg/dL (-7.9%) (P=0.04). Individuals with low GPS showed greater increases in their HDL cholesterol than those with high GPS. Therefore, the GPS can be useful for predicting the HDL cholesterol response to diet.

Causal modeling in a multi-omic setting: insights from GAW20

BackgroundIncreasingly available multilayered omics data on large populations has opened exciting analytic opportunities and posed unique challenges to robust estimation of causal effects in the setting of complex disease phenotypes. The GAW20 Causal Modeling Working Group has applied complementary approaches (eg, Mendelian randomization, structural equations modeling, Bayesian networks) to discover novel causal effects of genomic and epigenomic variation on lipid phenotypes, as well as to validate prior findings from observational studies.ResultsTwo Mendelian randomization studies have applied novel approaches to instrumental variable selection in methylation data, identifying bidirectional causal effects of CPT1A and triglycerides, as well as of RNMT and C6orf42, on high-density lipoprotein cholesterol response to fenofibrate. The CPT1A finding also emerged in a Bayesian network study. The Mendelian randomization studies have implemented both existing and novel steps to account for pleiotropic effects, which were independently detected in the GAW20 data via a structural equation modeling approach. Two studies estimated indirect effects of genomic variation (via DNA methylation and/or correlated phenotypes) on lipid outcomes of interest. Finally, a novel weighted R2 measure was proposed to complement other causal inference efforts by controlling for the influence of outlying observations.ConclusionsThe GAW20 contributions illustrate the diversity of possible approaches to causal inference in the multi-omic context, highlighting the promises and assumptions of each method and the benefits of integrating both across methods and across omics layers for the most robust and comprehensive insights into disease processes.

Association of ABCC2 polymorphism and gender with high-density lipoprotein cholesterol response to simvastatin.

The clinical benefits of lipid-lowering therapy with statins are widely recognized.However, the lipid-lowering efficacy of statins shows significant differences between individuals. ABCC2 has been demonstrated to contribute to the transmembrane transport of the substrate compounds. The ABCC2 SNPs may be important factors that affect individual differences in clinical drug response. The aim of this study was to evaluate the association of rs717620 of ABCC2 with treatment response to simvastatin in a Chinese Han population. A total of 318 subjects were medicated with simvastatin 20mg/day for 12 weeks after enrollment. Venous blood was obtained before and after simvastatin treatment for measurement of blood lipid profile. Subjects were classified into high-response and low-response groups depending on whether their lipid profile change was higher or lower than median change values. The ABCC2 SNP rs717620 was genotyped from blood samples with a snapshot assay. A total of 12 weeks of treatment with simvastatin significantly decreased low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TGs) and significantly increased high-density lipoprotein cholesterol (HDL-C; p < 0.05). In multivariate analysis, there were no significant genetic effects of SNP rs717620 on the incidence of high- or low-response patients among TC, TG and LDL-C groups. However, rs717620 A-allele and female gender are significantly associated with the risk of low-response of HDL-C elevation after simvastatin treatment. ABCC2 rs717620 and female gender may be related to the low-effect of simvastatin treatment on the HDL-C level in the Chinese Han population. Female Chinese patients with hyperlipidemia carrying rs717620 GA/AA genotypes might have reduced benefit from simvastatin treatment.

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

BackgroundIn addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained...

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

Differential Lipid Response to Statins Is Associated With Variants in the BUD13-APOA5 Gene Region.

Genetic variants within the BUD13-APOA5 gene region are known to be associated with high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. Recent studies suggest that single nucleotide polymorphisms (SNPs) within this region affect HDL-C response to statin-fibrate combination therapy and low-density lipoprotein cholesterol (LDL-C) response to statin therapy. We hypothesized that SNPs within the BUD13-APOA5 region are associated with TG, HDL-C, and LDL-C response to statin therapy. We examined 1520 observations for 1086 patients from the Personalized Medicine Research Project, a large biorepository at the Marshfield Clinic Research Foundation, who had received statin therapy and been previously genotyped for polymorphisms in the 11q23 chromosomal region. A significant differential response to statin therapy was observed for 3 SNPs. The minor allele at rs11605293 significantly attenuated TG-lowering response to pravastatin (P = 0.000159), whereas the minor allele at rs12806755 was associated with a similar response to lovastatin (P = 0.000192). Genotypes at rs947990 significantly attenuated LDL-C reduction to atorvastatin therapy (P = 0.000668) with some patients with the minor allele having LDL-C increase after therapy. No SNPs within the BUD13-APOA5 region were associated with a significant effect on HDL-C reduction in response to statin therapy. In conclusion, this study suggests that common SNPs within the BUD13-APOA5 can affect TG and LDL-C response to statin therapy in a North American population.

Early Improvement of Postprandial Lipemia After Bariatric Surgery in Obese Type 2 Diabetic Patients

Bariatric surgery (BS) is able to positively influence fasting lipid profile in obese type 2 diabetic patients (T2DM), but no data is available on the impact of BS on postprandial lipid metabolism neither on its relation with incretin hormones. We evaluated the short-term (2 weeks) effects of BS on fasting and postprandial lipid metabolism in obese T2DM patients and the contribution of changes in active GLP-1. We studied 25 obese T2DM patients (age = 46 ± 8 years, BMI = 44 ± 7 kg/m2), of which 15 underwent sleeve gastrectomy and 10 underwent gastric bypass. Lipid and incretin hormone concentrations were evaluated for 3 h after ingestion of a liquid meal before and 2 weeks after BS. After BS, there was a significant reduction in body weight (p < 0.001), fasting plasma glucose (p < 0.001), fasting plasma insulin (p < 0.05), HOMA-IR (p < 0.001), and fasting plasma lipids (p < 0.05). The meal response of plasma triglycerides, total cholesterol, and HDL cholesterol was significantly lower compared to pre-intervention (p < 0.05, p < 0.001). In particular, the incremental area under the curve (IAUC) of plasma triglycerides decreased by 60% (p < 0.005). The meal-stimulated response of active GLP-1 increased, reaching a statistical significance (p < 0.001). BS leads to an early improvement of fasting and postprandial lipemia. The fall in fasting triglycerides is associated with an improvement of insulin resistance, while the reduction of postprandial lipemia is likely related to reduced intestinal lipid absorption consequent to bariatric surgery.

Low level of high-density lipoprotein cholesterol correlates with poor prognosis in extranodal natural killer/T cell lymphoma

Studies have found that lymphoma patients often exhibit abnormal lipid metabolism, and a decrease in serum high-density lipoprotein cholesterol (HDL-C) may occur during lymphomagenesis and tumor growth. However, no literatures have investigated the role of HDL-C in patients with extranodal natural killer/T cell lymphoma (ENKTL). In this study, we retrospectively reviewed the HDL-C level in 107 patients newly diagnosed with ENKTL that received either l-asparaginase-based regimen or EPOCH regimen as induction chemotherapy, and evaluated its prognostic value. The mean level of HDL-C was 1.10 mmol/L (range, 0.15–2.63), and the HDL-C level was significantly lower in patients with elevated LDH and beta 2-microglobulin (β2-MG) (p = 0.017 and 0.001, respectively) and those who underwent disease progression and died (p = 0.031 and 0.007, respectively). In univariate survival analysis, higher Eastern Cooperative Oncology Group performance status score (≥1), Ann Arbor stage III–IV, elevated LDH, higher international prognostic index (IPI) score (≥2 vs. 1 vs. 0), decreased HDL-C level (<40 mg/dL), elevated β2-MG level, and response status after induction chemotherapy correlated significantly with poor progression-free survival (PFS) and overall survival (OS) (p < 0.05). In a multivariate Cox regression model that included IPI score, HDL-C level, β2-MG level, and response status after induction chemotherapy, it was found that HDL-C level and response status after chemotherapy were independent prognostic factors for OS (p = 0.014 and 0.010, respectively) and PFS (p = 0.016 and 0.020, respectively). In conclusion, HDL-C was found to be a valuable independent prognostic factor in ENKTL, and the mechanism needs to be further investigated, which may offer the possibility of therapeutic targets.

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins.

Effect of an isoenergetic traditional Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome

BackgroundThe impact of the Mediterranean diet (MedDiet) on high-density lipoprotein (HDL) kinetics has not been studied to date. The objective of this study was therefore to investigate the effect of the MedDiet in the absence of changes in body weight on apolipoprotein (apo) A-I kinetic in men with metabolic syndrome (MetS).MethodsTwenty-six men with MetS (NCEP-ATP III) were recruited from the general community. In this fixed sequence study, participants’ diet was first standardized to a control diet reflecting current averages in macronutrient intake in North American men, with all foods and beverages provided under isoenergetic conditions for 5 weeks. Participants were then fed an isoenergetic MedDiet over a subsequent period of 5 weeks to maintain their weight constant. During the last week of each diet, participants received a single bolus dose of [5,5,5-2H3] L-leucine and fasting blood samples were collected at predetermined time points. ApoA-I kinetic was determined by multicompartmental modeling using isotopic enrichment data over time. Data were analyses using MIXED models.ResultsThe response of HDL-cholesterol (C) to MedDiet was heterogeneous, such that there was no mean change compared with the control diet. Plasma apoA-I concentration (−3.9%) and pool size (−5.3%, both P < 0.05) were significantly lower after MedDiet and apoA-I production rate tended to be reduced (−5.7%, P = 0.07) with no change in apoA-I fractional catabolic rate (FCR, -1.6%, P = 0.64). Participants among whom HDL-C concentrations were increased with MedDiet (responders: mean ∆HDL-C: +9.9 ± 3.2%, N = 11) showed significantly greater reductions in apoA-I FCR and in apoB and very-low-density lipoprotein-triglycerides (VLDL-TG) concentrations (all P < 0.04) than those among whom HDL-C levels were reduced after the MedDiet (non-responders: mean ∆HDL-C: -12.0 ± 3.9%, N = 8). Correlation analysis revealed that only variations in apoA-I FCR (r = -0.48, P = 0.01) and in plasma VLDL-TG (r = −0.45, P = 0.03) concentrations were correlated with the individual HDL-C response to the MedDiet.ConclusionsData from this controlled feeding study suggest that the heterogeneous response of HDL-C to MedDiet, in the absence of important weight loss, is primarily related to individual variations in apoA-I FCR and in plasma VLDL-TG concentrations.Trial registrationClinicalTrial.gov registration number: NCT00988650

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 proteins have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts.

Two Weeks of Low Dose Fish Oil Supplementation Followed By A Single Bout of Exercise Increases High Density Lipoprotein Cholesterol in College-Aged and Middle-Aged Men

There is a significant inverse relationship between high density lipoprotein cholesterol (HDL-C) and cardiovascular events. Previous studies have reported increased HDL-C in response to 4 weeks of pharmacological doses of omega-3 fatty acids (n-3 FA) (3-5g/day). Our hypothesis was that a low dose of n-3 FA (eicosapentaenoic and docosahexaenoic acid), one achievable in the diet, ingested in the form of one fish oil capsule three times per day by college-aged and middle-aged men, over a short period of 2 weeks, preceded and followed by a single bout of exercise, would increase HDL-C levels. We determined serum lipid profile (triglyceride, VLDL-C, LDL-C, HDL-C, total cholesterol) in response to a single bout of exercise (60 min, 55-60% HRmax) after consuming a low dose of 0.9 g n-3 FA/day for 14 days in eight middle-aged men (age 48.9 ± 1.4) and seven college-aged men (age 21 ± 2.5). There were no significant changes with blood lipids except in HDL-C. In middle-aged and college-aged men HDL-C significantly increased (P<0.005). The college-aged men’s TC/HDL-C ratio significantly increased (P<0.05). Our findings suggest that two weeks of ingesting dietary achievable doses of n-3 FA followed by a single bout of exercise increase HDL-C, which is associated with a decreased risk for coronary heart disease (CHD).

Paradoxical Negative HDL Cholesterol Response to Atorvastatin and Simvastatin Treatment in Chinese Type 2 Diabetic Patients

There is extensive but controversial evidence on the diverse effects of statins on the level of high-density lipoprotein cholesterol (HDL-C). Some of these effects may limit the benefits of statins in terms of cardiovascular risk reduction. To identify the conditions for beneficial effects, this study investigated the response to atorvastatin and simvastatin treatment in type 2 diabetic patients with elevated low-density lipoprotein cholesterol (LDL-C). 2,872 subjects with type 2 diabetes from a disease management program were investigated. Patients with LDL-C ≥130 mg/dl or total cholesterol ≥200 mg/dl were put onto statin therapy by the National Health Insurance system in Taiwan. 1,080 patients who completed 1 year of statin treatment were analyzed. There were significant reductions in LDL-C in both the atorvastatin (37.1%) and simvastatin (34.3%) group after one year of treatment compared with baseline levels. Unexpectedly, the majority of diabetic patients who received atorvastatin or simvastatin did not show an increase in HDL-C levels. 59.8% of patients had a significant HDL-C reduction (ΔHDL-C ≤ -3%) after atorvastatin treatment. Multivariate logistic regression analysis showed that the following patients were at higher risk of HDL-C reduction after 12 months: (i) patients in whom statin therapy was initiated aged <65 years and who had a BMI ≥24 kg/m(2), (ii) male patients with a baseline HDL-C >40 mg/dl, and (iii) female patients with a baseline HDL-C >50 mg/dl. However, diabetic patients with severe atherogenic dyslipidemia (LDL-C ≥130, TG ≥204, and HDL-C ≤34 mg/dl) obtained more benefits in terms of HDL-C change after statin therapy. Diabetic patients, except those with severe atherogenic dyslipidemia, are prone to a decrease in serum HDL-C level after statin treatment, particularly after atorvastatin treatment.

CNR1 genotype influences HDL-cholesterol response to change in dietary fat intake.

BackgroundSuccess in further reducing the burden of cardiovascular disease (CVD) is threatened by the increasing prevalence of obesity-related atherogenic dyslipidemia. HDL-cholesterol (HDL-C) level is inversely correlated with CVD risk; each 1 mg/dl decrease in HDL-C is associated with a 6% reduction in risk. We previously showed that a common CNR1 haplotype, H3 (frequency 20%), is protective against the reduction in HDL-C that typically accompanies weight gain. In the present study, we extend that observation by reporting the effect of CNR1 haplotype on HDL-C response to modification of dietary fat intake in weight maintenance and weight loss.MethodsSix haplotype tagging SNPs that cover the CNR1 gene locus were genotyped in 590 adults of varying body mass index (cohort 1 is 411 males with BMI 18.5–30.0 kg/m2; cohort 2 is 71 females with BMI18.5–30.0 kg/m2; and cohort 3 is 108 females with BMI 30–39.9 kg/m2). Dietary intakes were modified so that fat intake in the “high fat” condition was 15–20% greater than in the “low fat” condition, and lipid profiles were compared between carriers versus noncarriers for each of the five commonly observed CNR1 haplotypes (H1–H5).ResultsIn normal to overweight subjects on eucaloric diets, the H3 haplotype was significantly associated with short-term high fat diet induced changes in HDL-C level in females (carriers 5.9 mg/dl>noncarriers, p = 0.007). The H3 haplotype was also significantly associated with HDL-C level after 16 weeks on high fat calorie restricted diet in obese females (carriers 6.8 mg/dl>noncarriers, p = 0.009).ConclusionVariability within the CNR1 gene locus contributes to gender-related differences in the HDL-cholesterol response to change in dietary fat intake. Functional characterization of this relationship in vitro may offer insights that potentially yield therapeutic guidance targeting dietary macronutrient composition, a direction much needed in the current epidemic of obesity.

Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia

ObjectiveAtherogenic dyslipidemia is highly associated with coronary heart disease and is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). The combination of statins and fibrates is a common modality to treat individuals with atherogenic dyslipidemia.We sought to identify single nucleotide polymorphisms (SNPs) associated with HDL-C, TG, and apolipoprotein A1 (ApoA-I) response to combination therapy with statins and fenofibric acid (FA) in individuals with atherogenic dyslipidemia. Methods2228 individuals with mixed dyslipidemia who were participating in a multicenter, randomized, double-blind, active-controlled study comparing FA alone, in combination with a statin, or statin alone for a 12-week period, were genotyped for 304 candidate SNPs. A multivariate linear regression analysis for percent change in HDL-C, ApoA-I and TG levels was performed. ResultsSNPs in the apolipoprotein (APO) A5-ZNF259 region rs3741298 (P=1.8×10−7), rs964184 (P=3.6×10−6), rs651821 (P=4.5×10−5), and rs10750097 (P=1×10−4), were significantly associated with HDL-C response to combination therapy with statins and FA, with a similar association identified for ApoA-I. A haplotype composed of the minor alleles of SNPs rs3741298, rs964184, and rs10750097, was associated with a positive response to statins and FA (P=8.7×10−7) and had a frequency of 18% in the study population. ConclusionIn a population with atherogenic dyslipidemia, common SNPs and haplotypes within the APOA5-ZNF259 region are highly associated with HDL-C and ApoA-I response to combination therapy with statins and FA.

Hip circumference is associated with high density lipoprotein cholesterol response following statin therapy in hypertensive subjects.

This report investigated the relationship between anthropometric measurements of body fat distribution and lipid response to statins in hypercholesterolemic hypertensive patients. We prospectively examined 129 subjects who used either simvastatin 20 mg/day (no.=83) or atorvastatin 10 mg/day (no.=46) for 3 months. Anthropometry included evaluation of body mass index, waist and hip circumferences, and waist-to-hip-ratio. Significant decreases in LDL (p<0.001), total cholesterol (p<0.001), and triglycerides (p=0.04) levels were detected after 3 months of therapy in the whole sample. At baseline, only an inverse correlation between waist circumference and HDLcholesterol levels was detected (r=-0.18; p=0.04). Conversely, a direct relationship between hip circumference and HDLcholesterol response to statins was found in the whole sample (r=0.24; p=0.006), while no other anthropometric measurement displayed significant correlation with lipid changes. The association between HDL-cholesterol response and hip circumference was further confirmed by stepwise regression analysis adjusted for baseline HDL-cholesterol levels, metabolic syndrome, body mass index, and waist circumference. Hip circumference, a surrogate marker of peripheral adiposity, is associated with HDL-cholesterol changes following statin therapy in hypertensive patients.