Associations between apolipoprotein e genotype and circulating F-2-isoprostane levels in humans

Apolipoprotein E (apoE), an important determinant of plasma lipoprotein metabolism, has three common alleles (ε 2, ε 3, and ε 4). Population studies have shown that the risk of diseases characterized by oxidative damage, such as coronary heart disease and Alzheimer's disease, is significantly higher in ε 4 carriers. We evaluated the association between apoE genotypes and plasma F-2-isoprostane levels, an index of lipid peroxidation, in humans. Two hundred seventy-four healthy subjects (104 males, 170 females; 46.9 ± 13.0 yr; 200 whites, 74 blacks; 81 nonsmokers, 64 passive smokers, and 129 active smokers) recruited for a randomized clinical antioxidant intervention trial were included in this analysis. ApoE genotype was determined by PCR and restriction enzyme digestion. Free plasma F2-isoprostane was measured by GC-MS. Genotype groups were compared using multiple regression analysis with adjustment for sex, age, race, smoking status, body mass index, plasma ascorbic acid, and β-carotene. Subjects with ε 3/ε 4 and ε 4/ε 4 genotype (ε 4-carriers) and with ε 2/ε 3 and ε 3/ε 3 (non-ε 4-carriers) were pooled for analysis. In subjects with high cholesterol levels (total cholesterol above 200 mg/dl), plasma F-2-isoprostane levels were 29% higher in ε 4 carriers than in non-ε 4-carriers (P= 0.0056). High-cholesterol subjects that are ε 4 carriers have significantly higher levels of lipid peroxidation as assessed by circulating F-2-isoprostane levels.

Effects of genotype and environment on free amino acid levels in wheat grain: implications for acrylamide formation during processing

Acrylamide forms from free asparagine and reducing sugars during cooking, with asparagine concentration being the key parameter determining the formation in foods produced from wheat flour. In this study free amino acid concentrations were measured in the grain of varieties Spark and Rialto and four doubled haploid lines from a Spark x Rialto mapping population. The parental and doubled haploid lines had differing levels of total free amino acids and free asparagine in the grain, with one line consistently being lower than either parent for both of these factors. Sulfur deprivation led to huge increases in the concentrations of free asparagine and glutamine, and canonical variate analysis showed clear separation of the grain samples as a result of treatment (environment, E) and genotype (G) and provided evidence of G x E interactions. Low grain sulfur and high free asparagine concentration were closely associated with increased risk of acrylamide formation. G, E, and G x E effects were also evident in grain from six varieties of wheat grown at field locations around the United Kingdom in 2006 and 2007. The data indicate that progress in reducing the risk of acrylamide formation in processed wheat products could be made immediately through the selection and cultivation of low grain asparagme varieties and that further genetically driven improvements should be achievable. However, genotypes that are selected should also be tested under a range of environmental conditions.

Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study

Background: The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well established and likely to contribute to cardioprotective benefits. Objectives: We aimed to determine the effect of moderate EPA and DHA intakes (< 2 g EPA + DHA/d) on the plasma fatty acid profile, lipid and apolipoprotein concentrations, lipoprotein subclass distribution, and markers of oxidative status. We also aimed to examine the effect of age, sex, and apolipoprotein E (APOE) genotype on the observed responses. Design: Three hundred twelve adults aged 20-70 y, who were prospectively recruited according to age, sex, and APOE genotype, completed a double-blind placebo-controlled crossover study. Participants consumed control oil, 0.7 g EPA + DHA/d (0.7FO), and 1.8 g EPA + DHA/d (1.8FO) capsules in random order, each for an 8-wk intervention period, separated by 12-wk washout periods. Results: In the group as a whole, 8% and 11% lower plasma triacylglycerol concentrations were evident after 0.7FO and 1.8FO, respectively (P < 0.001): significant sex x treatment (P = 0.038) and sex x genotype x treatment (P = 0.032) interactions were observed, and the greatest triacylglycerol-lowering responses (reductions of 15% and 23% after 0.7FO and 1.8FO, respectively) were evident in APOE4 men. Furthermore, lower VLDL-cholesterol (P = 0.026) and higher LDL-cholesterol (P = 0.010), HDL-cholesterol (P < 0.001), and HDL2 (P < 0.001) concentrations were evident after fish-oil intervention. Conclusions: Supplements providing EPA + DHA at doses as low as 0.7 g/d have a significant effect on the plasma lipid profile. The results of the current trial, which used a prospective recruitment approach to examine the responses in population subgroups, are indicative of a greater triacylglycerol-lowering action of long-chain n-3 polyunsaturated fatty acids in males than in females.

Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil

Objectives: To investigate the impact of apolipoprotein E (apoE) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) intervention in humans. Methods and results: 38 healthy normolipidaemic males, prospectively recruited on the basis of apoE genotype (n = 20 E3/E3 and n = 18 E3/E4), completed a double-blind placebo-controlled cross-over trial, consisting of 3 × 4 week intervention arms of either control oil, EPA-rich oil (ERO, 3.3 g EPA/day) or DHA-rich oil (DRO, 3.7 g DHA/day) in random order, separated by 10 week wash-out periods. A significant genotype-independent 28% and 19% reduction in plasma triglycerides in response to ERO and DRO was observed. For total cholesterol (TC), no significant treatment effects were evident; however a significant genotype by treatment interaction emerged (P = 0.045), with a differential response to ERO and DRO in E4 carriers. Although the genotype × treatment interaction for LDL-cholesterol (P = 0.089) did not reach significance, within DRO treatment analysis indicated a 10% increase in LDL (P = 0.029) in E4 carriers with a non-significant 4% reduction in E3/E3 individuals. A genotype-independent increase in LDL mass was observed following DRO intervention (P = 0.018). Competitive uptake studies in HepG2 cells using plasma very low density lipoproteins (VLDL) from the human trial, indicated that following DRO treatment, VLDL2 fractions obtained from E3/E4 individuals resulted in a significant 32% (P = 0.002) reduction in LDL uptake relative to the control. Conclusions: High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

APOE genotype influences triglyceride and C-reactive protein responses to altered dietary fat intake in UK adults

Background: The response of plasma lipids to dietary fat manipulation is highly heterogeneous, with some indications that APOE genotype may be important. Objective: The objective was to use a prospective recruitment approach to determine the effect of dietary fat quantity and composition on both lipid and nonlipid cardiovascular disease biomarkers according to APOE genotype. Design: Participants had a mean (±SD) age of 51 ± 9 y and a BMI (in kg/m2) of 26.0 ± 3.8 (n = 44 E3/E3, n = 44 E3/E4) and followed a sequential dietary intervention (the SATgenϵ study) in which they were assigned to a low-fat diet, a high-fat high-SFA (HSF) diet, and the HSF diet with 3.45 g DHA/d (HSF-DHA), each for 8 wk. Fasting blood samples were collected at the end of each intervention arm. Results: An overall diet effect was evident for all cholesterol fractions (P < 0.01), with no significant genotype × diet interactions observed. A genotype × diet interaction (P = 0.033) was evident for plasma triglycerides, with 17% and 30% decreases in APOE3/E3 and APOE3/E4 individuals after the HSF-DHA diet relative to the low-fat diet. A significant genotype × diet interaction (P = 0.009) was also observed for C-reactive protein (CRP), with only significant increases in concentrations after the HSF and HSF-DHA diets relative to the low-fat diet in the APOE3/E4 group (P < 0.015). Conclusions: Relative to the wild-type APOE3/E3 group, our results indicate a greater sensitivity of fasting triglycerides and CRP to dietary fat manipulation in those with an APOE3/E4 genotype (25% population), with no effect of this allelic profile on cholesterol concentrations. The SATgenϵ study was registered at clinicaltrials.gov as NCT01384032.

Fish oil supplementation alters numbers of circulating endothelial progenitor cells and micro particles independent of eNOS genotype

Background Emerging cellular markers of endothelial damage and repair include endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) respectively. Effects of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) and influence of genetic background on these markers are not known. Objective This study investigated the effects of fish oil supplementation on both classical and novel markers of endothelial function in subjects prospectively genotyped for the Asp298 eNOS polymorphism and at moderate risk of CVD. Design 84 subjects with moderate risk of CVD (n=40 GG and n=44 GT/TT) completed a randomized, double-blind, placebo-controlled, 8-week cross-over trial of fish oil supplementation providing 1.5 g/d LC n-3 PUFA. Effects of genotype and fish oil supplementation on the blood lipid profile, inflammatory markers, vascular function (EndoPAT) and numbers of circulating EPCs and EMP (flow cytometry) were assessed. Results There was no significant effect of fish oil supplementation on blood pressure, plasma lipids or plasma glucose, although there was a trend (P = 0.069) towards a decrease in plasma TG concentration after FO supplementation compared to placebo. GT/TT subjects tended to have higher levels of total cholesterol and LDL-cholesterol, but vascular function was not affected by either treatment or eNOS genotype. Biochemical markers of endothelial function were also unaffected by treatment and eNOS genotype. In contrast, there was a significant effect of fish oil supplementation on cellular markers of endothelial function. Fish oil supplementation increased numbers of EPCs and reduced numbers of EMPs relative to the placebo, potentially favouring maintenance of endothelial integrity. There was no influence of genotype for any of the cellular markers of endothelial function, indicating that the effects of fish oil supplementation were independent of eNOS genotype. Conclusions Emerging cellular markers of endothelial damage, integrity and repair appear to be sensitive to potentially beneficial modification by dietary n-3 PUFA.

Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?

Background: We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n − 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n − 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4−). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60 − 400 (VLDL1), and Sf 20 − 60 (VLDL2) according to APOE genotype. Methods: Postprandial TRL fractions were obtained in 11 E4+ (ε3/ε4) and 12 E4− (ε3/ε3) male from the SATgenε study following high saturated fat diet + 3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography. Results: At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P = 0.046) as well as a trend towards higher relative% of EPA (P=0.063) in theSf >400 fraction of E4+. Total n − 3 PUFA in the Sf 60 − 400 and Sf 20 − 60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time × genotype interaction (P=0.081) for EPA in theSf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2 = 0.816). Conclusion: Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n − 3 PUFA metabolism after receiving a high-dose of DHA. Trial registration: Registered at clinicaltrials.gov/show/NCT01544855.

Interaction between BMI and APOE genotype is associated with changes in the plasma long-chain-PUFA response to a fish-oil supplement in healthy participants

BACKGROUND: Carriers of the apolipoprotein E ɛ4 (APOE4) allele are lower responders to a docosahexaenoic acid (DHA) supplement than are noncarriers. This effect could be exacerbated in overweight individuals because DHA metabolism changes according to body mass index (BMI; in kg/m²). OBJECTIVES: We evaluated the plasma fatty acid (FA) response to a DHA-rich supplement in APOE4 carriers and noncarriers consuming a high-saturated fat diet (HSF diet) and, in addition, evaluated whether being overweight changed this response. DESIGN: This study was part of the SATgenɛ trial. Forty-one APOE4 carriers and 41 noncarriers were prospectively recruited and consumed an HSF diet for 8-wk followed by 8 wk of consumption of an HSF diet with the addition of DHA and eicosapentaenoic acid (EPA) (HSF + DHA diet; 3.45 g DHA/d and 0.5 g EPA/d). Fasting plasma samples were collected at the end of each intervention diet. Plasma total lipids (TLs) were separated into free FAs, neutral lipids (NLs), and phospholipids by using solid-phase extraction, and FA profiles in each lipid class were quantified by using gas chromatography. RESULTS: Because the plasma FA response to the HSF + DHA diet was correlated with BMI in APOE4 carriers but not in noncarriers, the following 2 groups were formed according to the BMI median: low BMI (<25.5) and high BMI (≥25.5). In response to the HSF + DHA diet, there were significant BMI × genotype interactions for changes in plasma concentrations of arachidonic acid and DHA in phospholipids and TLs and of EPA in NLs and TLs (P ≤ 0.05). APOE4 carriers were lower plasma responders to the DHA supplement than were noncarriers but only in the high-BMI group. CONCLUSIONS: Our findings indicate that apolipoprotein E genotype and BMI may be important variables that determine the plasma long-chain PUFA response to dietary fat manipulation. APOE4 carriers with BMI ≥25.5 may need higher intakes of DHA for cardiovascular or other health benefits than do noncarriers

Detection of a new mumps virus genotype during parotitis epidemic of 2006-2007 in the state of Sao Paulo, Brazil

Nucleoticle sequence analyses of the SH gene of 18 mumps virus isolates collected in the 2006-2007 parotitis epidemic in the state of Sao Paulo identified a new genotype, designated genotype M. This new designation fulfills all the parameters required to define a new mumps virus genotype. The parameters were established by an expert panel in collaboration with the World Health Organization (WHO) in 2005. This information will enhance the mumps virus surveillance program both at the national and global levels.

Apolipoprotein E genotype is related to nitric oxide production in platelets

The presence of the, 4 allele of apolipoprotein E (APOE) is considered a risk factor for sporadic Alzheimer`s disease (AD). Our recent data demonstrated that the systemic modulation of oxidative stress in platelets and erythrocytes is disrupted in aging and AD. In this study, the relationship between APOE genotype and oxidative stress markers, both in AD patients and controls, was evaluated. The AD group showed an increase in the content of thiobarbituric acid-reactive substances (TBARS) and in the activities of nitric oxide synthase (NOS) and Na, K-ATPase, when compared to controls. Both groups had a similar cGMP content and superoxide dismutase activity. APOE epsilon 4 allele carriers showed higher NOS activity than non-carriers. These results suggest a possible influence of APOE genotype on nitric oxide (NO) production that might enhance the effects of age-related specific factor(s) associated with neurodegenerative disorders. Copyright (C) 2008 John Wiley & Sons, Ltd.

Differential response to resistance training in CHF according to ACE genotype

Background : The Angiotensin Converting Enzyme (ACE) gene may influence the risk of heart disease and the response to various forms of exercise training may be at least partly dependent on the ACE genotype. We aimed to determine the effect of ACE genotype on the response to moderate intensity circuit resistance training in chronic heart failure (CHF) patients.

Methods : The relationship between ACE genotype and the response to 11 weeks of resistance exercise training was determined in 37 CHF patients (New York Heart Association Functional Class = 2.3 ± 0.5; left ventricular ejection fraction 28 ± 7%; age 64 ± 12 years; 32:5 male:female) who were randomised to either resistance exercise (n = 19) or inactive control group (n = 18). Outcome measures included VO_2peak power output and muscle strength and endurance. ACE genotype was determined using standard methods.

Results : At baseline, patients who were homozygous for the I allele had higher VO_2peak (p = 0.02) and peak power (p = 0.003) compared to patients who were homozygous for the D allele. Patients with the D allele, who were randomised to resistance training, compared to non-exercising controls, had greater peak power increases (ID p < 0.001; DD p < 0.001) when compared with patients homozygous for the I allele, who did not improve. No significant genotype-dependent changes were observed in VO_2peak, muscle strength, muscle endurance or lactate threshold.

Conclusion : ACE genotype may have a role in exercise tolerance in CHF and could also influence the effectiveness of resistance training in this condition.

Functional (GT)n polymorphisms in promoter region of N-methyl-d-aspartate receptor 2A subunit (GRIN2A) gene affect hippocampal and amygdala volumes

The glutamate system including N-methyl-d-aspartate (NMDA) affects synaptic formation, plasticity and maintenance. Recent studies have shown a variable (GT)n polymorphism in the promoter region of the NMDA subunit gene (GRIN2A) and a length-dependent inhibition of transcriptional activity by the (GT)n repeat. In the present study, we examined whether the GRIN2A polymorphism is associated with regional brain volume especially in medial temporal lobe structures, in which the NMDA-dependent synaptic processes have been most extensively studied. Gray matter regions of interest (ROIs) for the bilateral amygdala and hippocampus were outlined manually on the magnetic resonance images of 144 healthy individuals. In addition, voxel-based morphometry (VBM) was conducted to explore the association of genotype with regional gray matter volume from everywhere in the brain in the same sample. The manually measured hippocampal and amygdala volumes were significantly larger in subjects with short allele carriers (n = 89) than in those with homozygous long alleles (n = 55) when individual differences in intracranial volume were accounted for. The VBM showed no significant association between the genotype and regional gray matter volume in any brain region. These findings suggest that the functional GRIN2A (GT)n polymorphism could weakly but significantly impact on human medial temporal lobe volume in a length-dependent manner, providing in vivo evidence of the role of the NMDA receptor in human brain development.

Hemoglobin genotype has minimal influence on the physiological response of juvenile atlantic cod (Gadus morhua) to environmental challenges

Hemoglobin (Hb) polymorphism in cod is associated with temperature‐related differences in biogeographical distribution, and several authors have suggested that functional characteristics of the various hemoglobin isoforms (HbIs) directly influence phenotypic traits such as growth rate. However, no study has directly examined whether Hb genotype translates into physiological differences at the whole animal level. Thus, we generated a family of juvenile Atlantic cod consisting of all three main Hb genotypes (HbI‐1/1, HbI‐2/2, and HbI‐1/2) by crossing a single pair of heterozygous parents, and we compared their metabolic and cortisol responses to an acute thermal challenge (10&deg;C to their critical thermal maximum [CTM] or 22&deg;C, respectively) and tolerance of graded hypoxia. There were no differences in routine metabolism (at 10&deg;C), maximum metabolic rate, metabolic scope, CTM (overall mean 22.9&deg; ± 0.2&deg;C), or resting and poststress plasma cortisol levels among Hb genotypes. Further, although the HbI‐1/1 fish grew more (by 15%&ndash;30% during the first 9 mo) when reared at 10&deg; ± 1&deg;C and had a slightly enhanced hypoxia tolerance at 10&deg;C (e.g., the critical O2 levels for HbI‐1/1, HbI‐2/2, and HbI‐1/2 cod were 35.56% ± 1.24%, and 40.20% ± 1.99% air saturation, respectively), these results are contradictory to expectations based on HbI functional properties. Thus, our findings (1) do not support previous assumptions that growth rate differences among cod Hb genotypes result from a more efficient use of the oxygen supply&mdash;that is, reduced standard metabolic rates and/or increased metabolic capacity&mdash;and (2) suggest that in juvenile cod, there is no selective advantage to having a particular Hb genotype with regards to the capacity to withstand ecologically relevant environmental challenges.

Association between serotonin transporter genotype, brain structure and adolescent onset major depressive disorder: a longitudinal prospective study

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13&ndash;19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.