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Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in Show less

The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, immunosuppressives, antipsychotics, antidepressants, retinoids, L-asparaginase, and propofol. A third uncommon cause of the chylomicronemia syndrome is familial forms of partial lipodystrophy. Development of pancreatitis is the most feared complication of the chylomicronemia syndrome, but the risk of cardiovascular disease as well as non-alcoholic steatohepatitis is also increased. Treatment consists of dietary fat restriction and weight reduction combined with the use of triglyceride lowering medications such as fibrates, omega 3 fatty acids and niacin. Effective management of aggravating factors such as improving diabetes control, discontinuing alcohol and replacing or reducing the dose of medications that raise triglyceride levels is essential. Importantly, many if not most cases of the chylomicronemia syndrome can be prevented by effective identification of polygenic hypertriglyceridemia in people with conditions that increase its likelihood or before starting medications that may increase triglyceride levels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk. Show less

The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population. Show less

Hypertriglyceridaemia is a very rare disorder caused by the mutations of LPL gene, with an autosomal recessive mode of inheritance. Here, we identified two unrelated Chinese patients manifested with severe hypertriglyceridaemia and acute pancreatitis. The clinical symptoms of proband 1 are more severe than proband 2. Whole exome sequencing and Sanger sequencing were performed. Functional analysis of the identified mutations has been done. Whole exome sequencing identified two pairs of variants in LPL gene in the proband 1 (c.162C>A and c.1322+1G>A) and proband 2 (c.835C>G and c.1322+1G>A). The substitution (c.162C>A) leads to the formation of a truncated (p.Cys54*) LPL protein. The substitution (c.835C>G) leads to the replacement of leucine to valine (p.Leu279Val). The splice donor site mutation (c.1322+1G>A) leads to the formation of alternative transcripts with the loss of 134 bp in exon 8 of the LPL gene. The proband 1 and his younger son also harbouring a heterozygous variant (c.553G>T; p.Gly185Cys) in APOA5 gene. The relative expression level of the mutated LPL mRNA (c.162C>A, c.835C>G and c.1322+1G>A) showed significant differences compared to wild-type LPL mRNA, suggesting that all these three mutations affect the transcription of LPL mRNA. These three mutations (c.162C>A, c.835C>G and c.1322+1G>A) showed noticeably decreased LPL activity in cell culture medium but not in cell lysates. Here, we identified three mutations in LPL gene which causes severe hypertriglyceridaemia with acute pancreatitis in Chinese patients. We also described the significance of whole exome sequencing for identifying the candidate gene and disease-causing mutation in patients with severe hypertriglyceridaemia and acute pancreatitis. Show less

Coronary artery diseases (CAD) are clinical cardiovascular events associated with dyslipidemia in common. The interaction between environmental and genetic factors can be responsible for CAD. The present paper aimed to examine the association between c.56C > G (rs3135506) APOA5 gene polymorphism and CAD in Moroccan individuals and to perform an association update meta-analysis. The c.56C > G variant was genotyped in 122 patients with CAD and 134 unrelated controls. Genetic association analysis and comparison of biochemical parameters were performed using The case-control study data showed that the c.56C > G polymorphism was associated with CAD susceptibility under codominant ( Our case-control study revealed a significant association between c.56C > G polymorphism and CAD in the Moroccan population. In addition, meta-analysis data supported the implication of this polymorphism in CAD susceptibility. Show less

In the present study, candidate genes affected by rosiglitazone to exert glycemic control in the treatment of type 2 diabetes mellitus (T2DM) and associated with its adverse cardiovascular effects were identified using a bioinformatics analysis. The gene expression profiles of the dataset GSE36875 from the Gene Expression Omnibus database, including heart samples from 5 non-diabetic control mice (NC), 5 untreated diabetic mice (NH) and 5 rosiglitazone-treated diabetic mice (TH), were used to identify differentially expressed genes (DEGs) in the NC vs. NH, NC vs. TH and TH vs. NH groups. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by the DEGs were determined. Furthermore, genes associated with the action of rosiglitazone were identified using Short Time-series Expression Miner, which were then subjected to enrichment analysis in gene ontology (GO) terms in the category biological process (BP), and networks of the GO terms, KEGG pathways and genes associated with the action of rosiglitazone were constructed. Finally, biological abnormalities associated with these genes were identified using WebGestalt. A set of 791 DEGs in three groups (NC vs. NH, NC vs. TH and NH vs. TH) were identified. Subsequently, 72 DEGs [e.g., apolipoprotein (Apo)A1, ApoA5, cytochrome P450 (Cyp)2c37, Cyp2J5, Cyp2b9 and Cyp2b10] were identified as genes associated with the action of rosiglitazone. In addition, a network of 13 GO terms in the category BP, 6 KEGG pathways and 41 genes associated with the action of rosiglitazone was constructed, with major terms/pathways including oxidation/reduction, lipid transport, peroxisome proliferator-activated receptor signaling pathway and metabolism of xenobiotics by Cyp. Finally, 15 biological abnormalities (including abnormal triglyceride levels, abnormal cholesterol homeostasis, abnormal lipid homeostasis) associated with these genes were identified. ApoA1, ApoA5, Cyp2c37, Cyp2J5, Cyp2b9 and Cyp2b10 were differently expressed after rosiglitazone treatment, which may be accountable for affecting cardiovascular outcomes and glycemic control in T2DM. The present results may expand the current understanding of the mechanism of action of rosiglitazone to exert glycemic control in T2DM, as well as its effects on the cardiovascular system. Show less

Hypertriglyceridemia (HTG) is one of the most common etiologies of acute pancreatitis (AP). Variants in five genes involved in the regulation of plasma lipid metabolism, namely LPL, APOA5, APOC2, GPIHBP1 and LMF1, have been frequently reported to cause or predispose to HTG. A Han Chinese patient with HTG-induced AP was assessed for genetic variants by Sanger sequencing of the entire coding and flanking sequences of the above five genes. The patient was a 32-year-old man with severe obesity (Body Mass Index = 35) and heavy smoking (ten cigarettes per day for more than ten years). At the onset of AP, his serum triglyceride concentration was elevated to 1450.52 mg/dL. We sequenced the entire coding and flanking sequences of the LPL, APOC2, APOA5, GBIHBP1 and LMF1 genes in the patient. We found no putative deleterious variants, with the exception of a novel and heterozygous nonsense variant, c.1024C > T (p.Arg342*; rs776584760), in exon 7 of the LMF1 gene. This is the first time that a heterozygous LMF1 nonsense variant was found in a HTG-AP patient with severe obesity and heavy smoking, highlighting an important interplay between genetic and lifestyle factors in the etiology of HTG. Show less

To explore the association of rs662799 variants of Apolipoprotein A5 gene with metabolic syndrome in Pakistani population. The case-control study was conducted at Pakistan Institute of Medical Sciences, Islamabad, Pakistan from 2014 to2016, and comprised subjects enrolled from the out-patient clinics. Groups were formed on the basis of preliminary screening for risk factors like obesity, insulin resistance, hypertension, dyslipidemia and fasting blood glucose levels. Met S was diagnosed based on the international diabetes federation criteria. Blood samples were collected for biochemical testing and deoxyribonucleic acid extraction. Genotyping of rs662799 was performed a the Genome Research Centre of the University of Hong Kong using Sequenom Mass ARRAY, iPLEX Gold technology. Data was analysed using SPSS 16and Plink software. :There were 712 subjects in two groups of 356(50%) each. The overall mean age was 41.59}7.18 years. There was a significant association of risk allele C of rs662799 with metabolic syndrome (p=0.002). The risk showed strong association with dyslipidaemia (p=0.03) and obesity (p=0.01) which are risk phenotypes of metabolic syndrome in age- and gender-adjusted model. The association of risk allele C of genetic variant rs662799 of Apolipoprotein A5 gene with dyslipidaemia and obesity may lead to the development of metabolic syndrome in the Pakistan adult population. Show less

Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD. Show less

Fulminant liver failure (FHF) is a serious clinical problem and liver transplantation is the major intervention. But the overall survival rate of FHF is low owing to the donated organ shortage. Apolipoprotein A-V (ApoA5) is a regulator of triglyceride metabolism and has been reported to act as a predictor for remnant liver growth after preoperative portal vein embolization and liver surgery. This study aimed to investigate the therapeutic effect of ApoA5 on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced fulminant liver failure in mice. FHF mouse model was established using LPS/D-GalN and ApoA5 plasmid was injected by tail vein prior to LPS/D-GalN treatment. The expressions of ApoA5, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B p65 (NF-κBp65) were assessed by real-time PCR and western blotting. Serum alanine aminotransferase (ALT) and tumor necrosis factor-α (TNF-α) levels were measured using automatic biochemical analyzer. Histological assessment and immunohistochemical (IHC) staining were conducted. Survival rate after LPS/D-GalN administration was also determined with Kaplan-Meier curve. Meanwhile, the expression of ApoA5 in injured huh7 cells was tested. Cell apoptosis analysis was performed after huh7 cells were transfected with ApoA5 plasmid and stimulated with LPS. The expressions of ApoA5 decreased both in injured huh7 cells and FHF mice. ApoA5 overexpression reduced cell death rate using flow cytometry. ApoA5 not only decreased the serum ALT and TNF-α levels but also attenuated hepatic damage in hematoxylin-eosin (HE)-stained liver section. The protein expressions of TLR4, MyD88 and NF-κBp65 were inhibited when ApoA5 overexpressed. But the inhibitory effect would weaken with the increasing concentration of LPS in spite of ApoA5 overexpression. Besides, ApoA5 improved liver injury in a dose-dependent manner and the survival rate in FHF mice increased with increasing concentration of ApoA5. ApoA5 had a protective effect against LPS/D-GalN-induced fulminant liver failure in mice within a certain range by inhibiting TLR4-mediated NF-κB pathway. Show less

In this association study on chromosome 11, the data from 12,537 Korean individuals within the Health Examinee (HEXA) and the Korea Association Resource (KARE) projects were analysed to identify genetic loci correlating with increased and decreased plasma triglyceride (TG) levels. We identified a locus in chromosomal region 11q23.3 that harbours genes BUD13, ZNF259, APOA5, APOA1, and SIK3, which may be associated with plasma TG levels. In this locus, 13 relevant single-nucleotide polymorphisms (SNPs) were found: rs184616707, rs118175510, rs60954647, rs79408961, and rs180373 (near BUD13); rs11604424 (in ZNF259); rs2075291, rs651821, and rs7123666 (in or near APOA5); rs525028 (near APOA1), and rs645258, rs10160754, and rs142395187 (in or near SIK3). All 13 SNPs satisfied the genome-wide significance level (P < 5.0 × 10 Show less

Hepatitis B virus (HBV) infection remains a global health issue associated with substantial morbidity and mortality. Serum apolipoprotein C3 (ApoC3) and apolipoprotein A5 (ApoA5) levels were decreased in chronic hepatitis B (CHB) patients, however the relationship between ApoC3 or ApoA5 and HBV DNA load remains elusive. A total of 384 CHB patients including 194 HBsAg(+) HBeAg(-) and 190 HBsAg(+) HBeAg(+) and 154 healthy individuals were recruited in our study. Serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), total cholesterol (Chol), triglycerides (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), high-density lipoproteins cholesterol (HDL-C), low-density lipoproteins cholesterol (LDL-C) and lipoprotein a (Lpa) were examined in an automatic biochemical analyzer. Apolipoprotein A5 (ApoA5) and apolipoprotein C3 (ApoC3) were detected via ELISA. Serum ApoA1, ApoB, ApoC3 and ApoA5 levels were reduced in CHB patients. In HBeAg(-) CHB patients, plasma ApoC3 levels were negatively associated with HBV DNA load (r = 0.219, P < 0.001). But no correlation between ApoA5 and HBV DNA load was observed in CHB patients. These data showed that HBV infection inhibits lipid metabolism and ApoC3 is negatively associated with HBV DNA load in HBeAg (-) CHB patients. These findings provided new evidence about the link between ApoC3-related lipid metabolism and immune response. Show less

To investigate the association of -1131T>C polymorphism of apolipoprotein A5 (APOA5) with metabolic syndrome and associated traits. A cross-sectional comparative study. Department of Physiology, University of Health Sciences Lahore, from July 2016 to December 2017. Study population included 200 cases of metabolic syndrome and 200 controls. Cases were selected from Sheikh Zayed Hospital, Lahore according to the International Diabetes Federation guidelines. Fasting blood sample of 8 ml was taken for biochemical and genetic analysis, as per objective. Demographics, waist circumferance and blood pressure (BP) were also recorded. Subjects with metabolic syndrome had significantly higher waist circumference, BP, serum lipid and glycemic parameters as compared to the controls (p<0.001). The observed frequency of APOA5-1131T>C genotype TT was 180 (45%), 202 (50.5%) for TC and 18 (4.5%) for CC. Minor C allele frequency of APOA5-1131T>C variant was significantly higher in metabolic syndrome as compared to the controls (0.33 vs. 0.26: p = 0.031*). In the Dominant genotype model (TC+CC vs. TT), 'TC+CC' genotype was significantly associated with the increased risk of metabolic syndrome (OR: 1.50, CI: 1.01-2.23, p = 0.044*). Waist circumference and fasting triglyceride levels were significantly higher in 'TC +CC' genotype as compared to the 'TT' in metabolic syndrome and controls (p = <0.001 and 0.043; p = 0.022 and 0.006). There was significant association of the 'TC+CC' genotype of APOA5 -1131T>C with the increased risk of Met S and the association remained significant after controlling for age and gender. Show less

Although choline requirements are unknown, enhanced postruminal supply may decrease liver triacylglycerol (TAG) storage and increase flux through the methionine cycle, helping cows during a negative energy balance (NEB). The objective was to investigate effects of postruminal choline supply during NEB on hepatic activity of betaine-homocysteine methyltransferase (BHMT), methionine synthase (MTR), methionine adenosyltransferase, transcription of enzymes, and metabolite concentrations in the methionine cycle. Ten primiparous rumen-cannulated Holstein cows (158 ± 24 d postpartum) were used in a replicated 5 × 5 Latin square design with 4-d treatment periods and 10 d of recovery (14 d/period). Treatments were unrestricted intake with abomasal infusion of water (A0), restricted intake (R; 60% of net energy for lactation requirements to induce NEB) with abomasal infusion of water (R0) or R plus abomasal infusion of 6.25, 12.5, or 25 g/d of choline ion. Liver tissue was collected on d 5 after the infusions ended, blood on d 1 to 5, and milk on d 1 to 4. Statistical contrasts were A0 versus R0 (CONT1) and tests of linear (L), quadratic (Q), and cubic (C) effects of choline dose. Plasma choline increased with R (CONT1) and choline (L). Although R decreased milk yield (CONT1), choline increased milk yield and liver phosphatidylcholine (PC), but decreased TAG (L). No differences were observed in plasma PC or very-low-density lipoprotein concentrations with R or choline. Activity and mRNA abundance of BHMT were greater with R (CONT1) and increased with choline (L). Although activity of MTR was lower with R (CONT1), it tended to increase with choline (L). No effect of R was detected for activity of methionine adenosyltransferase, but it changed cubically across dose of choline. Those responses were associated with linear increases in the concentrations of liver tissue (+13%) and plasma methionine concentrations. The mRNA abundance of CPT1A, SLC22A5, APOA5, and APOB, genes associated with fatty acid oxidation and lipoprotein metabolism, was upregulated by choline (Q). Overall, enhanced supply of choline during NEB increases hepatic activity of BHMT and MTR to regenerate methionine and PC, partly to help clear TAG. The relevance of these effects during the periparturient period merits further research. Show less

Different models that include clinical variables and blood markers have been investigated to predict acute ischemic stroke treatment course and recovery. The aim of the study was to investigate associations between lipid levels, lifestyle factors, hemostatic (F5, F2, SERPINE1, F13A1, and FGB), and atherogenic (APOA5 and ACE) gene variants and acute ischemic stroke (AIS) severity. This study included 250 patients with AIS in which F5, F2, SERPINE1, F13A1, FGB, APOA5, and ACE genotypes were determined. Total cholesterol (TC), high-density cholesterol, low-density cholesterol, and triglycerides concentrations were measured within 24 h of the AIS onset. Examination of the neurological deficit was done using National Institutes of Health Stroke Scale/Score (NIHSS). APOA5 genotype [TC + CC] was more frequent (P = 0.026) in patients with the NIHSS score ≥ 21. Univariate regression analysis has shown that triglycerides (OR 0.55, 95% CI 0.34-0.91; P = 0.019), obesity (0.28, 95% CI 0.10-0.73; P = 0.010), age (OR 1.08, 95% CI 1.04-1.13; P < 0.001), and APOA5 genotype (TC + CC) (OR 2.40, 95% CI 1.10-5.25; P = 0.034) are significantly associated with a severe stroke. When all variables were included in model age (OR 1.06, 95% CI 1.01-1.11; P = 0.018), obesity (OR 0.25, 95% CI 0.08-0.77; P = 0.016) and APOA5 genotype (TC + CC) (OR 3.26, 95% CI 1.29-8.23; P = 0.012) remained significant for the risk of severe AIS. APOA5 genotype (TC + CC), age, and obesity could be used as prognostic risk factors for a very severe stroke (NIHSS ≥ 21). Show less

Male EBP disorder with neurologic defects (MEND) syndrome is an X-linked disease caused by hypomorphic mutations in the EBP (emopamil-binding protein) gene. Modifier genes may explain the clinical variability among individuals who share a primary mutation. We studied four males (Patient 1 to Patient 4) exhibiting a descending degree of phenotypic severity from a family with MEND syndrome. To identify candidate modifier genes that explain the phenotypic variability, variants of homeostasis cholesterol genes identified by whole-exome sequencing (WES) were ranked according to the predicted magnitude of their effect through an in-house scoring system. Twenty-seven from 105 missense variants found in 45 genes of the four exomes were considered significant (-5 to -9 scores). We found a direct genotype-phenotype association based on the differential accumulation of potentially functional gene variants among males. Patient 1 exhibited 17 variants, both Patients 2 and 3 exhibited nine variants, and Patient 4 exhibited only five variants. We conclude that APOA5 (rs3135506), ABCA1 (rs9282541), and APOB (rs679899 and rs12714225) are the most relevant candidate modifier genes in this family. Relative accumulation of the deficiencies associated with variants of these genes along with other lesser deficiencies in other genes appears to explain the variable expressivity in MEND syndrome. Show less

Statins are widely used worldwide in the prevention and treatment of coronary atherosclerotic heart disease and ischaemic stroke. However, in clinical application, statins have shown great individual differences in terms of the efficacy and safety, some of which are related to genetic factors. The purpose of this article was to summarize the recent advances about the correlation between gene polymorphisms and the efficacy/safety of statins. We searched the databases including PharmGKB and PubMed (published before June 2019) using the keywords such as 'statin', 'gene polymorphism' and 'SNP' and obtained more than 100 articles. In this review, we described the clinical studies of genetic variants associated with both the efficacy and adverse reactions of statins. We also clarified the importance of taking pharmacogenetic variation into account to improve the clinical application of statins. The available data were collected and analysed to present the polymorphisms of candidate genes encoding the most promising proteins including SLCO1B1 (encoding uptake transporters); ABCB1, ABCC2, ABCG2 (encoding effluent transporter); APOE, APOA5 (encoding apolipoprotein); genes encoding cytochrome P450 enzyme system; KIF6, HMGCR, LDLR, LPA, PCSK9, COQ2, CETP, etc These genes were proved to be related to the pharmacodynamics and pharmacokinetics of statins, thus affecting the efficacy and safety. In this paper, the correlation between gene polymorphisms and the efficacy/safety of statins was summarized. The authors reached a consensus that the variants of the genes encoding uptake and effluent transporters have the most effect on the efficacy/safety of statins. It pointed out that it is desirable to do genetic testing of these transporter genes to reduce the incidence of myopathy or to achieve better outcomes before patients use statins, especially in the regions with high frequency of risk allele. Show less

Gene environment interactions leading to epigenetic alterations play pivotal role in the pathogenesis of Coronary Artery Disease (CAD). Altered DNA methylation is one such epigenetic factor that could lead to altered disease etiology. In this study, we comprehensively identified methylation sites in several genes that have been previously associated with young CAD patients. The study population consisted of 42 healthy controls and 33 young CAD patients (age group <50 years). We performed targeted bisulfite sequencing of promoter as well as gene body regions of several genes in various pathways like cholesterol synthesis and metabolism, endothelial dysfunction, apoptosis, which are implicated in the development of CAD. We observed that the genes like GALNT2, HMGCR were hypermethylated in the promoter whereas LDLR gene promoter was hypomethylated indicating that intracellular LDL uptake was higher in CAD patients. Although APOA1 did not show significant change in methylation but APOC3 and APOA5 showed variation in methylation in promoter and exonic regions. Glucokinase (GCK) and endothelial nitric oxide synthase 3 (NOS3) were hyper methylated in the promoter. Genes involved in apoptosis (BAX/BCL2/AKT2) and inflammation (PHACTR1/LCK) also showed differential methylation between controls and CAD patients. A combined analysis of the methylated CpG sites using machine learning tool revealed 14 CpGs in 11 genes that could discriminate CAD cases from controls with over 93% accuracy. This study is unique because it highlights important gene methylation alterations which might predict the risk of young CAD in Indian population. Large scale studies in different populations would be important for validating our findings and understanding the epigenetic events associated with CAD. Show less

Plasma triglyceride (TG) values are significant predictors of cardiovascular and total mortality. The plasma levels of TGs have an important genetic background. We analyzed whether 32 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies are discriminators of hypertriglyceridemia (HTG) in the Czech population. The objective of this study was to replicate and test the original findings in an independent study and to re-analyze the gene score leading to HTG. In total, we analyzed 32 SNPs in 209 patients with plasma TG levels over 10 mmol/L (HTG group) and compared them in a case-control design with 524 treatment-naïve controls (normotriglyceridemic [NTG] group) with plasma TG values below 1.8 mmol/L. Sixteen SNPs were significantly associated with an increased risk of HTG development, with odds ratios (ORs) (95% confidence interval [CI]) varying from 1.40 (1.01-1.95) to 4.69 (3.29-6.68) (rs964184 within the APOA5 gene). Both unweighted (sum of the risk alleles) and weighted gene scores (WGS) (log of the achieved ORs per individual genotype) were calculated, and both gene scores were significantly different between groups. The mean score of the risk alleles was significantly increased in the HTG group compared to the NTG group (18.5 ± 2.5 vs. 15.7 ± 2.3, respectively; P < 0.00001). Subjects with a WGS over 9 were significantly more common in the HTG group (44.5%) than in the NTG group, in which such a high score was observed in only 4.7% of subjects (OR 16.3, 95% CI 10.0-36.7; P < 0.0000001). An increased number of risk genetic variants, calculated both in a weighted or unweighted manner, significantly discriminates between the subjects with HTG and controls. Population-specific sets of SNPs included into the gene score seem to yield better discrimination power. Show less

Metabolic syndrome (MetS) risk is influenced by genetic and environmental factors. The present study explored genetic risk scores (GRS) of genetic variants that influence the MetS and the effect of interactions between GRS and nutrient intake on MetS risk. The genetic variants that influence MetS risk were selected by genome-wide association study after adjusting for age, sex, area of residence and BMI in 8840 middle-aged adults. GRS were calculated by summing the risk alleles of the selected SNP and divided into low (0-1), medium (2-3) and high (4-7) risk groups, and the relationships between the MetS and GRS were determined by logistic regression after adjusting covariates involved in MetS risk. We also analysed the interaction between GRS and lifestyles. Four genetic variants (APOA5_rs651821, EFCAB4B_rs4766165, ZNF259_rs2160669 and APOBEC1_rs10845640) were selected because they increased MetS risk after adjusting for covariates. Individuals with medium-GRS and high-GRS alleles had a higher MetS risk by 1·48- and 2·23-fold, respectively, compared with those with low-GRS after adjusting for covariates. The increase in MetS risk was mainly related to serum TAG and HDL-cholesterol concentrations. The GRS had an interaction with carbohydrate (CHO) and Na intakes and daily physical activities for MetS risk. In conclusion, Asian middle-aged adults with high-GRS alleles were at increased MetS risk mainly due to dyslipidaemia. High daily physical activity (≥1 h moderate activity per d) reduced the MetS risk but a low-CHO diet (<65 % of total energy intake) increased the risk in carriers with high-GRS alleles. Low Na intake (<1·6 g Na intake/4 MJ) did not decrease its risk. Show less

Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS. Approach and Results: Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in Show less

Acute hyperlipidaemic pancreatitis (HP) may develop in pregnancy in patients with genetic predisposition. There are no accepted guidelines for the management of this rare but life-threatening condition in pregnancy. Plasma exchange (PEX) was suggested as a suitable option to treat HP in pregnancy; however, further evidence from case reports/case series are needed. Three PEX procedures (2000 ml of plasma replaced with 5% albumin) were performed in one week in a pregnant patient at 25 weeks of gestational age with severe HP. Triglyceride related genes (LPL, APOA5, APOE, GPIHBP1, GPD1, LMF1, CREB3L3) were screened by DNA sequencing. Medline and Embase databases were searched electronically in January 2018 using different combinations of the relevant medical subject headings for "pancreatitis in pregnancy" and "therapeutic apheresis". Gene profiling assessed a combined heterozygous state for the variants pSer19Trp of the APOA5 gene and pCys130Arg of the APOE (allele E4) gene. PEX led to significant and progressive reduction of triglyceride plasma levels along with cholesterol and C-reactive protein. Meanwhile a fast improvement of pregnant clinical condition was observed. This allowed the delivery at term of a healthy newborn without gestational complications. An outcome hardly achievable in patients managed exclusively by a pharmacological approach. PEX led to a positive maternal outcome in absence of foetal and gestational complications in a case of severe HP in pregnancy. As clinical trials are lacking, case reports still represent the best way to reasonably implement clinical management of this rare but life-threatening disease. Show less

A 44-year-old woman was admitted with pancreatitis caused by hypertriglyceridaemia (fasting triglycerides 28 mmol/L). She used oral contraceptives and ezetimibe 10 mg. She was overweight (body mass index 29.7 kg/m Show less

Apolipoprotein C3 (apoC3) and apolipoprotein A5 (apoA5), encoded by APOA1/C3/A4/A5 gene cluster, are two critical regulators of plasma triglyceride (TG) metabolism. Deficiency of apoC3 or apoA5 led to significant decreased or increased plasma TG levels, respectively. Recent studies indicated apoC3 and apoA5 also played roles in plasma remnant cholesterol, high density lipoprotein (HDL) and hepatic TG metabolisms. Moreover, large scale population genetic studies indicated that loss of function mutations in APOC3 and APOA5 gene conferred decreased and increased risk of coronary artery disease (CAD), respectively. This manuscript mainly reviewed existing evidences suggesting the opposite role of apoC3 and apoA5 in lipid metabolism and CAD risk, and discussed the potential correlation between these two apolipoproteins. Show less

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. It is currently the most common chronic liver disease with complex pathogenesis and challenging treatment. Here, we investigated the hepatoprotective role of green tea (GT) and determined the involvement of miRNAs and its mechanism of action. Male C57Bl/6 mice were fed with a high-fat diet for 4 weeks. After this period, the animals received gavage with GT (500 mg/kg body weight) over 12 weeks (5 days/week). HepG2 cell lines were transfected with miR-34a or miR-194 mimetics and inhibitors to validate the GT supplementation protects against NAFLD development by altering lipid metabolism, increasing gene expression involved in triglycerides and fatty acid catabolism, and decreasing uptake and lipid accumulation. This phenotype was accompanied by miR-34a downregulation and an increase in their mRNA targets Our study identified for the first time that the beneficial effects of GT in the liver can be due to the modulation of miRNAs, opening new perspectives for the treatment of NAFLD focusing on epigenetic regulation of miR-34a and miR-194 as green tea targets. Show less

Plasma triglyceride (TG) levels represent a significant risk factor of cardiovascular and total mortality. Concentrations of TG in the plasma depend, to a large extent, on the genetic background, and the apolipoprotein A5 (APOA5) gene seems to be one of the most powerful players in the plasma TG metabolism regulation. In total, we analysed three tagging APOA5 (rs964184 rs662799, rs3135506) SNPs in 209 patients with plasma TG levels over 10 mmol/l (HTG) on at least one occasion and in 379 treatment-naïve controls (NTG) with plasma TG values within the normal range. Minor alleles of all three analysed APOA5 polymorphisms significantly (all P < 0.0001) increased the risk of hypertriglyceridaemia. The most significant association (P < 0.0000001) was observed for the rs964184 polymorphism, where the minor GG homozygotes had the odds ratio (OR, 95% CI) for hypertriglyceridaemia development 21.30 (8.09-56.07, P < 0.000001) in comparison with the major CC allele homozygotes. Carriers of at least one minor allele at rs3135506 had OR (95% CI) 4.19 (2.75-6.40); (P < 0.000005) for HTG development and similarly, carriers of a minor allele at rs662799 had OR (95% CI) 3.07 (2.00-4.72) (P < 0.0001). The cumulative presence of risk alleles (unweighted gene score) significantly differed between patients with episodes of high TG and controls at P < 0.0000001. There were 73 % of subjects without any of the risk alleles among the controls and 46 % in the patients. In contrast, the controls just included 3 % of subjects with score 3 and more in comparison with 18 % in HTG patients. We conclude that common APOA5 variants are very important genetic determinants of episodic hypertriglyceridaemia in the Czech population with a high potential to be applied in personalized medicine. Show less

Dyslipidemia can be influenced by genetic and dietary risk factors. This study set out to investigate diet and genetic variations in Brazilian people in a cross-sectional population-based survey and to analyze the relationship between single nucleotide polymorphisms (SNPs) of genes involved in lipid metabolism and cardiometabolic-related phenotypes using a genetic risk score (GRS). We recruited 228 adults (mean age 36.5 years) who participated in the Health Survey of São Paulo (HS-SP), Brazil. Clinical and anthropometric parameters, as well as the interaction between the GRS and the Brazilian Healthy Eating Index Revised (BHEI-R) were evaluated. We analyzed the relationship between SNPs in APOA5 (rs662799), APOB (rs693, rs1367117), LDLR (rs688, rs5925) and LIPC (rs2070895, rs1800588) and cardiometabolic-related phenotypes using a GRS. High-density lipoprotein cholesterol (HDLC) levels were associated with the BHEI-R ( p=0.026; β= -0.183) and with its SoFAAS component (solid fats, alcoholic beverages and added sugars) ( p=0.007; β=0.279). Non-HDL cholesterol levels were associated with the BHEI-R vegetable component ( p=0.015; β=0.002) and the meat, eggs and beans component ( p=0.003; β=0.007). Triacylglycerol levels were associated with the BHEI-R vegetable component ( p=0.027; β=0.003); the meat, eggs and beans component ( p=0.041; β=0.001); and the total protein component ( p=0.013; β=0.032). Significant effects were observed for the interactions between the GRS and both the BHEI-R oils component ( p=0.019) and the SoFAAS component ( p<0.001) on the dyslipidemia risk. The evaluation of dietary quality, especially fat quality, together with the lipid metabolism GRS could be a useful tool to manage cardiometabolic risk. Show less

We aimed to evaluate whether the longitudinal interaction between APOA5-1131C variants and overweight could accelerate age-related increases in arterial stiffness and circulating triglycerides in healthy subjects. This 3-year prospective cohort study included 503 healthy subjects. Brachial-ankle pulse wave velocity (baPWV), triglycerides, APOA5 -1131T > C, apolipoprotein (apo) A-V level, and low-density lipoprotein (LDL) particle size were measured at baseline and within a mean follow-up period of 3 years. At the 3-year follow-up, in the overweight group, subjects with the C allele showed increases in triglycerides and baPWV relative to baseline. Additionally, in the overweight group, there was a genotype effect on changes in triglycerides: subjects with the C allele had greater increases in triglyceride concentrations than subjects with the TT genotype. Furthermore, overweight subjects with the C allele had greater increases in triglyceride concentrations than normal-weight subjects with the C allele (P-interaction = 0.013). Overweight subjects with the C allele had greater increases in baPWV than normal-weight subjects with the C allele (P-interaction = 0.047). Changes in baPWV were affected by age, baseline baPWV, and changes in systolic blood pressure (BP) and triglycerides. Changes in triglycerides were affected by APOA5 -1131T > C genotype, age, baseline triglyceride level, and changes in BMI and apo A-V. In the overweight group, changes in baPWV were affected by changes in systolic BP, LDL particle size, and triglycerides. This prospective study shows that the interactive effect between APOA5 -1131C variants and overweight can accelerate age-related increase in arterial stiffness via the regulation of circulating triglycerides in healthy subjects. Show less

Dyslipidemia is a well-established risk factor for CVD. Studies suggest that similar fat accumulation in a given population might result in different levels of dyslipidemia risk among individuals; for example, despite similar or leaner body composition compared with Caucasians, Asians of Korean descent experience a higher prevalence of dyslipidemia. These variations imply a possible role of gene-obesity interactions on lipid profiles. Genome-wide association studies have identified more than 500 loci regulating plasma lipids, but the interaction structure between genes and obesity traits remains unclear. We hypothesized that some loci modify the effects of obesity on dyslipidemia risk and analyzed extensive gene-environment interactions (G×Es) at genome-wide levels to search for replicated gene-obesity interactive SNPs. In four Korean cohorts (n = 18,025), we identified and replicated 20 gene-obesity interactions, including novel variants ( Show less