Cholesterol Response Research Articles

Genotype-by-diet effects on co-variation in Lp-PLA2 activity and LDL-cholesterol concentration in baboons fed an atherogenic diet

Both lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity, a biomarker of inflammation, and concentration of its primary associated lipoprotein, LDL, are correlated with adverse coronary outcomes. We previously reported a quantitative trait locus (QTL) corresponding to HSA2p24.3-p23.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-cholesterol (LDL-C) concentration in baboons fed a basal diet. Here, our goal was to locate pleiotropic QTLs influencing both traits in the same baboons fed a high-cholesterol, high-fat (HCHF) diet, and to assess whether shared genetic effects on these traits differ between diets. We assayed Lp-PLA(2) activity and LDL-C concentration in 683 baboons fed the HCHF diet. We used a bivariate maximum likelihood-based variance components approach in whole-genome linkage screens to locate a QTL [logarithm of odds (LOD) = 3.13, genome-wide P = 0.019] corresponding to HSA19q12-q13.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-C levels in the HCHF diet. We additionally found significant evidence of genetic variance in response to diet for Lp-PLA(2) activity (P = 0.0017) and for LDL-C concentration (P = 0.00001), revealing a contribution of genotype-by-diet interaction to covariation in these two traits. We conclude that the pleiotropic QTLs detected at 2p24.3-p23.2 and 19q12-q13.2 on the basal and HCHF diets, respectively, exert diet-specific effects on covariation in Lp-PLA(2) activity and LDL-C concentration.

Comparison of the Safety and Efficacy of a Combination Tablet of Niacin Extended Release and Simvastatin vs Simvastatin Monotherapy in Patients With Increased Non–HDL Cholesterol (from the SEACOAST I Study)

The efficacy and safety of 2 regimens of a combination of a proprietary niacin extended release plus simvastatin (NER/S; 1,000/20 and 2,000/20 mg/day) were compared with simvastatin monotherapy (20 mg/day) for 24 weeks in 319 high-risk patients with predominantly mixed dyslipidemia who were already at National Cholesterol Education Program Adult Treatment Panel III risk-adjusted goals for low-density lipoprotein cholesterol. After a run-in on simvastatin 20 mg/day, both NER/S doses (1,000/20 and 2,000/20 mg/day) resulted in greater decreases in non-high-density lipoprotein (HDL) cholesterol vs simvastatin 20 mg/day (-13.9% and -22.5% vs -7.4%, respectively; p <0.01). Significant improvements in HDL cholesterol, triglycerides, apolipoprotein B, lipoprotein(a), and total/HDL cholesterol ratio were also observed. Patients with hypertriglyceridemia (triglycerides > or =200 mg/dl) typically had greater lipid responses to NER/S with the notable exception that HDL cholesterol responses to NER/S were similar in those with or without increased triglycerides. Treatment with both doses of NER/S was well tolerated; < or =60% of patients in any treatment group experienced flushing, >90% of flushing was mild or moderate in intensity, and only 7.5% of patients in both NER/S treatment groups discontinued because of flushing. The safety of NER/S was consistent with the safety profile of each individual component. In conclusion, this study showed that NER/S provided additional clinically relevant improvements in multiple lipid parameters and was safe and well tolerated.

Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment

Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR, a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response. Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C (P=0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (-1.23+/-0.04 mmol/L, n=209, versus -1.45+/-0.06 mmol/L, n=117; P=0.0008) and percent response (-36.9+/-1.0% versus -40.6+/-1.3%; P=0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (-28.2+/-4.9%, n=12 H2+H7 carriers, versus -41.5+/-0.5%, n=650 H2/H7 noncarriers; P=0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites. HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.

Dietary Cholesterol and Skeletal Muscle Hypertrophy with Resistance Training: A Randomized Placebo‐Controlled Trial

Background:We recently reported a strong positive association of dietary cholesterol and skeletal muscle responses to resistance training (Riechman, 2007). To confirm these findings we conducted a randomized placebo controlled trial in which we supplemented the diet with whole egg or egg white (control).Methods:3 groups of 50–69 year old generally healthy subjects (N=30) underwent 12 weeks of resistance exercise training (RET, 3x/week, 2–3 sets, 8–12 reps, 70% of max strength). Each group consumed 3.5 mg/kg lean/day (&lt;200 mg/day, LC), 7.0 mg/kg lean/day (∼400 mg/day, MC), or 14.0 mg/kg lean/day (∼800 mg/day, HC) of cholesterol. Subjects were asked to complete 48 food records over the 12 wks to confirm dietary compliance. Body composition (DEXA) and maximal strength tests were conducted before and after the training.Results:Summary strength gain (chest press +leg press) was increased significantly (P&lt;0.05) with increasing dietary cholesterol (HC=52±8%, MC=38±8%, LC=21±8%). The mean gain in lean mass was 1.7±1.0 kg (3.7%) where subjects also lost 0.5±1.7 kg of fat mass (1.6%). Changes in lean mass and fat mass between groups was not significantly different (P&gt;0.05).Conclusion:Our results confirm our previous finding that high dietary cholesterol contributes to strength gain with resistance training; however, lean mass gains were inconsistent. Supported by US Poultry and Egg Association.

Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice

Low-density lipoprotein (LDL)-lowering with pharmacologic therapy has been repeatedly shown to substantially reduce risk of vascular disease. LDL cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (HDL-C) are the cholesterol indices used to measure the adequacy of LDL-lowering therapy, whereas apolipoprotein B (ApoB) is the most widely used index of atherogenic particle number. This study examines whether LDL-lowering therapy reduces cholesterol indices and ApoB to the same extent. If they are not equally affected, they may not be equally informative about change in risk. Data from 11 studies, which include 17,035 subjects, were analyzed. All the statins in common use were included, as well as all the doses at which they are commonly used. More limited data are presented on combination therapy with statins and ezetimibe. Reductions in LDL-C, non-HDL-C, and ApoB differed significantly, averaging 42.1%, 39.6%, and 33.1%, respectively (P < 0.001 ApoB versus LDL-C or non-HDL-C). Mean value for the measure in question was expressed as the percentile level from a distribution analysis of two reference populations (Framingham Offspring Study and National Health and Nutrition Examination Survey III). The lower the population percentile, the more effective the apparent response. For LDL-C, non-HDL-C, and ApoB, these were the 21st, the 29th, and the 55th percentile of the population, respectively. This value for ApoB was significantly different from both LDL-C and non-HDL-C (P < 0.001). Very similar results were obtained in eight studies of LDL-lowering in 889 subjects in which the responses of LDL-C and LDL particle number (LDL-P) assessed by nuclear magnetic resonance spectroscopy were compared. LDL-C was reduced to the 27th percentile of the population, whereas LDL-P was only reduced to the 51st percentile of the population (P < 0.001). Many patients who achieve LDL-C and non-HDL-C target levels will not have achieved correspondingly low population-equivalent ApoB or LDL-P targets. Reliance on LDL-C and non-HDL-C can create a treatment gap in which the opportunity to give maximal LDL-lowering therapy is lost.

Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase

The cholesterol content of the endoplasmic reticulum (ER) and the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) imbedded therein respond homeostatically within minutes to changes in the level of plasma membrane cholesterol. We have now examined the roles of sterol regulatory element-binding protein (SREBP)-dependent gene expression, side chain oxysterol biosynthesis, and cholesterol precursors in the short term regulation of ER cholesterol levels and HMGR activity. We found that SREBP-dependent gene expression is not required for the response to changes in cell cholesterol of either the pool of ER cholesterol or the rate of cholesterol esterification. It was also found that the acute proteolytic inactivation of HMGR triggered by cholesterol loading required the conversion of cholesterol to 27-hydroxycholesterol. High levels of exogenous 24,25-dihydrolanosterol drove the inactivation of HMGR; lanosterol did not. However, purging endogenous 24,25-dihydrolanosterol, lanosterol, and other biosynthetic sterol intermediates by treating cells with NB-598 did not greatly affect either the setting of their ER cholesterol pool or the inactivation of their HMGR. In summary, neither SREBP-regulated genes nor 27-hydroxycholesterol is involved in setting the ER cholesterol pool. On the other hand, 27-hydroxycholesterol, rather than cholesterol itself or biosynthetic precursors of cholesterol, stimulates the rapid inactivation of HMGR in response to high levels of cholesterol.

Effect of Probiotics, Yeast, Vitamin E and Vitamin C Supplements on Performance and Immune Response of Laying Hen During High Environmental Temperature

In order to evaluate the effects of dietary probiotics, yeast, vitamin E and vitamin C supplementation on performance, serum and yolk cholesterol and immune response of heat stressed laying hens, a trial was conducted with sixty white layer hens of Hy-Line variety. Experiment was conducted by using completely randomized design with 5 treatments, 3 replicates and 4 hens in each replicate. The treatments involved: control, basal diet plus 50 mg multi strains probiotic, basal diet plus 1 g yeast of Saccharomyces cerevisiae, basal diet plus 200 mg vitamin C and basal diet plus 200 mg vitamin E per Kg of diet. Results indicated no significant difference in hen performance, egg quality (shell thickness, shell resistance, shell percent and haugh unit) and serum and yolk cholesterol concentrations. Yolk percent was increased significantly and the highest yolk percent was observed in vitamin E treatment. Immune response of laying hens with multi strains probiotic and yeast supplementation was greater than others. However, dietary vitamin E and C supplementation increased immune response, but differences were not significant compare with other groups.

Effect of probiotic (Lactobacillus sporogenes) feeding on egg production and quality, yolk cholesterol and humoral immune response of White Leghorn layer breeders

AbstractThe effect of probiotic (Lactobacillus sporogenes) feeding on egg production and quality, yolk cholesterol and humoral immune response of White Leghorn (WL) layer breeders was studied. WL layer breeders (24 weeks) were randomly distributed into three groups of 28 each and were housed in individual California type cages. Considering one bird (individual feeding) as a replicate, 28 such replicates were randomly allotted to one of the three dietary treatments: basal (control) or basal with probiotic supplementation at a rate of 100 or 150 mg kg−1 feed. The probiotic used in the study was a commercial preparation containing L. sporogenes with 6000 million spores g−1 of the product. Dietary supplementation of L. sporogenes at 100 mg (6 × 108 spore) kg−1 diet significantly increased egg production and feed efficiency. However, body weight gain, feed intake, egg weight, specific gravity and Haugh unit was not influenced by probiotic feeding. The eggshell breaking strength, shell weight and shell thickness increased significantly by feeding 100 mg probiotic kg−1 diet. The serum concentration of calcium and protein increased, and that of cholesterol decreased by L. sporogenes supplementation. The yolk cholesterol followed the same trend of serum cholesterol. Feeding of L. sporogenes significantly enhanced antibody production. No difference in antibody production could, however, noticed between the levels (100 or 150 mg) of probiotic. It is concluded that feeding of L. sporogenes at 100 mg (6 × 108 spore) kg−1 diet significantly enhanced the egg production, shell quality and humoral immune response of WL layer breeders during 25–40 weeks of age. Copyright © 2007 Society of Chemical Industry

Abstract 905: Alternative Splicing of HMGCR is Associated with Plasma LDL Cholesterol Response to Simvastatin

Statins can substantially lower plasma LDL cholesterol and reduce risk for coronary heart disease, but their efficacy varies among individuals. To test whether this variation is related to single nucleotide polymorphisms (SNPs) in the gene for 3-hydroxy-3-methylglutaryl-coenzyme A reductase ( HMGCR ), the key regulatory enzyme of cholesterol synthesis and the target of statin inhibition, we resequenced HMGCR exons, splice sites and 1.5kb of 5′ and 3′ flanking regions in 96 individuals. Subjects were equally derived from the upper and the lower 5% of the LDL-response distribution from the Cholesterol and Pharmacogenetics (CAP) study, a 6 week trial in which 944 subjects were treated with 40 mg/day simvastatin. Intronic SNP 20144 (rs3846662) was significantly (p&lt;0.05) associated with high versus low LDL cholesterol response status, and was part of a previously reported haplotype associated with a 14.8% smaller reduction in LDL cholesterol in the CAP cohort. Since SNP 20144 is adjacent to exon 13, a site of HMGCR alternative splicing, we measured expression levels of the splice variant lacking exon 13 ( HMGCRv 1 ) in 170 immortalized lymphocytes derived from the CAP subjects, and found that the SNP was associated with greater statin-induced HMGCR alternative splicing (p&lt;0.05). Moreover, there was a significant correlation between the increased magnitude of expression of HMGCRv 1 following statin exposure in vitro and smaller reductions of total cholesterol, LDL cholesterol, apoB and triglycerides in the plasma of the corresponding subjects in vivo (p&lt;0.0001). There was no relationship between the full-length transcript and in vivo response. Additionally, we used siRNA to specifically knock-down expression of the full-length HMGCR transcript by 68%, resulting in cells enriched in the HMGCRv 1 transcript. We then measured HMGCR enzyme activity and found that the remaining enzyme demonstrated 9 –15% greater residual activity in the presence of simvastatin concentrations ranging from 0.15nM to 6.0nM (n=10). These results suggest that HMGCR genetic variation influences the production of an HMGCR isoform with reduced statin sensitivity, and that variation in expression of this isoform is a determinant of inter-individual differences in statin response.

1E-5 Inverse correlation between birthweight and serum low-density lipoprotein cholesterol (LDLC) response to a high fat diet in the juvenile baboon

1E-5 Inverse correlation between birthweight and serum low-density lipoprotein cholesterol (LDLC) response to a high fat diet in the juvenile baboon

Genetic determinants of HDL: monogenic disorders and contributions to variation

This review focuses on recent progress towards the characterization of genetic variations that contribute to interindividual variation in plasma high-density lipoprotein cholesterol levels in the general population. Many of the genes that harbor rare mutations leading to extreme high-density lipoprotein cholesterol levels contain common variation that influences plasma high-density lipoprotein cholesterol in several study populations. Candidate gene association studies provide evidence that some of these variations have an effect on high-density lipoprotein cholesterol, dependent on epistatic interactions or environmental context. Both rare and common variations contribute to interindividual high-density lipoprotein cholesterol variation. Recent comparisons of candidate gene sequences between individuals in the tails of the high-density lipoprotein cholesterol distributions (the upper or lower 1-5%) of several study populations indicate that as many as 20% of individuals with low high-density lipoprotein cholesterol harbor a rare mutation in an investigated gene. For example, the ABCA1 gene region harbors rare mutations and common variants that contribute to interindividual high-density lipoprotein cholesterol variation in the general population. The genetic control of high-density lipoprotein cholesterol level is complex. Maximizing the utility of genetic knowledge for predicting an individual's high-density lipoprotein cholesterol level or response to intervention will require a better understanding of the action of combinations of genetic variants and environmental exposures.

Apolipoprotein A-V Genetic Variation and Plasma Lipoprotein Response to Fibrates

The field of pharmacogenetics has begun to reveal solid evidence for the relationship between interindividual variability in response to drug treatment and one’s genetic background. In the lipoprotein field, response to statin treatment and the severity of adverse events from statin treatment has been linked to genetic variation. Now, new evidence of a relationship between apolipoprotein A-V genetic variation and plasma lipoprotein response to fibrates has been found. See page 1417 The field of pharmacogenetics promises to explain interindividual variability in response to both beneficial and adverse effects of medications.1–3 In theory, interindividual differences in drug response could be the result of functional polymorphisms in the human genome that encode differences in: (1) gene products that act within pathophysiological pathways underlying the disease whose natural history is being targeted by the drug; (2) pharmacokinetic activity of drug transporters or of processing or metabolizing enzymes; and (3) pharmacodynamics of gene products expressed as carriers or receptors for drug molecules. In the lipoprotein field, inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) (HMG-CoA) reductase (“statins”) have been studied pharmacogenetically, with genotypes of many common DNA polymorphisms associated with variation in plasma low-density lipoprotein (LDL) cholesterol responsiveness (reviewed by Kajinami et al1). The associated genes typically encode proteins that are involved in cholesterol biosynthesis, such as HMG-CoA reductase, in plasma LDL metabolism, such as the LDL receptor, apolipoprotein (apo) E and B, and in drug metabolism, such as certain cytochrome P450 enzymes.1 Furthermore, the severity of adverse events from statin treatment, such as myopathy, could be determined in part by interindividual variation in genes involved in ubiquitination.4 Similarly, plasma LDL cholesterol response to the cholesterol absorption inhibitor ezetimibe has been associated with variation in Niemann-Pick C like protein 1 (NPC1L1), the presumed target of ezetimibe (reviewed by Huff et al5 …

Effects of ezetimibe on lipids and lipoproteins in patients with hyper­cholesterolemia and different apolipoprotein E genotypes

ABSTRACTBackground: The ε4 allele of the gene encoding apolipoprotein E (apoE) is associated with elevated serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL‑C), as well as an increased risk of coronary heart disease (CHD), greater disease severity, and higher CHD mortality. ApoE ε4 allele carriers have also shown reduced lipid and lipoprotein responses to lipid-modifying pharmacotherapy and lifestyle modifications.Objective: To provide preliminary descriptive data on the effects of apoE genotype on lipid and lipoprotein responses to the cholesterol absorption inhibitor ezetimibe (Ezetrol/Zetia) in Hungarian subjects not at cholesterol goals at baseline.Methods: This prospective open-label study compared the effects of the cholesterol absorption inhibitor ezetimibe 10 mg/day for up to 6 weeks added to existing therapies on the lipid profiles of 14 ε4 allele carriers and 14 age- and gender-matched APOE3/APOE3 homozygotes.Results: Treatment with ezetimibe reduced TC, LDL‑, and triglycerides, and increased high-density lipoprotein cholesterol (HDL‑) significantly from baseline, and to similar extents, in both groups, lowering TC from baseline by 13.7% in APOE3/APOE3 homozygotes compared with 12.1% in ε4 allele carriers ( p = 0.139); LDL‑C by 22.8% (vs. 19.6%; p = 0.081); and triglycerides by 9.2% (vs. 9.1%; p = 0.120). Ezetimibe also increased HDL‑C by 8.0% in subjects with the ε3/ε3 genotype compared with 8.9% in ε4 allele carriers ( p = 0.263).Conclusions: Ezetimibe significantly improved lipid and lipoprotein profiles from baseline irrespective of apoE ε3/ ε3 or ε4 genotype in Hungarian subjects not at cholesterol goals. Limitations of our study include its open-label nature and small sample population, as well as the facts that patients with the ε4 allele were not included and data were not collected on initial cholesterol levels, initial statin doses, cholesterol responses to statins, and the safety and tolerability of ezetimibe. Further randomized controlled studies in larger numbers of people followed for longer intervals are warranted to confirm these findings.

Postprandial Lipemia Associates with Liver Fat Content

Postprandial lipemia and low adiponectin represent novel risk factors for vascular disease. This study aimed to determine whether liver fat content and adiponectin are predictors of postprandial triglyceride (TG)-rich lipoproteins (TRL). Twenty-nine men were allocated into subgroups with either low (< or =5%) or high (>5%) liver fat measured with magnetic resonance proton spectroscopy. Subjects underwent an oral fat tolerance test with measurements of postprandial TG, cholesterol, apolipoprotein B-48 (apoB-48), and apoB-100 in TRL fractions, a euglycemic hyperinsulinemic clamp, and determination of abdominal fat volumes by magnetic resonance imaging. Subjects with high liver fat displayed increased response of postprandial lipids in plasma, chylomicron, and very-low-density lipoprotein 1 (VLDL1) (Svedberg flotation rate 60-400) fractions. Liver fat correlated positively with postprandial responses (area under the curve) of TG (r = 0.597; P = 0.001), cholesterol (r = 0.546; P = 0.002), apoB-48 (r = 0.556; P = 0.002), and apoB-100 (r = 0.42; P = 0.023) in the VLDL1 fraction. Respective incremental areas under the curve correlated significantly with liver fat. Fasting adiponectin levels were inversely correlated with both postprandial lipids and liver fat content. Liver fat remained the only independent correlate in a multiple linear regression analysis for chylomicron and VLDL1 responses. Liver fat content is a close correlate of postprandial lipids predicting the responses of TRL in chylomicrons and VLDL1 better than measures of glucose metabolism or body adiposity. Low adiponectin concentration is closely linked to high liver fat content and impaired TRL metabolism. High liver fat content associated with postprandial lipemia represents potential risk factors for cardiovascular disease.

Soluble fiber extracted from potato pulp is highly fermentable but has no effect on risk markers of diabetes and cardiovascular disease in Goto-Kakizaki rats

The cholesterol-lowering and hypoglycemic effect of dietary fiber are commonly attributed to soluble fiber fractions. By enzymatic treatment of potato pulp, which is rich in cellulose and pectin, we prepared 3 fractions with different chemical composition and solubility, and compared their effects with commercially available crystalline cellulose (negative control) on central parameters related to risk factors of diabetes mellitus and cardiovascular disease in diabetic prone Goto-Kakizaki rats. Forty male rats were fed a semisynthetic Western-type diet containing 5% dietary fiber in the form of concentrated potato fiber (CF), insoluble potato fiber (IF), soluble fiber (SF), or cellulose (CEL) ad libitum for 4.5 weeks to study weight change and induce diabetic conditions. This was followed by 16 days of slightly restricted feeding, for the measurement of fecal organic matter digestibility, fecal dry matter, urinary glucose excretion, and fasting blood glucose. Finally, the rats were euthanized 2 hours postprandial for measurement of postprandial glucose, triacylglycerol and cholesterol levels, and cecal fermentation pattern to assess any relation between digestion processes and hematological risk markers. Diet SF had higher fecal organic matter digestibility and led to a significantly larger pool of organic acids with a higher proportion of propionate than the other diets. There was no difference in hematological parameters except for a small but significant reduction in postprandial plasma triacylglycerol concentration of rats fed diet SF compared to diet CEL and diet CF. In conclusion, increased fermentation and production of propionate with diet SF did not reduce plasma cholesterol or glycemic response.

Estrogen Receptor α Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture

We hypothesized that the estrogen receptor alpha (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture. We studied cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population controls. The CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Cross-sectionally, genotype did not influence high-density lipoprotein cholesterol response to hormone replacement therapy. In the cohort study, there were no differences in risks of CVD, cancer of reproductive organs, or hip fracture between genotypes. In case-control studies, risk of CVD did not differ between genotypes; however, the odds ratio for breast cancer in women with TT versus CC genotypes was 1.4 (95% CI, 1.1 to 1.7). Meta-analysis in men of 6 previous and the present 2 studies, including 4799 cases and 12,190 controls, showed odds ratios in CC versus CT and TT genotypes for fatal and nonfatal myocardial infarction of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21). ESR1 IVS1-397T/C polymorphism does not influence high-density lipoprotein cholesterol response to hormone replacement therapy or risk of CVD, most cancers of reproductive organs, or hip fracture.

Effect of weight loss on the postprandial response to high-fat and high-carbohydrate meals in obese women

To assess the effect of weight loss on the plasma lipid and remnant-like lipoprotein cholesterol (RLPc) response to a high-fat or a high-carbohydrate meal in a population of obese women. Nutritional intervention study. Sixteen obese women (mean body mass index (BMI): 37.6+/-5 kg/m(2)). Subjects were asked to follow an energy-restricted diet (800 kcal/day) for 7 weeks, followed by a 1-week maintenance diet. Before and after weight loss, each participant was given (in random order) two iso-energetic meals containing either 80% fat and 20% protein (the high-fat meal) or 80% carbohydrate and 20% protein (the high-carbohydrate meal). Blood samples were collected over the following 10-h period. A two-way analysis of variance with repeated measures was used to assess the effect of the meal and postprandial time on biological variables and postprandial responses (notably RLPc levels). Weight loss was associated with a significant decrease in fasting triglyceride (P=0.0102), cholesterol (P<0.0001), low-density lipoprotein cholesterol (P=0.0003), high-density lipoprotein-cholesterol (P=0.0009) and RLPc (P=0.0015) levels. The triglyceride response to the high-fat meal was less intense after weight reduction than before (interaction P<0.002). This effect persisted after adjustment on baseline triglyceride levels. The triglyceride response to the high-carbohydrate meal was biphasic (i.e. with two peaks, 1 and 6 h after carbohydrate intake). After adjustment on baseline values, weight reduction was associated with a trend towards a reduction in the magnitude of the second triglyceride peak (interaction P<0.054). In contrast, there was no difference in postprandial RLPc responses before and after weight loss, again after adjustment on baseline levels. Our data suggest that weight loss preferentially affects postprandial triglyceride metabolism.

Prevention of complex diseases by genotype-based nutrition: realistic concept or fiction?

The risk of numerous chronic diseases such diabetes,atherosclerosis and cancer is associated with nutritionalparameters and might, therefore, be reduced by an effectivedietary intervention [1]. More recently, when genomeresearch met with nutritional science, it became apparentthat the effects of certain gene variants on metabolicparameters and, consequently, also on disease risk, ismodified by nutritional parameters. Thus, the concept wasdeveloped that genotyping for critical variants couldprovide a personalized advice for individuals with a highdisease risk, thereby maximizing the efficacy of nutritionalrecommendations [2–4]. Commercial exploitation of theconcept has started already: Genotyping for a series ofapproximately 20 variant alleles that are associated withelevated disease risk and/or with a heterogeneous responseto a nutrient is offered together with nutritional advice.However, the value of genotyping to individualize nutri-tional recommendations has been questioned. Recently,these tests have provocatively been labelled ‘genetichoroscopes’ [5].This special issue of the Journal of Molecular Medicineis devoted to the relation between genotype and thebiological response to nutrients and intends to highlightsome current aspects as well as future perspectives of theconcept of a personalized nutrition. The contributions, twooriginal papers and two reviews, focus on metabolicdiseases such as obesity, diabetes and dyslipoproteinaemia.In these areas, well-defined endpoints and risk factors suchas body mass index, blood glucose, or LDL cholesterolfacilitate the study of genotype–nutrition interactions. Withregard to the variable nutrition, a common theme of thecontributions in this special issue is the dietary fat content.Proof of the concept that the genetic basis maydetermine the biological response to nutrients has initiallybeen derived from mouse models. In inbred mouse strains,the sensitivity of serum cholesterol to a high-fat diet isstrain-specific [6]. Moreover, in obese mouse strains,chromosomal regions have been identified that confersusceptibility for diabetes dependent on the dietary fat [7].These findings—if applicable to the human situation—suggested that it might be possible to identify individualswho would specifically benefit from a fat-reduced diet.Previously published date from human cohort studies haveindicated that the response of serum cholesterol to dietaryfat may depend on variants of genes such as ApoE4 [8],ApoA5 [9] or the hepatic lipase [10]. In the Framinghamcohort, dietary fat intake modifies the effect of a polymor-phism (−514C/T) in the promoter of the hepatic lipase geneon serum HDL-cholesterol: At low fat intake ( 30%), HDLlevels were significantly lower [10]. The study concludedthat TT carriers have an impaired adaptation to dietary fatthat could result in a higher cardiovascular risk.In this special issue of the Journal on MolecularMedicine, Corella et al. present additional data from theFramingham study suggesting that dietary fat significantlymodifies the association between the −1131T/C alleles ofapolipoprotein A5 and body weight. Recently, the samegroup has shown that in carriers of the −1131C allele ofapolipoprotein A5, high intake of n-6 PUFAwas associatedwith increased fasting triglycerides [11]. In the presentstudy, homozygous carriers of the T allele exhibited higherbody weights with increasing fat consumption, whereas

Effects of a carbohydrate-restricted diet with and without supplemental soluble fiber on plasma low-density lipoprotein cholesterol and other clinical markers of cardiovascular risk

Carbohydrate-restricted diets (CRDs) promote weight loss, reductions in plasma triacylglycerol (TAG) levels, and increases in high-density lipoprotein cholesterol (HDL-C) levels but may cause undesirable low-density lipoprotein cholesterol (LDL-C) responses in some people. The objective of the present study was to determine the effect of adding soluble fiber to a CRD on plasma LDL-C and other traditionally measured markers of cardiovascular disease. Using a parallel-arm, double-blind, placebo-controlled design, 30 overweight and obese men (body mass index, 25-35 kg/m 2) were randomly assigned to supplement a CRD with soluble fiber (Konjac-mannan, 3g/d) (n = 15) or placebo (n = 15). Plasma lipids, anthropometrics, body composition, blood pressure, and nutrient intake were evaluated at baseline and at 6 and 12 weeks. Compliance was excellent as assessed by 7-day weighed dietary records and ketonuria. Both groups experienced decreases in ( P < .01) body weight, percent body fat, systolic blood pressure, waist circumference, and plasma glucose levels. After 12 weeks, HDL-C and TAG improved significantly in the fiber (10% and −34%) and placebo (14%, −43%) groups. LDL-C decreased by 17.6% ( P < .01) at week 6 and 14.1% ( P < .01) at week 12 in the fiber group. Conversely, LDL-C reductions were significant in the placebo group only after 12 weeks (−6.0%, P < .05). We conclude that although clearly effective at lowering LDL-C, adding soluble fiber to a CRD during active and significant weight loss provides no additional benefits to the diet alone. Furthermore, a CRD led to clinically important positive alterations in cardiovascular disease risk factors.

Long‐term reversal of hypocholesterolaemia in patients with chronic hepatitis C is related to sustained viral response and viral genotype

Genotype-3 of hepatitis C virus (HCV) has been associated with serum lipid changes (reversible with sustained viral response) and liver steatosis. To characterize the relationships among hepatic steatosis, cholesterol and sustained viral response in these patients. Patients (n = 215) with chronic hepatitis C (157 with genotype-1 of HCV) had age, body mass index, gender, alcohol intake, glycaemia, serum lipids, transaminases, grade and stage (METAVIR and Scheuer), degree of liver steatosis, sustained viral response, insulinaemia, leptinaemia, beta-hydroxybutyrate and glycerol measured, and were compared with 32 hepatitis B virus (HBV)-infected subjects. Genotype-3 of HCV patients had age-adjusted hypocholesterolaemia and more frequent hepatic steatosis (P < 0.001). Steatosis was inversely correlated with serum cholesterol (P < 0.01) and directly with viral load (P < 0.03). In patients with genotype-3 of HCV and sustained viral response, serum cholesterol increased from 138 (95% CI: 120-151) to 180 mg/dL (95% CI: 171-199) 12 months after treatment conclusion (P < 0.0001). By contrast, cholesterol values were unchanged in genotype-3 of HCV non-responders and in patients with genotype-1 of HCV regardless of response. Rising cholesterol in sustained viral response did not parallel the changes in beta-hydroxybutyrate. Besides causing hepatic steatosis, genotype-3 specifically decreases serum cholesterol. This interference with the metabolic lipid pathway is related to viral load, is reversed with sustained viral response, and seems unrelated to mitochondrial dysfunction.