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Apolipoprotein A5 (apoA5) is a potent regulator of triglyceride (TG) metabolism and therefore may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a disease characterised by excessive TG-rich lipid droplets in hepatocytes. To test this hypothesis, we examined the mRNA expression of apoA5 in paediatric NAFLD livers in comparison to healthy controls. According to microarray and quantitative real-time PCR, human NAFLD livers exhibited elevated apoA5 expression compared to healthy controls. The apoA5 expression levels were positively correlated with hepatic TG storage and a marker for lipid droplets (perilipin), but were not correlated with plasma TG levels. These observations were confirmed with a NAFLD rat model. Interestingly, apoA5 expression was not altered in cultured fat-laden HepG2 cells, demonstrating that fat storage does not induce apoA5 in NAFLD livers. Therefore, the correlation between apoA5 and intracellular fat storage is likely explained by the potent effect of apoA5 in promoting intracellular fat storage. Our NAFLD patients and rats had elevated insulin resistance, which may have a role in elevating apoA5 expression in NAFLD livers. Our data support the hypothesis that apoA5 promotes hepatic TG storage and therefore contributes to the pathogenesis of NAFLD, and may represent a potential target for therapeutic intervention. Show less

Previous studies have indicated that supplementation with probiotics might improve lipid metabolism. The objective of the study was to evaluate the effect of supplementation with probiotic strains Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on triglyceride (TG) and apolipoprotein A-V (apo A-V) levels. A randomized, double-blinded, placebo-controlled study was conducted with 128 non-diabetic subjects with hypertriglyceridemia. Over a 12-week test period, the probiotic group consumed 2 g/day of a powdered supplement containing L. curvatus HY7601 and L. plantarum KY1032, whereas the placebo group consumed a powder lacking probiotics. After the treatment, the probiotic group showed an 18.3% (P < 0.001) reduction in TGs and increases of 21.1% (P = 0.001) and 15.6% (P < 0.001) in the apo A-V and LDL particle size, respectively. The probiotic group had a significant reduction in TGs (P = 0.040) and increases in the plasma apo A-V (P = 0.003) and LDL particle size (P < 0.001) compared with the placebo group. In the probiotic group, the reduction in the TG levels was negatively correlated with changes in the apo A-V and baseline TGs, regardless of the APOA5 -1131T > C genotype. The consumption of two probiotic strains for 12 weeks reduced TGs and increased the apo A-V and LDL particle size in hypertriglyceridemic subjects. This effect was more pronounced in subjects with higher levels of fasting TGs regardless of their APOA5 -1131T > C genotype. Show less

Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis. Show less

HIV-infected patients treated with highly active antiretroviral therapy (HAART) may be predisposed to a lipid profile, associated with increased cardiovascular risk, derived from having high triglycerides (TG) and low high-density lipoprotein cholesterol (HDLc) levels. We propose that genetic variability leaves some HIV-infected patients more predisposed to this lipid profile than others. We performed a cross-sectional, observational study including 321 antiretroviral-treated HIV-infected patients classified as normolipidemic (n=173) or presenting with high TG (≥1.7 mmol/liter) and low HDLc [<1.02 (men) or 1.28 mmol/liter (women)] (n=148) to investigate the impact of 13 polymorphisms of 9 genes affecting lipid metabolism (APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5, and VLDLR genes). The polymorphism rs328 in LPL was 40% significantly more frequent in normolipidemics (p=0.018), and in the same group, polymorphisms rs708272 in CETP and rs1800588 in HL were 10% significantly more frequent (p=0.037 for both polymorphisms). Patients who presented a combination of one to six alleles from these polymorphisms had 10% increased HDLc levels [1.13 (0.40) vs. 1.24 (0.23) mmol/liter, p=0.002] and a trend toward lower triglycerides [2.23 (2.34) vs. 1.89 (1.24) mmol/liter] and lower remnant-like particle cholesterol (RLPc) [16.41 (11.42) vs. 12.99 (11.69) mmol/liter]. This effect was dependent on the number of protective alleles and independent of the regimen administered. Polymorphisms in LPL, CETP, and HL protect HIV-infected patients from developing the dyslipidemia derived from high TG and low HDLc levels in a dose-dependent manner. Show less

We aimed to evaluate the effect of atorvastatin on apolipoprotein AV (ApoAV) in HepG2 cells of insulin resistance (IR), and further explore its mechanism. Firstly, a model of IR in HepG2 cells was established by insulin, and then treated with various concentrations of atorvastatin (0, 10, 100 and 500 nM) for 12 h and 24 h, respectively. Detection of glucose concentration was performed by Glucose Oxidase kit. Subsequently, Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the concentrations of triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL). The mRNA levels of ApoAV and ApoAV-related genes, including glucose transporter 1 (Glut1), Glut2, peroxisome proliferator activated receptor α (PPARα), and liver X receptor α (LXRα) were detected by qRT-PCR. We successfully established IR model in HepG2 cells by 10-6 nM insulin. Subsequently, we found that the glucose extraction rate and mRNA level of ApoAV significantly reduced in HepG2 cells of IR (p < 0.05); however, atorvastatin increased the glucose extraction rate and ApoAV mRNA level. Furthermore, atorvastatin inhibited the concentration of TG in HepG2 cells of IR (p < 0.05); however, atorvastatin had no effect on HDL, LDL and VLDL. Also, atorvastatin could increase the mRNA levels of Glut2 but not Glut1, PPARα, and LXRα. Our study indicated that atorvastatin might inhibit IR induced by insulin through the TG-lowering role of ApoAV. Furthermore, Glut2 might be involved in the effect of atorvastatin on ApoAV in HepG2 cells of IR. Show less

Pharmacogenetics refers to the effect of single nucleotide polymorphisms (SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction (HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus (HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1 (MDR1) 3435C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity. Show less

Upon high-fat feeding, prostaglandin E receptor subtype 4 (EP4)-knockout mice gain less body weight than their EP4(+/+) littermates. We investigated the cause of the lean phenotype. The mice showed a 68.8% reduction in weight gain with diminished fat mass that was not attributable to reduced food intake, fat malabsorption, or increased energy expenditure. Plasma triglycerides in the mice were elevated by 244.9%. The increase in plasma triglycerides was independent of changes in hepatic very low density lipoprotein (VLDL)-triglyceride production or intestinal chylomicron-triglyceride synthesis. However, VLDL-triglyceride clearance was drastically impaired in the EP4-knockout mice. The absence of EP4 in mice compromised the activation of lipoprotein lipase (LPL), the key enzyme responsible for trafficking of plasma triglycerides into peripheral tissues. Deficiency in EP4 reduced hepatic mRNA expression of the transcriptional factor cAMP response element binding protein H (by 36.8%) and LPL activators, including apolipoprotein (Apo)a5 (by 40.2%) and Apoc2 (by 61.3%). In summary, the lean phenotype of EP4-deficient mice resulted from reduction in adipose tissue and accretion of other peripheral organs caused by impaired triglyceride clearance. The findings identify a new metabolic dimension in the physiologic role played by endogenous EP4. Show less

Apolipoprotein gene polymorphism has an important role in lipid metabolism and in the development of cerebro- and cardio-vascular disease (CCVD), including dementia. Dyslipidemia and hemostatic abnormalities are key risk factors associated with athero-sclerotic events preceding CCVD. The aim of this study was to evaluate the possible relationships of various apolipoprotein-species with hemostatic parameters and cognitive function. Lipid profile, gene polymorphism, coagulation markers, and mini-mental state examination (MMSE) scores were assessed in 109 dys-lipidemic subjects and in 107 healthy control volunteers. Thrombin-activatable fibrinolysis inhibitor (TAFI) plasma levels were significantly higher in apolipoprotein-E2 (apoE2) patients when compared to other apoE forms. The apoA5 -1131T>C polymorphism was associated with elevated D-dimer concentration in dyslipidemic TT homozygous individuals. MMSE did not correlate with lipid or coagulation profile. These data suggest that apoE and apoA5 variants have an effect on hemostatic parameters, but they neither influence nor predict cognitive performance in non-demented individuals. Show less

Apolipoprotein A5 (APOA5) is associated with plasma triglyceride (TG) levels, a risk factor for coronary heart disease (CHD). This study explored the association between CHD and the APOA5 rs662799 polymorphism. We collected 1,521 samples (783 CHD patients and 738 controls) for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software. Significant differences were observed between CHD cases and controls at the level of both genotype (χ2 = 8.964, df = 2, P = 0.011) and allele (χ2 = 9.180, df = 1, P = 0.002, OR = 1.275, 95% CI = 1.089-1.492). A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males (χ2 = 7.770, df = 1, P = 0.005; OR = 1.331, 95% CI = 1.088-1.628). An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001). Both our case-control study and meta-analysis confirm a significant association between APOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD. Show less

Our research aimed to investigate the relationship between Apolipoprotein A5 (APOA5) T1131C polymorphism and the risk of coronary artery disease (CAD). We searched the relevant articles in databases and 25 ones were chosen. The association between APOA5 T1131C polymorphism and CAD risk was evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs). The fixed-effect model or random-effect model was applied according to the heterogeneity analysis. Overall, significant association between CAD risk and APOA5 T1131C polymorphism was found (CC vs. TT: OR=1.47, 95% CI=1.22-1.78; CC+TC vs. TT: OR=1.13, 95% CI=1.07-1.20; CC vs. TT+TC: OR=1.37, 95% CI=1.13-1.66; allele C vs. allele T: OR=1.17, 95% CI=1.09-1.25; TC vs. TT: OR=1.12, 95% CI=1.06-1.20). In the ethnicity subgroup analysis, risk of CAD was observed in all genotypes among Asians (CC vs. TT: OR=1.40, 95% CI=1.17-1.68; CC+TC vs. TT: OR=1.13, 95% CI=1.06-1.20; CC vs. TT+TC: OR=1.30, 95% CI=1.08-1.56; allele C vs. allele T: OR=1.15, 95% CI=1.08-1.24; TC vs. TT: OR=1.13, 95% CI=1.06-1.21), While in Caucasians, the similar association was only found in several genotypes. In the subgroup analysis by source of control, we found that APOA5 T1131C polymorphism could increase the risk of CAD in population-based (PB) genetic group (CC vs. TT: OR=1.54, 95% CI=1.29-1.84; CC+TC vs. TT: OR=1.15, 95% CI=1.08-1.23; CC vs. TT+TC: OR=1.45, 95% CI=1.19-1.76; allele C vs. allele T: OR=1.19, 95% CI=1.12-1.25; TC vs. TT: OR=1.14, 95% CI=1.06-1.22). There was no correlation found in hospital-based (HB) genetic group yet. APOA5 T1131C polymorphism might be significantly associated with susceptibility to CAD. Show less

Fetal organs require much lipid for growth, but the cord blood had low TG concentrations, compared to adult serum. We investigated the association between the concentration of apolipoprotein A-V (apoA-V) and lipid profile in cord blood and neonatal serum. ApoA-V was identified as an important determinant of plasma triglyceride concentrations. We sought to determine the association between serum apoA-V concentrations and lipoprotein profile in preterm infants and its early postnatal change. Sixty-three neonates (35 males and 28 females; 15 term and 48 preterm) were included. Serum lipoprotein profile and apoA-V concentrations were determined at birth and 1 month. Cord blood apoA-V concentrations in appropriate-for-gestational age infants were extremely low (13.1 ± 3.4 ng/mL in term infants, 4.4 ± 0.9 ng/mL in preterm infants) compared with adult values, and those of small-for-gestational age infants were further low (6.4 ± 4.2 ng/mL, 2.2 ± 1.3 ng/mL, respectively). During the first month, serum apoA-V concentration markedly increased, and the concentration of preterm appropriate-for-gestational age infants caught up, whereas that of preterm small-for-gestational age infants did not. At birth, apoA-V concentration positively correlated with gestational age (r = 0.354, P = .0069) but not with birth weight Z-score. ApoA-V concentration had a positive association with very low-density lipoprotein triglyceride concentrations (r = 0.646, P < .0001), and the relationships still remained at 1 month (r = 0.283, P = .0348). ApoA-V in neonates was unique in its serum concentration and in the association with lipoprotein profile. Show less

We describe a kindred with high-density lipoprotein (HDL) deficiency due to APOA1 gene mutation in which comorbidities affected the phenotypic expression of the disorder. An overweight boy with hypertriglyceridemia (HTG) and HDL deficiency (HDL cholesterol 0.39 mmol/L, apoA-I 40 mg/dL) was investigated. We sequenced the candidate genes for HTG (LPL, APOC2, APOA5, GPIHBP1, LMF1) and HDL deficiency (LCAT, ABCA1 and APOA1), analyzed HDL subpopulations, measured cholesterol efflux capacity (CEC) of sera and constructed a model of the mutant apoA-I. No mutations in HTG-related genes, ABCA1 and LCAT were found. APOA1 sequence showed that the proband, his mother and maternal grandfather were heterozygous of a novel frameshift mutation (c.546₅₄₇delGC), which generated a truncated protein (p.[L159Afs*20]) containing 177 amino acids with an abnormal C-terminal tail of 19 amino acids. Trace amounts of this protein were detectable in plasma. Mutation carriers had reduced levels of LpA-I, preβ-HDL and large HDL and no detectable HDL-2 in their plasma; their sera had a reduced CEC specifically the ABCA1-mediated CEC. Metabolic syndrome in the proband explains the extremely low HDL cholesterol level (0.31 mmol/L), which was half of that found in the other carriers. The proband's mother and grandfather, both presenting low plasma low-density lipoprotein cholesterol, were carriers of the β-thalassemic trait, a condition known to be associated with a reduced low-density lipoprotein cholesterol and a reduced prevalence of cardiovascular disease. This trait might have delayed the development of atherosclerosis related to HDL deficiency. In these heterozygotes for apoA-I truncation, the metabolic syndrome has deleterious effect on HDL system, whereas β-thalassemia trait may delay the onset of cardiovascular disease. Show less

Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men. Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital. We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men. We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population. Show less

Diet is an important environmental factor that interacts with genes to modulate the likelihood of developing disorders in lipid metabolism and the relationship between diet and genes in the presence of other chronic diseases such as obesity. The objective of this study was to analyze the interaction of a high fat diet with the APOA2 (rs3813627 and rs5082), APOA5 (rs662799 and rs3135506) and LEPR (rs8179183 and rs1137101) polymorphisms and its relationship with obesity and dyslipidemia in young subjects. The study included 200 young subjects aged 18 to 25 years (100 normal-weight and 100 obese subjects). Dietary fat intake was measured using the frequency food consumption questionnaire. Genotyping of polymorphisms was performed by PCR-RFLP. Individuals carrying the APOA5 56 G/G genotype with a high saturated fatty acid consumption (OR = 2.7, p = 0.006) and/or total fat (OR = 2.4, p = 0.018), associated with an increased risk of obesity. We also found that A/G + G/G genotypes of the 668 A/G polymorphism in the LEPR gene with an intake ≥ 12 g/d of saturated fatty acids, have 2.9 times higher risk of obesity (p = 0.002), 3.8 times higher risk of hypercholesterolemia (p = 0.002) and 2.4 times higher risk of hypertriglyceridemia (p = 0.02), than those with an intake <12 g/d of saturated fatty acids. Similarly, LEPR 668 A/G + G/G carriers with a high fat total intake had 3.0 times higher risk of obesity (p = 0.002) and 4.1 times higher risk of hypercholesterolemia (p = 0.001). Our results suggest that dietary fat intake modifies the effect of APOA5 and LEPR polymorphisms on serum triglycerides, cholesterol levels and obesity in young subjects. Show less

Triglycerides (TGs) are proatherogenic lipoproteins involving the risk of coronary heart disease (CHD), while apolipoprotein A5 (APOA5) and apolipoprotein C3 (APOC3) are main lipoproteins composing TG-rich lipoproteins. In this study, we aim to explore the correlation of CHD with APOA5 -1131 T > C and APOC3 -455 T > C single nucleotide polymorphisms (SNPs). A sum of 210 CHD patients, hospitalized between Jan. 2013 and Mar. 2015 at China-Japan Union Hospital, Jilin University, were selected as our case group and 223 healthy individuals who had physical examination at same hospital at the same period were selected as control group. The frequency distribution of genotypes of APOA5 -1131 T > C and APOC3 -455 T > C SNPs were measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Stata 12.0 software was utilized for statistical analyses. There was no significant difference on age and sex between case and control group (P > 0.05). History of smoking, drinking, hypertension and diabetes mellitus, body mass index and levels of TG and fasting blood sugar in case group were shown to be higher than control group (P < 0.05), while levels of total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in case group were lower than control group (P < 0.05). Both CC and TC' + CC frequencies of APOA5 -1131 T > C and APOC3 -455 T > C in case group were higher compared to control group (both P < 0.05). Additionally, T allele frequencies of the two SNPs in case group were lower than control group, while C allele in case group has higher frequencies compared to control group (both P < 0.05). The results of meta-analysis under allele and dominant models showed that APOA5 -1131 T > C and APOC3 -455 T > C SNPs are likely to increase the risk of CHD (both P < 0.05). APOA5 -1131 T > C and APOC3 -455 T > C SNPs may play potent roles in the development and progression of CHD. Show less

Apolipoprotein A5 gene promoter region T-1131C polymorphism (APOA5 T-1131C) is known to be associated with elevated plasma TG levels, although little is known of the influence of the interaction between APOA5 T-1131C and lifestyle modification on TG levels. To investigate this matter, we studied APOA5 T-1131C and plasma TG levels of subjects participating in a three-month lifestyle modification program. A three-month lifestyle modification program was conducted with 297 participants (Age: 57 ± 8 years) in Izumo City, Japan, from 2001-2007. Changes in energy balance (the difference between energy intake and energy expenditure) and BMI were used to evaluate the participants' responses to the lifestyle modification. Even after adjusting for confounding factors, plasma TG levels were significantly different at baseline among three genotype subgroups: TT, 126 ± 68 mg/dl; TC, 134 ± 74 mg/dl; and CC, 172 ± 101 mg/dl. Lifestyle modification resulted in significant reductions in plasma TG levels in the TT, TC, and CC genotype subgroups: -21.9 ± 61.0 mg/dl, -20.9 ± 51.0 mg/dl, and -42.6 ± 78.5 mg/dl, respectively, with no significant differences between them. In a stepwise regression analysis, age, APOA5 T-1131C, body mass index (BMI), homeostasis model assessment-insulin resistance (HOMA-IR), and the 18:1/18:0 ratio showed independent association with plasma TG levels at baseline. In a general linear model analysis, APOA5 T-1131C C-allele carriers showed significantly greater TG reduction with decreased energy balance than wild type carriers after adjustment for age, gender, and baseline plasma TG levels. The genetic effects of APOA5 T-1131C independently affected plasma TG levels. However, lifestyle modification was effective in significantly reducing plasma TG levels despite the APOA5 T-1131C genotype background. Show less

The complexity of obesity and onset and susceptibility of cardio-metabolic disorders are still poorly understood and is addressed here through studies of genetic influence on weight gain and increased metabolic risk longitudinally. Twenty seven previously identified obesity, eating disorder or metabolic risk susceptibility SNPs were tested for association with weight or metabolically related traits longitudinally in 3999 adults participating both in the HUNT2 (1995-97) and HUNT3 (2006-08) surveys. Regression analyses were performed with changes from normal weight to overweight/obesity or from metabolically healthy to adverse developments with regards to blood pressure, glucose, HDL cholesterol, triglycerides or metabolic syndrome as outcomes. Additionally, a sub-sample of 1380 adolescents was included for testing association of nine SNPs with longitudinal weight gain into young adulthood. The most substantial effect on BMI-based weight gain from normal to overweight/obesity in adults was observed for the DRD2 variant (rs6277)(OR: 0.79, 95% CI: 0.69-0.90, P = 3.9x10(-4), adj. P = 0.015). DRD2 was not associated with BMI on a cross-sectional level. In the adolescent sample, FTO (rs1121980) was associated with change to overweight at adulthood in the combined male-female sample (OR: 1.27, 95% CI: 1.09-1.49, P = 3.0x10(-3), adj. P = 0.019) and in females (OR: 1.53, 95% CI: 1.23-1.91, P = 1.8x10(-4), adj. P = 0.003). When testing for association to longitudinal adverse developments with regard to blood pressure, blood lipids and glucose, only rs964184 (ZNF259/APOA5) was significantly associated to unfavourable triglyceride changes (OR: 1.66, 95% CI: 1.36-2.03, P = 5.7x10(-7), adj. P = 0.001). Pleiotropic effects on metabolic traits, however, were observed for several genetic loci cross-sectionally, ZNF259/APOA5, LPL and GRB14 being the most important. DRD2 exhibits effects on weight gain from normal weight to overweight/obesity in adults, while, FTO is associated to weight gain from adolescence to young adulthood. Unhealthy longitudinal triglyceride development is strongly affected by ZNF259/APOA. Our main finding, linking the DRD2 variant directly to the longitudinal weight gain observed, has not previously been identified. It suggests a genetic pre-disposition involving the dopaminergic signalling pathways known to play a role in food reward and satiety linked mechanisms. Show less

Coronary heart disease (CHD) is an archetypical multifactorial disorder that is influenced by genetic susceptibility as well as both modifiable and nonmodifiable risk factors, and their interactions. Advances during recent years in the field of multifactorial genetics, in particular genomewide association studies (GWASs) and their meta-analyses, have provided the statistical power to identify and replicate genetic variants in more than 50 risk loci for CHD and in several hundreds of loci for cardiometabolic risk factors for CHD such as blood lipids and lipoproteins. Although for a great majority of these loci both the causal variants and mechanisms remain unknown, progress in identifying the causal variants and underlying mechanisms has already been made for several genetic loci. Furthermore, identification of rare loss-of-function variants in genes such as PCSK9, NPC1L1, APOC3 and APOA5, which cause a markedly decreased risk of CHD and no adverse side effects, illustrates the power of translating genetic findings into novel mechanistic information and provides some optimism for the future of developing novel drugs, given the many genes associated with CHD in GWASs. Finally, Mendelian randomization can be used to reveal or exclude causal relationships between heritable biomarkers and CHD, and such approaches have already provided evidence of causal relationships between CHD and LDL cholesterol, triglycerides/remnant particles and lipoprotein(a), and indicated a lack of causality for HDL cholesterol, C-reactive protein and lipoprotein-associated phospholipase A2. Together, these genetic findings are beginning to lead to promising new drug targets and novel interventional strategies and thus have great potential to improve prevention, prediction and therapy of CHD. Show less

Fenofibrate lowers triglycerides (TG) and raises high density lipoprotein cholesterol (HDLc) in dyslipidemic individuals. Several studies have shown genetic variability in lipid responses to fenofibrate treatment. It is, however, not known whether epigenetic patterns are also correlated with the changes in lipids due to fenofibrate treatment. The present study was therefore undertaken to examine the changes in DNA methylation among the participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. A total of 443 individuals were studied for epigenome-wide changes in DNA methylation, assessed using the Illumina Infinium HumanMethylation450 array, before and after a 3-week daily treatment with 160 mg of fenofibrate. The association between the change in DNA methylation and changes in TG, HDLc, and low-density lipoprotein cholesterol (LDLc) were assessed using linear mixed models adjusted for age, sex, baseline lipids, and study center as fixed effects and family as a random effect. Changes in DNA methylation were not significantly associated with changes in TG, HDLc, or LDLc after 3 weeks of fenofibrate for any CpG. CpG changes in genes known to be involved in fenofibrate response, e.g., PPAR-α, APOA1, LPL, APOA5, APOC3, CETP, and APOB, also did not show evidence of association. In conclusion, changes in lipids in response to 3-week treatment with fenofibrate were not associated with changes in DNA methylation. Studies of longer duration may be required to detect treatment-induced changes in methylation. Show less

This study evaluated the triglyceride (TG)-lowering effects of consuming dual probiotic strains of Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on the fasting plasma metabolome. A randomized, double-blind, placebo-controlled study was conducted on 92 participants with hypertriglyceridemia but without diabetes. Over a 12-week testing period, the probiotic group consumed 2 g of powder containing 5 × 10(9) colony-forming units (cfu) of L. curvatus HY7601 and 5 × 10(9) cfu of L. plantarum KY1032 each day, whereas the placebo group consumed the same product without probiotics. Fasting plasma metabolomes were profiled using UPLC-LTQ-Orbitrap MS. After 12 weeks of treatment, the probiotic group displayed a 20% reduction (p = 0.001) in serum TGs and 25% increases (p=0.001) in apolipoprotein A-V (apoA-V). At the 12-week follow-up assessment, the following 11 plasma metabolites were significantly reduced in the probiotic group than the placebo group: palmitoleamide, palmitic amide, oleamide, and lysophosphatidyl choline (lysoPC) containing C14:0, C16:1, C16:0, C17:0, C18:3, C18:2, C18:1, and C20:3. In the probiotic group, changes (▵) in TG were negatively correlated with ▵ apoA-V, which was positively correlated with ▵ FFA. In addition, ▵ FFA was strongly and positively correlated with ▵ lysoPCs in the probiotic group but not the placebo group. The triglyceride-lowering effects of probiotic supplementation, partly through elevated apoA-V, in borderline to moderate hypertriglyceridemic subjects showed reductions in plasma metabolites, fatty acid primary amides and lysoPCs (NCT02215694; http://www.clinicaltrials.gov). Clinical trials: NCT02215694; http://www.clinicaltrials.gov. Show less

Although many studies have investigated the association of the APOA5 -1131T/C polymorphism with coronary artery disease (CAD), definite conclusions have not been drawn. To understand the effects of the APOA5 -1131T/C polymorphism on the risk of developing CAD, we performed an updated meta-analysis in the Chinese population. Relevant studies published till April 2015 were identified from databases such as PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine. A total of 19 studies including 3983 patients and 4358 controls were involved in this meta-analysis. The crude OR with 95%CI was calculated to assess the strength of the association. With the pooled data from the studies included in this meta-analysis, we found a significant association between the APOA5 -1131T/C polymorphism and CAD risk in the Chinese population (C vs T: OR = 1.34, 95%CI = 1.16-1.54; CC vs TT: OR = 1.73, 95%CI = 1.30-2.30; CC vs TT and TC: OR = 1.51, 95%CI = 1.17-1.95; CC vs TC: OR = 1.30, 95%CI = 1.03-1.65). Stratified analyses according to the geographical location and source of controls revealed significantly increased risk in South China and in population-based studies. In conclusion, our meta-analysis provides substantial evidence that the APOA5 -1131T/C polymorphism might contribute to CAD development in the Chinese population. Show less

Apolipoprotein (apo) A-V is a protein synthesized only in the liver that dramatically modulates plasma triglyceride levels. Recent studies suggest a novel role for hepatic apoA-V in regulating the absorption of dietary triglycerides, but its mode of action on the gut remains unknown. The aim of this study was to test for apoA-V in bile and to determine whether its secretion is regulated by dietary lipids. After an overnight recovery, adult male Sprague-Dawley bile fistula rats indeed secreted apoA-V into bile at a constant rate under fasting conditions. An intraduodenal bolus of intralipid (n = 12) increased the biliary secretion of apoA-V but not of other apolipoproteins, such as A-I, A-IV, B, and E. The lipid-induced increase of biliary apoA-V was abolished under conditions of poor lymphatic lipid transport, suggesting that the stimulation is regulated by the magnitude of lipids associated with chylomicrons transported into lymph. We also studied the secretion of apoA-V into bile immediately following bile duct cannulation. Biliary apoA-V increased over time (∼6-fold increase at hour 16, n = 8) but the secretions of other apolipoproteins remained constant. Replenishing luminal phosphatidylcholine and taurocholate (n = 9) only enhanced apoA-V secretion in bile, suggesting that the increase was not due to depletion of phospholipids or bile salts. This is the first study to demonstrate that apoA-V is secreted into bile, introducing a potential route of delivery of hepatic apoA-V to the gut lumen. Our study also reveals the uniqueness of apoA-V secretion into bile that is regulated by mechanisms different from other apolipoproteins. Show less

The aim of the present study is to explore the association between the APOA5 polymorphisms and haplotypes with obesity in Moroccan patients. The study was performed in 459 subjects, Obese (n=164) and non-obese (n=295). All subjects were genotyped for the APOA5 -1131T>C (rs662799) and c.56C>G (rs3135506) polymorphisms. The contribution of APOA5 polymorphisms and haplotypes in the increased risk of obesity were explored using logistic regression analyses. The -1131T>C and c.56C>G polymorphisms were significantly associated with obesity. Both polymorphisms were strongly associated with increased BMI. Analysis of constructed haplotypes showed a significant association between CG haplotype and susceptibility to obesity (OR [95%CI]=3.09 [1.93-4.97]; P<0.001). These results support a potential role for APOA5 common variants and related haplotypes as risk factors for obesity. Show less

In this case-control study we investigated the relative contribution of commons APOA5 polymorphisms and haplotypes to the risk of metabolic syndrome in Moroccan patients. Using the International Diabetes Federation (IDF) criteria for metabolic syndrome, the study included 176 patients and 105 controls. We genotyped APOA5 polymorphisms (-1131 T > C, c.56C > G, c.553G > T and c.1259 T > C) by PCR-RFLP analysis. The effects of APOA5 polymorphisms and constructed haplotypes on metabolic syndrome were estimated using logistic regression analyses. The statistical analysis showed a significant association between APOA5 -1131 T > C and APOA5 c.56C > G polymorphisms with metabolic syndrome in both Codominant and Dominant models. The APOA5 -1131 T > C polymorphism was associated with increased fasting glucose (p = 0.0295) and reduced HDL levels (p = 0.0091). Carriers of the APOA5 c.56G allele had increased triglyceride levels (p = 0.0435) and waist circumference (p = 0.0122). Similarly the APOA5 1259 T > C variant was associated with increased waist circumference (p = 0.0463). The haplotypes CCGT (OR = 3.223; p = 0.00278) and CGGT (OR = 8.234; p = 0.00534) were significantly associated with susceptibility to metabolic syndrome. Our results confirms the association of APOA5 -1131 T > C and c.56C > G variants with the predisposition to metabolic syndrome complications. Show less

Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP-SNP interaction, SNP-environment interaction, and SNP-clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS. Show less

Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n = 8) and wild-type (WT, n = 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [(3)H]triolein and [(14)C]cholesterol. ApoA-V KO mice showed a twofold increase in (3)H (P < 0.001) and a threefold increase in (14)C (P < 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P < 0.05) in mucosal (3)H, suggesting that apoA-V KO mice more rapidly secreted [(3)H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P < 0.05), as measured by the transit time of [(14)C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency. Show less

Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A>T and c.1306G>A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families. Show less

To evaluate whether the Chinese Han population harbors genetic markers associated with risk of acute myocardial infarction (MI), which have previously been identified in other ethnic populations. According to predefined criteria, 549 Chinese patients with acute MI and 551 Chinese subjects (controls) without a history of coronary artery disease (CAD) were selected for the study. Three prevalent single nucleotide polymorphisms (SNPs; rs1412444(LIPA), rs662799(APOA5) and rs964184(ZNF259)) associated with CAD and MI in other ethnic populations, were selected for sequence and association analyses within blood DNA of the Chinese Han population. Only two SNPs, rs662799 (APOA5) and rs964184 (ZNF259) found at two independent loci, were associated with risk of MI in the Chinese Han population. Using Bonferroni correction methods, significant differences in the association of these two SNPs (rs662799 (p = 0.0228) and rs964184 (p = 0.0060)) between Chinese patients with MI versus controls were revealed. We identified a significant association between two SNPs (rs964184 and rs662799) on chromosome 11q23.3 and MI risk in the Chinese Han population, which extends their clinical relevance to predicting the risk of MI in diverse ethnic populations. Show less

The aim of this study was to investigate correlations between apolipoprotein A-V (APOA5) -1131T>C and apolipoprotein C-III (APOC3) -455T>C polymorphisms and coronary heart disease (CHD). PubMed, Ovid, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched using combinations of keywords relating to these polymorphisms and CHD. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria, and Comprehensive Meta-Analysis Version 2.0 software was used for statistical analyses. In total, 115 studies were initially retrieved and after further selection, 11 were included in the meta-analysis. These 11 articles comprised 4840 patients with CHD in the case group and 4913 healthy participants in the control group. Meta-analysis revealed that APOA5 -1131T>C and APOC3 -455T>C polymorphisms increased CHD risk. In addition, subgroup analysis by ethnicity showed that while the -1131T>C polymorphism elevated the risk of CHD in the Caucasian population under both allelic and dominant models, this increased risk was observed only under a dominant model in the Asian population. The results of our meta-analysis point to a strong link between both APOA5 -1131T>C and APOC3 -455T>C polymorphisms and an increased risk of CHD. Thus, these polymorphisms constitute important predictive indicators of CHD susceptibility. Show less