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Steroid induced osteonecrosis of the femoral head (ONFH) frequently leads to femoral head collapse and subsequent hip arthritis. This study aimed to investigate the potential therapeutic mechanism of miR-27a on steroid-induced ONFH. Levels of IL-6, TNF-α, miR-27a, Runx2, PPAR-γ and ApoA5 were first examined in bone marrow tissues from steroid-induced ONFH and controls. Subsequently, we overexpressed or knocked down miR-27a in bone marrow mesenchymal stem cells (BMSCs) and detected cell proliferation, osteogenic differentiation, adipogenic differentiation. In addition, miR-27a mimics and BMSCs were injected into the established steroid-induced ONFH rats, and the osteoprotective effects of both were evaluated. Dual luciferase reporter was used to test the targeting effect of miR-27a-3p and PPARG. miR-27a and Runx2 were lowly expressed in steroid-induced ONFH, PPAR-γ and ApoA5 were highly expressed. Overexpression of miR-27a in BMSCs promoted cell proliferation and osteogenic differentiation, inhibited adipogenic differentiation. Furthermore, increasing miR-27a and BMSCs obviously reduced bone loss in steroid induced ONFH rats. The expressions of Runx2 in BMSCs and steroid-induced ONFH rats was significantly up-regulated, while IL-6, TNF-α, PPAR-γ and ApoA5 were down-regulated with miR-27a overexpression. Additionally, PPARG was the target of miR-27a-3p. The results of the present study reveal a role for miR-27a in promoting osteogenesis and may have a synergistic effect with BMSCs. Show less

Acute myocardial infarction occurs when blood supply to a particular coronary artery is cut off, causing ischemia or hypoxia and subsequent heart muscle destruction in the vascularized area. With a mortality rate of 17% per year, myocardial infarction (MI) is still one of the top causes of death globally. Numerous studies have been done to identify the genetic risk factors for myocardial infarction, as a positive family history of heart disease is one of the most potent cardiovascular risk factors. The goal of this review is to compile all the information currently accessible in the literature on the genes associated with AMI. We performed a big data analysis of genes associated with acute myocardial infarction, using the following keywords: "myocardial infarction", "genes", "involvement", "association", and "risk". The analysis was done using PubMed, Scopus, and Web of Science. Data from the title, abstract, and keywords were exported as text files and imported into an Excel spreadsheet. Its analysis was carried out using the VOSviewer v. 1.6.18 software. Our analysis found 28 genes which are mostly likely associated with an increased risk for AMI, including: PAI-1, CX37, IL18, and others. Also, a correlation was made between the results obtained in the big data analysis and the results of the review. The most important genes increasing the risk for AMI are lymphotoxin-a gene (LTA), LGALS2, LDLR, and APOA5. A deeper understanding of the underlying functional genomic circuits may present new opportunities for research in the future. Show less

The aggregation and interaction of metabolic risk factors leads to highly heterogeneous pathogeneses, manifestations, and outcomes, hindering risk stratification and targeted management. To deconstruct the heterogeneity, we used baseline data from phase II of the Fangshan Family-Based Ischemic Stroke Study (FISSIC), and a total of 4632 participants were included. A total of 732 individuals who did not have any component of metabolic syndrome (MetS) were set as a reference group, while 3900 individuals with metabolic abnormalities were clustered into subtypes using multi-trait limited mixed regression (MFMR). Four metabolic subtypes were identified with the dominant characteristics of abdominal obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariate logistic regression showed that the hyperglycemia-dominant subtype had the highest coronary heart disease (CHD) risk (OR: 6.440, 95% CI: 3.177-13.977) and that the dyslipidemia-dominant subtype had the highest stroke risk (OR: 2.450, 95% CI: 1.250-5.265). Exome-wide association studies (EWASs) identified eight SNPs related to the dyslipidemia-dominant subtype with genome-wide significance, which were located in the genes Show less

Primary hypertriglyceridemia (PHTG) is characterized by a high concentration of triglycerides (TG); it is divided between familial hyperchylomicronemia syndrome and multifactorial chylomicronemia syndrome. In Mexico, hypertriglyceridemia constitutes a health problem in which the genetic bases have been scarcely explored; therefore, our objective was to describe biochemical-clinical characteristics and variants in the Show less

Severe hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as The 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient. The infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45₄₈dupGCGG (Pro17Alafs Our study expands on the spectrum of Show less

Chylomicronaemia accompanies hypertriglyceridaemia, usually due to a polygenic predisposition in combination with secondary risk factors. Monogenic chylomicronaemia represents a small subgroup of patients with hypertriglyceridaemia. This article describes three patients and illustrates the heterogeneity in the presentation of monogenic chylomicronaemia. The first case is a man with mild hypertriglyceridaemia who is a compound heterozygote for two variants in the Show less

A diet deficient in donors of methyl group, such as methionine, affects DNA methylation and hepatic lipid metabolism. Methionine also affects other epigenetic mechanisms, such as microRNAs. We investigated the effects of methionine-supplemented or methionine-deficient diets on the expression of chromatin-modifying genes, global DNA methylation, the expression and methylation of genes related to lipid metabolism, and the expression of microRNAs in mouse liver. Female Swiss albino mice were fed a control diet (0.3% methionine), a methionine-supplemented diet (2% methionine), and a methionine-deficient diet (0% methionine) for 10 weeks. The genes most affected by the methionine-supplemented diet were associated with histone and DNA methyltransferases activity, while the methionine-deficient diet mostly altered the expression of histone methyltransferases genes. Both diets altered the global DNA methylation and the expression and gene-specific methylation of the lipid metabolism gene Apoa5. Both diets altered the expression of several liver homeostasis-related microRNAs, including miR-190b-5p, miR-130b-3p, miR-376c-3p, miR-411-5p, miR-29c-3p, miR-295-3p, and miR-467d-5p, with the methionine-deficient diet causing a more substantial effect. The effects of improper amounts of methionine in the diet on liver pathologies may involve a cooperative action of chromatin-modifying genes, which results in an aberrant pattern of global and gene-specific methylation, and microRNAs responsible for liver homeostasis. Show less

Lung injury caused by pulmonary inflammation is one of the main manifestations of respiratory diseases. Vasorin (VASN) is a cell-surface glycoprotein encoded by the VASN gene and is expressed in the lungs of developing mouse foetuses. Previous research has revealed that VASN is associated with many diseases. However, its exact function in the lungs and the underlying mechanism remain poorly understood. To investigate the molecular mechanisms involved in lung disease caused by VASN deficiency, a VASN gene knockout (VASN We believe that these data provide molecular evidence for the regulatory role of VASN in inflammation in the context of lung injury. Show less

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m Show less

The Apolipoprotein A5 (APOA5) rs662799 was significantly associated with blood lipid level at genome-wide significance level. Whether dynamic changes of adiposity influence the effect of lipid loci on long-term blood lipid profile remains unclear. We assessed interactions of 5-year body mass index (BMI) change and rs662799 genotypes with risk of incident dyslipidemia and longitudinal changes in serum lipids in a prospective cohort. We included 4329 non-dyslipidemia participants aged ≥ 40 years at baseline from a well-defined community-based cohort and followed up for an average of 5 years. BMI and blood lipids were measured at baseline and follow-up. The association of each rs662799 A-allele with risk of incident dyslipidemia was stronger along with the increase in BMI change level, with the odds ratios (OR) increasing from 1.03 in the lowest tertile of BMI change (< 0.02 kg/m BMI changes significantly modulate rs662799 genetic contribution to dyslipidemia and long-term lipid profile, which provide new evidence for personalized clinical management of lipids according to individual genetic background. Show less

Metabolic syndrome (MetS) is characterized by the coexistence of disorders such as diabetes, hypertension, hyperlipidemia, and obesity and is affected by genetic factors. Previous genome-wide association studies (GWAS) suggested that APOA5 gene variants were significantly associated with MetS and its components. Dietary factors such as red and processed meat consumption can cause chronic diseases, including hypertension, diabetes, and vascular depression. The aim of this study was to investigate the modulation of the incidence of MetS by the interaction between APOA5 rs662799 polymorphism and red and processed meat consumption. In this prospective cohort study, 3266 participants were collected from the Korea Association REsource (KARE) cohort of the Korean Genome and Epidemiology Study (KoGES) from 2001 to 2016. APOA5 rs662799 polymorphism was extracted by GWAS using the Korean Chip. Red and processed meat consumption data were assessed using a semi-quantitative food frequency questionnaire. The incidence of MetS in carriers of the minor G allele of rs662799 (AG + GG) and the third tertile of red and processed meat consumption (serving/day) was higher than those with the major allele of rs662799 (AA) and the first tertile of red and processed meat consumption (HR 1.70, 95% CI 1.30-2.22, p interaction = 0.002). An association between the presence of the minor alleles of rs662799 and high red and processed meat consumption and the incidence of MetS was observed in Korean adults. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease, prevalence 1:200,000 - 1:1,000,000, and is characterized by fasting chylomicrons and very high triglycerides > 880 mg/dl. LPL is the most frequently affected gene, then APOC2, GPIHBP1, APOA5, LMF1, all of them compromising the function of lipoproteinlipase. FCS commonly presents in childhood with recurrent abdominal pain, eruptive xanthomas, failure to thrive, pancreatitis, and sometimes asymptomatic. The conventional treatment is dietetic fat restriction. The clinical outcome of 20 pediatric patients with FCS recruited from 4 hospitals in Argentina is reported. Show less

The discovery of apolipoprotein A5 (APOA5) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome-wide association studies have consistently identified APOA5 as a regulator of plasma TG levels, which is further supported by studies in transgenic and knockout mouse models. The present review describes recent concepts pertaining to the roles of APOA5 in TG metabolism as related to the vascular compartment, liver, adipose tissue and the gut. Recent evidence indicates that APOA5 may also affect postprandial TG metabolism through influencing chylomicron formation and transport by the intestine into the intestinal lymph. While substantial evidence supports the notion that APOA5 plays both extracellular and intracellular roles in TG homeostasis, mysteries remain on how this low-abundance, liver-derived protein may modulate TG homeostasis, including via the gut. Given the strong correlation between elevated plasma TG and cardiometabolic diseases, there is great scientific and public interest in understanding the intriguing mysteries presented by APOA5. Show less

The prevalence of dyslipidemia has increased steadily in Korea, and the incidence of dyslipidemia differs by sex. In this study, we identified single nucleotide polymorphisms (SNPs) related to dyslipidemia in Korean cohorts through genome-wide association study (GWAS) analysis. Genotyping was conducted to determine the genotypes of 72,298 participants and investigate genotypes for 7,079,946 SNPs. Sex, age, and BMI were set as covariates for GWAS, and significant SNPs were identified in the discovery and replication stages using logistic regression. GWAS of the entire cohort revealed a total of five significant SNPs: rs117026536 (LPL), rs651821 (APOA5), rs9804646 (APOA5), rs9926440 (CETP), and rs429358 (APOE). GWAS of the male subjects revealed a total of four significant SNPs. While rs9804646 (APOA5) and rs429358 (APOE) were significant for all the subjects, rs662799 (APOA5) and rs56156922 (CETP) were significant only for the male subjects. GWAS of the female subjects revealed two significant SNPs, rs651821 (APOA5) and rs9804646 (APOA5), both of which were significant in all the subjects. This is the first study to identify sex-related differences in genetic polymorphisms in Korean populations with dyslipidemia. Further studies considering environmental variables will be needed to elucidate these sex-related genetic differences in dyslipidemia. Show less

Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM₀₅₂₉₆₈: c.579₅₉₂delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM₀₀₀₂₃₇.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease. Show less

Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD. This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 μmol/L olanzapine (low-dose group), 50 μmol/L olanzapine (medium-dose group), and 100 μmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 μmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively. After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups ( The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease. Show less

Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a high global incidence. Hypertriglyceridemia is a major risk factor for both cardiovascular disease and T2DM. In this study, we determined the allele and genotype frequencies of apolipoprotein A5 ( Show less

Lysoforte (LFT) plays a vital role in maintaining broilers' health and intestinal morphology. However, the mechanism behind the effects of LFT improving intestinal morphology and health is still unclear. Therefore, this study was implemented to explore the central genes linked to the regulatory effect of LFT. Seventy-five newly hatched Cobb 500 male broilers were randomly divided into three groups: control, LFT500, and LFT1000 groups, with 25 chicks per group. The control chicks were provided with the basal diet, and the birds in LFT500 and LFT1000 groups were offered the same basal diet with 500 g/ton and 1,000 g/ton LFT, respectively. GSE94622 dataset consisted of the control and two LFT-treated groups (LFT500 and LFT1000). Jejuna samples were obtained from Gene Expression Omnibus (GEO). Totally 106-344 DEGs were obtained by comparing LFT500 and LFT1000 vs. control and LFT1000 vs. LFT500. Gene ontology (GO) enrichment suggested that the DEGs are mainly related to the phosphatidylethanolamine biosynthetic process and neuron projection extension. KEGG analysis suggested the DEGs were enriched in AGE-RAGE, fatty acid elongation, ECM-receptor interaction (ECMRI), glycerophospholipid metabolism, focal adhesion, unsaturated fatty acids biosynthesis, and ABC transporters. Moreover, 29 genes, such as Show less

Pulmonary arterial hypertension (PAH) is a chronic, progressive lung vascular disease accompanied by elevated pulmonary vascular pressure and resistance, and it is characterized by increased pulmonary artery smooth muscle cell (PASMC) proliferation. Apolipoprotein A5 (ApoA5) improves monocrotaline (MCT)-induced PAH and right heart failure; however, the underlying mechanism remains unknown. Here we speculate that ApoA5 has a protective effect in pulmonary vessels and aim to evaluate the mechanism. ApoA5 is overexpressed in an MCT-induced PAH animal model and platelet-derived growth factor (PDGF)-BB-induced proliferating PASMCs. Lung vasculature remodeling was measured by immunostaining, and PASMC proliferation was determined by cell counting kit-8 and 5-ethynyl-2'-deoxyuridine5-ethynyl-2'-deoxyuridine incorporation assays. Coimmunoprecipitation-mass spectrometry was used to investigate the probable mechanism. Next, its role and mechanism were further verified by knockdown studies. ApoA5 level was decreased in MCT-induced PAH lung as well as PASMCs. Overexpression of ApoA5 could help to inhibit the remodeling of pulmonary artery smooth muscle. ApoA5 could inhibit PDGF-BB-induced PASMC proliferation and endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78 (GRP78). After knocking down GRP78, the protecting effects of ApoA5 have been blocked. ApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism. Show less

Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown. We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls. We performed two-sample Mendelian randomization (MR) with multiple cis instruments as well as network and enrichment analysis using data from blood protein quantitative trait loci (pQTL) (2,965 blood proteins) measured in 3,301 individuals. Nineteen blood proteins were causally associated with HF, were not subject to reverse causality and were enriched in ligand-receptor and glycosylation molecules. Network pathway analysis of the blood proteins showed enrichment in NF-kappa B, TGF beta, lipid in atherosclerosis and fluid shear stress. Cross-phenotype analysis of HF identified genetic overlap with cardiovascular drugs, myocardial infarction, parental longevity and low-density cholesterol. Multi-trait MR identified causal associations between HF-associated blood proteins and cardiovascular outcomes. Multivariable MR showed that association of BAG3, MIF and APOA5 with HF were mediated by the blood pressure and coronary artery disease. According to the directional effect and biological action, 7 blood proteins are targets of existing drugs or are tractable for the development of novel therapeutics. Among the pathways, sialyl Lewis x and the activin type II receptor are potential druggable candidates. Integrative MR analyses of the blood proteins identified causally-associated proteins with HF and revealed pleiotropy of the blood proteome with cardiovascular risk factors. Some of the proteins or pathway related mechanisms could be targeted as novel treatment approach in HF. Show less

SLE is associated with increased cardiovascular risk (CVR). High serum concentrations of triglyceride-rich lipoproteins and apolipoprotein B-rich particles constitute the characteristic dyslipidaemia of SLE. A cross-sectional study was conducted to study the relationship between genetic variants involved in polygenic hypertriglyceridaemia, subclinical atherosclerosis and lipoprotein abnormalities. 73 women with SLE and 73 control women age-matched with the case group were recruited (age range 30-75 years). Serum analysis, subclinical atherosclerosis screening studies for the detection of plaque, and genetic analysis of the Triglyceride concentrations and the prevalence of hypertension, dyslipidaemia and carotid atherosclerosis were higher in women with SLE than in the control group. Multivariate logistic regression showed that CC homozygosity for the Show less

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Show less

The effect of genetic polymorphisms on fasting blood lipid levels have been widely studied but the effects of these within the context of a high-fat meal challenge remain less characterized. The current study aimed to investigate the association of SNPs in lipoprotein-related genes with blood lipid profiles in healthy adults in the U.S. Subjects (n = 393) between 18-66 years of age with BMIs ranging from 18.5-45 kg/m Women carrying the C allele of rs3135506 in APOA5 or men carrying the C allele of rs429358 in APOE had reduced HDL-cholesterol levels during fasting and postprandially. The C allele in APOE was also correlated to increased LDL-C levels. The TT genotype of rs2854116 in APOC3 was associated with elevated total cholesterol. Additive effect of the risk alleles of APOA5 and APOE or APOC3 and APOE was detected. Nevertheless, the tested SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. We found no significant effects of SNPs in APOB (rs1042034) or LDLR (rs2228671) on triglycerides, cholesterol, or free fatty acid levels. In healthy adults, fasting and postprandial cholesterol levels are strongly correlated with the tested APOA5, APOE, and APOC3 genotypes. Sex contributes to the genetic impact of the tested SNPs on lipid profiles. ClinicalTrials.gov, NCT02367287. Registered February 20, 2015, https://clinicaltrials.gov/ct2/show/NCT02367287 . Show less

Plasma triglyceride (TG) levels are a significant risk factor for cardiovascular disease (CVD). The APOA5 gene is one of the crucial factors in plasma TG metabolism regulation. The rs662799 polymorphism in the APOA5 gene has been reported to be associated with cardiovascular disease. The goal of this study was to evaluate the potential association of this variant with CVD in patients with end-stage kidney disease.  METHODS: In this case-control study the polymorphism was analyzed using the PCR-RFLP method in 800 consecutive patients with ESKD and 500 healthy controls. The genotype and allele distribution was compared between subgroups of patients with CVD (552) versus those without CVD (248). The frequency of the minor allele (C) in the healthy individuals was 9% compared to 12% in ESRD group (p = 0.09). The difference between groups was slightly higher for CC homozygote (3.5% versus 1.6%, p = 0.042). The ESKD patient group was analyzed according to the presence or absence of CVD. The significant differences in the polymorphism distribution were revealed in this analysis. The frequency of the C allele in the CVD + subgroup was 14% compared to 6% in CVD- patients (p = 0.001). In the CVD + subgroup the ORs (95% CI) for the C allele and CC genotype were 2.41 (1.61-3.6), p < 0.001 and 3.13 (1.07-9.14), p = 0.036, respectively. This indicates to the association of the variant C allele with cardiovascular disease in ESKD patients. The CC homozygotes have a threefold higher odds of CVD compared to TT homozygotes. The highest frequency of the C allele (18%) was observed in subgroup of patients with diabetic nephropathy, with OR (95% CI) 3.40 (2.13-5.43), p < 0.001.The presence of minor allele (CC and CT genotypes) was significantly associated with increased plasma triglyceride levels (p < 0.001 for both CVD + and CVD- groups). The present study demonstrated the effect of rs662799 polymorphism on plasma TG levels and its association with the development of cardiovascular disease in ESKD patients. Show less

Bicuspid aortic valve (BAV) is the most common congenital heart defect in human beings, with an estimated prevalence in the general population of between 0.5 and 2%. Moreover, BAV is the most common cause of aortic stenosis in the pediatric population. Patients with BAV may have no symptoms for life, and some of them may progress to aortic stenosis. Genetic factors increase the susceptibility and development of BAV. However, the pathogenesis and BAV are still unclear, and more genetic variants are still needed for elucidating the molecular mechanism and stratification of patients. The present study carried out screening of variants implicated in disease in BAV patients. The whole-exome sequencing (WES) was performed in 20 BAV patients and identified 40 different heterozygous missense mutations in 36 genes (MIB2, FAAH, S100A1, RGS16, MAP3K19, NEB, TTN, TNS1, CAND2, CCK, KALRN, ATP10D, SLIT3, ROS1, FABP7, NUP205, IL11RA, NPR2, COL5A1, CUBN, JMJD1C, ANXA7, TRIM8, LGR4, TPCN2, APOA5, GPR84, LRP1, NCOR2, AKAP11, ESRRB, NGB, AKAP13, WWOX, KCNJ12, ARHGEF1). The mutations in these genes were identified as recurrent variants implicated in disease by in silico prediction tool analysis. Nine genes (MIB2, S100A1, TTN, CCK, NUP205, LGR4, NCOR2, ESRRB, and WWOX) among the 36 genes were identified as variants implicated in disease via unanimous agreement of in silico prediction tool analysis and sequenced in an independent cohort of 137 BAV patients to validate the results of WES. BAV patients carrying these variants demonstrated reduced left ventricular ejection fractions (LVEF) (63.8 ± 7.5% vs. 58.4 ± 5.2%, P < 0.001) and larger calcification volume [(1129.3 ± 154) mm Show less

This cross-sectional study investigated the interaction between the genetic risk score (GRS) and abnormal high-density lipoprotein (HDL) cholesterol lipid levels, which are modified by low-carbohydrate diets (LCDs) and their effects on the prevalence of hypo-HDL-cholesterolemia (hypo-HDL-C) in Korean adults. Baseline data were obtained from the Ansan and Ansung study of the Korean Genome and Epidemiology Study (KoGES), conducted from 2001 to 2002, that targeted 8,314 Korean adults aged 40-69 years, including old men (47.6%) and women (52.4%), and whole genomic single nucleotide polymorphism (SNP) genotyping was performed. We identified 18 SNPs significantly associated with hypo-HDL-C in the proximity of several genes, including Show less

Chylomicronemia has either a monogenic or multifactorial origin. Multifactorial chylomicronemia is the more common form and is due to the interaction of genetic predisposition and secondary factors such as obesity, diabetes, unhealthy diet, and medications. We report a case of a 38-year-old man who was diagnosed with multifactorial chylomicronemia following presentation with a subarachnoid hemorrhage requiring emergency surgery through a burr hole; lactescent cerebrospinal fluid mixed with blood was observed through the burr hole. The serum triglyceride concentration was 52⋅4 mmol/L with a detectable triglyceride concentration in the cerebrospinal fluid. Rapid weight gain leading to obesity and related unfavorable lifestyle factors were identified as key secondary causes of chylomicronemia. Gene testing revealed a homozygous variant in Show less

Branched-chain amino acid (BCAA) levels are associated with skeletal muscle cross-sectional area (CSA). Serum BCAA levels are enhanced by whey protein supplementation (WPS), and evidence in clinical populations suggests an association of single nucleotide polymorphisms (SNPs) with BCAA metabolite levels. It is not known whether the same SNPs are associated with the ability to catabolise BCAAs from exogenous sources, such as WPS. The present study investigated whether possessing a higher number of alleles associated with increased BCAA metabolites correlates with muscle fiber CSA of m. vastus lateralis in physically active participants, and whether any relationship is enhanced by WPS. Endurance-trained participants (n = 75) were grouped by self-reported habitual WPS consumption and genotyped for five SNPs (PPM1K rs1440580, APOA5 rs2072560, CBLN1 rs1420601, DDX19B rs12325419, and TRMT61A rs58101275). Body mass, BMI, and fat percentage were significantly lower and muscle mass higher in the WPS group compared to Non-WPS. The number of BCAA-increasing alleles was correlated with fiber CSA in the WPS group (r = 0.75, p < 0.0001) and was stronger for fast-twitch fibers (p = 0.001) than slow-twitch fibers (p = 0.048). Similar results remained when corrected for multiple covariates (age, physical activity, and meat and dairy intake). No correlation was found in the Non-WPS group. This study presents novel evidence of a positive relationship between BCAA-increasing alleles and muscle fiber CSA in athletes habitually consuming WPS. We suggest that a high number of BCAA-increasing alleles improves the efficiency of WPS by stimulation of muscle protein synthesis, and contributes to greater fiber CSA. Show less

Triglycerides (TG) are required for fatty acid transport and storage and are essential for human health. Angiopoietin-like-protein 8 (ANGPTL8) has previously been shown to form a complex with ANGPTL3 that increases circulating TG by potently inhibiting LPL. We also recently showed that the TG-lowering apolipoprotein A5 (ApoA5) decreases TG levels by suppressing ANGPTL3/8-mediated LPL inhibition. To understand how LPL binds ANGPTL3/8 and ApoA5 blocks this interaction, we used hydrogen-deuterium exchange mass-spectrometry and molecular modeling to map binding sites of LPL and ApoA5 on ANGPTL3/8. Remarkably, we found that LPL and ApoA5 both bound a unique ANGPTL3/8 epitope consisting of N-terminal regions of ANGPTL3 and ANGPTL8 that are unmasked upon formation of the ANGPTL3/8 complex. We further used ANGPTL3/8 as an immunogen to develop an antibody targeting this same epitope. After refocusing on antibodies that bound ANGPTL3/8, as opposed to ANGPTL3 or ANGPTL8 alone, we utilized bio-layer interferometry to select an antibody exhibiting high-affinity binding to the desired epitope. We revealed an ANGPTL3/8 leucine zipper-like motif within the anti-ANGPTL3/8 epitope, the LPL-inhibitory region, and the ApoA5-interacting region, suggesting the mechanism by which ApoA5 lowers TG is via competition with LPL for the same ANGPTL3/8-binding site. Supporting this hypothesis, we demonstrate that the anti-ANGPTL3/8 antibody potently blocked ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowered TG levels in vivo. Together, these data show that an anti-ANGPTL3/8 antibody targeting the same leucine zipper-containing epitope recognized by LPL and ApoA5 markedly decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. Show less