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Abstract Background and purpose Genome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 (APOA5), within the most significant loci identified through GWAS on MetS. Methods GWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth. Results According to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects. Conclusion This study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS.

Background and purpose: Genome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 (APOA5), within the most significant loci identified through GWAS on MetS. Methods: GWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth. Results: According to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects. Conclusion: This study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS. [ABSTRACT FROM AUTHOR]

Abstract Background The association between Apolipoprotein A5 (APOA5) genetic polymorphisms and susceptibility to metabolic syndrome (MetS) has been established by many studies, but there have been conflicting results from the literature. We performed a meta-analysis of observational studies to evaluate the association between APOA5 gene polymorphisms and the prevalence of MetS. Methods PubMed, Web of Science, Embase, and Scopus were searched up to April 2024. The random effects model was used to estimate the odds ratios (ORs) and 95% confidence intervals (CI) of the association between APOA5 gene polymorphisms and the prevalence of MetS development. The potential sources of heterogeneity were evaluated by subgroup analyses and sensitivity analyses. Results A total of 30 studies with 54,986 subjects (25,341 MetS cases and 29,645 healthy controls) were included. The presence of rs662799 and rs651821 polymorphisms is associated with an approximately 1.5-fold higher likelihood of MetS prevalence (OR = 1.42, 95% CI: 1.32, 1.53, p

Background: Polycystic ovary syndrome (PCOS) is a common endocrinological condition affecting women of reproductive age, associated with insulin resistance and obesity. PCOS pathogenesis is complex and multifactorial, involving genetic and environmental factors. Objectives: This study aimed to determine and compare genotype and allele frequencies of single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 (APOA5 ; rs662799) and perilipin 1 (PLIN1 ; rs894160, rs1052700 and rs6496589) genes in Western Saudi women to investigate their association with PCOS and its clinical characteristics. Design and methods: This was a case-control study conducted on women with (n = 104) and without (n = 87) PCOS. The SNPs were genotyped using TaqMan genotyping assays. Results: Significant and direct associations were detected between PCOS susceptibility and APOA5 SNP rs662799 and PLIN1 SNP rs894160 (P <.001). For APOA5 SNP rs662799, women with the A allele were more likely to have PCOS (relative risk [RR] = 1.348, odds ratio [OR] = 2.313, P <.001) and hypertriglyceridaemia (OR = 17.0, P =.5) than women with the G allele. For PLIN1 SNP rs894160, women with the T allele were more likely to have PCOS than women with the C allele (RR = 8.043, OR = 7.427, P <.001). For PLIN1 SNP rs1052700, women with the TT genotype were more likely to have hyperandrogenism (OR = 29.75, P =.02) and an irregular period (OR = 0.07, P =.040) than women with the AT genotype. Conclusion: We identified novel alleles and genotypes contributing to the genetic risk of PCOS in the Western Saudi population. [ABSTRACT FROM AUTHOR]

Type 2 diabetic Mellitus (T2DM) is the most common systemic and endocrine disease in humans, and diabetic nephropathy is one of the most serious complications of this disorder. The polymorphisms in the apolipoprotein A5 (ApoA5) gene are strongly related to hypertriglyceridemia and are considered a predisposing factor for diabetic nephropathy. The current study proposed to examine the association of APOA5-S19W polymorphism with serum lipids levels in patients with type 2 diabetic nephropathy in Mazandaran province. This case-control study was designed to determine the association of APOA5–S19W polymorphism with plasma lipid profile in 161 T2DM patients with nephropathy (DN+), without nephropathy (DN−), and in 58 healthy individuals. Lipid profile values were measured using Pars Azmoun commercial kits. S19W variant, one of the polymorphisms of the APOA5 gene, was determined by PCR–restriction fragment length polymorphism (PCR-RFLP) and Taq1 restriction enzyme. In comparison between the three groups, DN+ had a higher mean TG than DN− and the control group (p<0.001). The incidence of the G allele in DN+ was not significant compared to groups of DN−. Comparing the relationship between the mean of biochemical variables with CC and CG genotypes showed that the mean level of TG in people with CC genotype was increased compared to people with CG genotype in diabetic patients. However, this increase was not significant (p=0.19). There was no association between SNP APOA5 S19W and serum lipids in diabetic patients with and without nephropathy. [ABSTRACT FROM AUTHOR]

Abstract Background 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). Results 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

Abstract Background 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. Methods 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. Results 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. Conclusion ApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism.

Background: 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).Results: 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).Conclusion: 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. [ABSTRACT FROM AUTHOR]

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 Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: ApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism. [ABSTRACT FROM AUTHOR]

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 (APOA5) single nucleotide polymorphism (SNP) rs662799 and perilipin 1 (PLIN1) SNPs rs894160, rs6496589, and rs1052700 and evaluated their association with T2DM risk in western Saudis. Only rs6496589 was found to be significantly associated with T2DM risk. We determined the risk allele for each SNP based on relative risk, and found that the G allele of rs662799, T allele of rs894160, G allele of r6496589, and T allele of rs1052700 correlated with T2DM risk. The effect of each SNP on T2DM risk and five of its clinical phenotypes was explored using multiple logistic regression. We found significant correlations between the C/G and G/G genotypes of rs6496589 and T2DM risk in the unadjusted model, whereas G/G was the only genotype that correlated with the risk of T2DM in the adjusted model. There was no significant correlation between rs662799, rs894160, and rs1052700 genotypes and T2DM risk. In conclusion, we have identified novel risk alleles and genotypes that contribute to genetic risk for T2DM in the western Saudi population. [ABSTRACT FROM AUTHOR]

Objective Investigate the relationship between rs651821polymorphism of apolipoprotein A5 (ApoA5) gene and metabolic syndrome (MS) . Methods 160patients with MS treated in a health center of Tongdao Dong Autonomous County, Hunan Province from June 2017to June 2018 were selected as MS group, and 145healthy people were selected as control group. The genotype and allele frequency distribution of the two groups were compared, and the relationship between single nucleotide polymorphism at rs651821of ApoA5gene and MS was analyzed. Results There were significant differences in clinical and biochemical indexes between the two groups (P<0. 05) . There were significant differences in genotype and allele frequency distribution between the two groups (P<0. 05) . There were no significant differences in body mass index, diastolic blood pressure, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol among carriers of TT, TC and CC genotype (P>0. 05) . The waist circumference, systolic blood pressure, total cholesterol and triglyceride levels of CC genotype carriers were significantly higher than those of TC and TT genotype carriers (P<0. 05) . The risk of MS in TC genotype carriers was 1. 743times higher than that in TT genotype carriers (95%CI:0. 843-3. 604, P<0. 05) . The risk of MS in CC genotype carriers was 11. 508times higher than that in TT genotype carriers (95%CI:3. 296-40. 185, P<0. 05) . Conclusion In the Dong population of Tongdao Dong Autonomous County, the rs651821polymorphism of ApoA5gene is closely related to MS, and the risk of MS will increase in the population with CC genotype. [ABSTRACT FROM AUTHOR]

Abstract 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.

Background Obesity has long been a severe threat to public health as an epidemic, and studies on its pathogenesis and treatment have been ongoing. Our study aims to compare the serum levels of bone morphogenetic protein 1 (BMP1), neuregulin 4 (NRG4), and apolipoprotein A5 (ApoA5) in obese and non-obese individuals and investigate their association with obesity. Methodology Our study included a total of 111 participants, of whom 46 were obese (body mass index (BMI) ≥30 kg/m 2 ), aged 18-65 years, and had no comorbidities, and 65 were non-obese (BMI = 18.5-29.9 kg/m 2 ) without any additional disease. For all participants, BMP1, NRG4, and ApoA5 levels were determined and compared with clinical and biochemical parameters. Results Overall, 60.4% (n = 67) of the participants were female and 39.6% (n = 44) were male. In terms of the BMI scores, 58.6% (n = 65) had a BMI <30 kg/m 2 and 41.4% (n = 46) had a BMI ≥30 kg/m 2 . Both, the BMI and the gender groups did not differ significantly in terms of age (p = 0.093 and p = 0.795, respectively). The weight, fat-free mass, mineral quantity, protein quantity, fluid weight, and fluid ratio values of the male participants were significantly higher than females (p = 0.011, p = 0.001, p = 0.001, p = 0.001, p = 0.001, and p = 0.001, respectively). The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratios and the triglyceride/glucose (TG/Glu) ratios were found to be significantly higher in males than in females (p = 0.001 and p = 0.001, respectively). The respective BMP1 (15.88 vs. 13.35), AST/ALT (1.36 vs. 1.04) and TG/Glu ratios (1.47 vs. 1.29) were significantly higher, while the quantitative insulin sensitivity check index (QUICKI) was lower in obese individuals than in non-obese individuals (0.32 vs. 0.34). NRG4 and ApoA5 values were similar between the two groups. BMP1, QUICKI values, and AST/ALT ratios proved to be statistically significant in obesity through the univariable logistic regression analysis (β = 1.066, p = 0.048; β = 0.0001, p = 0.001, and β = 3.707, p = 0.003, respectively). On multiple logistic regression analysis, QUICKI values (β = 0.001, p = 0.001) had a negative and significant effect on obesity, and the AST/ALT ratios (β = 2.803, p = 0.033) had a positive and significant effect on obesity. Conclusions Our study indicates that detecting an important link between BMP1 in obese patients will help elucidate the pathogenesis of obesity and come up with a potential therapeutic candidate. BMP1 levels, along with AST/ALT and TG/Glu ratios, were significantly higher in obese patients. BMP1 levels were also an independent significant predictor of obesity together with AST/ALT ratio and QUICKI in this study, suggesting that it may exhibit a metabolic deterioration in obese individuals. However, the results cannot absolutely tell whether it supported deterioration or was a component of the repair mechanism. Althoughit is generally known from recent studies that BMP1 plays a role in osteogenesis, some encouraging results were obtained in our study indicating that BMP1 may play a role in the pathogenesis of obesity. It is expected that our results will not only promote the elucidation of the pathogenesis of obesity, but also provide a therapeutic agent., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Clinical Research Ethics Committee of Istanbul Bilim University issued approval 12.04.2016/48-01. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Saglam et al.)

Abstract Apolipoprotein A5 (apoA5) has been identified to play an important role in lipid metabolism, specifically in triglyceride (TG) and TG-rich lipoproteins (TRLs) metabolism. Numerous evidence has demonstrated for an association between apoA5 and the increased risk of obesity and metabolic syndrome, but the mechanism remains to be fully elucidated. Recently, several studies verified that apoA5 could significantly reduce plasma TG level by stimulating lipoprotein lipase (LPL) activity, and the intracellular role of apoA5 has also been proved since apoA5 is associated with cytoplasmic lipid droplets (LDs) and affects intrahepatic TG accumulation. Furthermore, since adipocytes provide the largest storage depot for TG and play a crucial role in the development of obesity, we could infer that apoA5 also acts as a novel regulator to modulate TG storage in adipocytes. In this review, we focus on the association of gene and protein of apoA5 with obesity and metabolic syndrome, and provide new insights into the physiological role of apoA5 in humans, giving a potential therapeutic target for obesity and associated disorders.

The women of China's Liaoning province display some morbidities in ways that defy medical explanation. Women have higher rates of hypertension, hypercholesterolemia, and metabolic syndrome than men, an anomaly for all three conditions. Most of these patients also suffer from Type 2 Diabetes Mellitus (T2DM) while there was a negative association between being female and T2DM for the rest of China. Each of these conditions can exist independently, but the increase in both their rates and congruence is a recent phenomenon. Stranger still is that Liaoning women are now presenting in hospital emergency departments with ST-Elevation Myocardial Infarction (STEMI), while diabetics predominantly suffer more benign Non-STEMI (NSTEMI) events. Confounding factors in any attempt to study this phenomenon include trace metals like manganese that have been shown to reduce systolic blood pressure in Asian men and raise it in Asian women. Some of the phenomenon may also be associated with the gene for Apolipoprotein 5, but its recent nature suggests other factors besides lipid profiles. Trace metals in the air, water, and diet of Liaoning province, or any urban environment, could play a role. [ABSTRACT FROM AUTHOR]

Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline‐induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor β1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase‐c‐Jun N‐terminal kinase‐Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH. [ABSTRACT FROM AUTHOR]

Apolipoprotein A‐V encoded by apolipoprotein 5 (APOA5) gene plays an important role in lipid metabolism, especially in the regulation of plasma triglycerol levels. The study aimed to evaluate the association of the APOA5‐rs662799 polymorphism with dyslipidemia in Vietnamese children and the potential modification of obesity‐related traits (body mass index, waist circumference, hip circumference, and waist‐to‐hip ratio) on this association. A case–control study was conducted with a total of 154 dyslipidemia cases and 389 controls at the age of 6 to 10 recruited at 31 primary schools in Hanoi city of Vietnam. Genotype for APOA5‐rs662799 polymorphism was determined by the restriction fragment length polymorphism analysis. The association of APOA5‐rs662799 polymorphism with dyslipidemia adjusting for age, sex, residence, and obesity‐related traits was analyzed by binary logistic regression analysis. The results showed that in comparison with T/T and T/C carriers, the C/C carriers had a higher concentration of serum TAG in cases (p =0.049). Carriers of the C allele (C/C + T/C) had higher risk for developing dyslipidemia and hypertriglyceridemia than subjects with T/T genotype (odds ratio, OR = 1.7, p =0.0062 and OR = 1.6, p = 0.026, respectively). The association remained significant after adjusting for age, gender, residence, and obesity status (OR = 1.75, p = 0.006 and OR = 1.53, p = 0.049, respectively) or other obesity‐related traits. The study suggested that the APOA5‐rs662799 polymorphism may be a determinant of dyslipidemia and hypertriglyceridemia in Vietnamese children, independent of obesity‐related traits. [ABSTRACT FROM AUTHOR]

The etiology of hypertriglyceridemia (HTG) and, consequently, HTG-induced acute pancreatitis (HTG-AP), is complex. Herein, we explore a possible gene–environment interaction between APOA5 c.553G>T (p.185Gly>Cys, rs2075291), a common variant associated with altered triglyceride levels, and pregnancy in HTG-AP. We enrolled 318 Chinese HTG-AP patients and divided them into 3 distinct groups: Group 1, male patients (n = 183); Group 2, female patients whose disease was unrelated to pregnancy (n = 105); and Group 3, female patients whose disease was related to pregnancy (n = 30). APOA5 rs2075291 genotype status was determined by Sanger sequencing. A total of 362 healthy Han Chinese subjects were used as controls. Data on body mass index, peak triglyceride level, age of disease onset, episode number, and clinical severity of HTG-AP were collected from each patient. Multiple comparisons, between patient groups, between patient groups and controls, or within each patient group, were performed. A robust association of APOA5 rs2075291 with HTG-AP in general, and HTG-AP during pregnancy in particular, was demonstrated. The minor T allele showed a stronger association with Group 3 patients than with either Group 1 or Group 2 patients. This stronger association was due mainly to the much higher frequency of TT genotype in Group 3 patients (20%) than that (<6%) in Group 1 and Group 2 patients. Moreover, the TT genotype was associated with a significantly higher peak triglyceride level in Group 3 patients compared with the GG genotype. Our findings provide evidence for an interaction between APOA5 rs2075291 and pregnancy in HTG-AP. • APOA5 c.553G>T has been previously associated with altered triglyceride levels. • Here, we report for the first time an association of APOA5 c.553G>T with hypertriglyceridemia-induced acute pancreatitis (HTG-AP). • We provide evidence that APOA5 c.553G>T interacts with pregnancy in causing HTG-AP. • Our findings provide novel insights into the complex etiology of HTG-AP. [ABSTRACT FROM AUTHOR]

The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo . Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

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. [ABSTRACT FROM AUTHOR]

Background: ApoA5 mainly synthesized and secreted by liver is a key modulator of lipoprotein lipase (LPL) activity and triglyceride-rich lipoproteins (TRLs). Although the role of ApoA5 in extrahepatic triglyceride (TG) metabolism in circulation has been well documented, the relationship between ApoA5 and nonalcoholic fatty liver disease (NAFLD) remains incompletely understood and the underlying molecular mechanism still needs to be elucidated. Methods: We used CRISPR/Cas9 gene editing to delete Apoa5 gene from Syrian golden hamster, a small rodent model replicating human metabolic features. Then, the ApoA5-deficient (ApoA5 -/- ) hamsters were used to investigate NAFLD with or without challenging a high fat diet (HFD). Results: ApoA5 -/- hamsters exhibited hypertriglyceridemia (HTG) with markedly elevated TG levels at 2300 mg/dL and hepatic steatosis on a regular chow diet, accompanied with an increase in the expression levels of genes regulating lipolysis and small adipocytes in the adipose tissue. An HFD challenge predisposed ApoA5 -/- hamsters to severe HTG (sHTG) and nonalcoholic steatohepatitis (NASH). Mechanistic studies in vitro and in vivo revealed that targeting ApoA5 disrupted NR1D1 mRNA stability in the HepG2 cells and the liver to reduce both mRNA and protein levels of NR1D1, respectively. Overexpression of human NR1D1 by adeno-associated virus 8 (AAV8) in the livers of ApoA5 -/- hamsters significantly ameliorated fatty liver without affecting plasma lipid levels. Moreover, restoration of hepatic ApoA5 or activation of UCP1 in brown adipose tissue (BAT) by cold exposure or CL316243 administration could significantly correct sHTG and hepatic steatosis in ApoA5 -/- hamsters. Conclusions: Our data demonstrate that HTG caused by ApoA5 deficiency in hamsters is sufficient to elicit hepatic steatosis and HFD aggravates NAFLD by reducing hepatic NR1D1 mRNA and protein levels, which provides a mechanistic link between ApoA5 and NAFLD and suggests the new insights into the potential therapeutic approaches for the treatment of HTG and the related disorders due to ApoA5 deficiency in the clinical trials in future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Single nucleotide polymorphisms associated with lipid metabolism and energy balance are implicated in the weight loss response caused by nutritional interventions. Diet-induced weight loss is also associated with differential global DNA methylation. DNA methylation has been proposed as a predictive biomarker for weight loss response. Personalized biomarkers for successful weight loss may inform clinical decisions when deciding between behavioral and surgical weight loss interventions. The aim of the present study was to investigate the association between global DNA methylation, genetic variants associated with energy balance and lipid metabolism, and weight loss following a non-surgical weight loss regimen. The present study included 105 obese participants that were enrolled in a personalized weight loss program based on their allelic composition of the following five energy balance and lipid metabolism-associated loci: Near insulin-induced gene 2 (INSIG2); melanocortin 4 receptor; adrenoceptor β2; apolipoprotein A5; and G-protein subunit β3. The present study investigated the association between a global DNA methylation index (GDMI), the allelic composition of the five energy balance and lipid metabolism-associated loci, and weight loss during a 12 month program, after controlling for age, sex and body mass index (BMI). The results demonstrated a significant association between the GDMI and near INSIG2 locus, after adjusting for BMI and weight loss, and significant trends were observed when stratifying by gender. In conclusion, a combination of genetic and epigenetic biomarkers may be used to design personalized weight loss interventions, enabling adherence and ensuring improved outcomes for obesity treatment programs. Precision weight loss programs designed based on molecular information may enable the creation of personalized interventions for patients, that use genomic biomarkers for treatment design and for treatment adherence monitoring, thus improving response to treatment. [ABSTRACT FROM AUTHOR]

It has previously been demonstrated that apolipoprotein A5 (apoA5) can be internalized by human adipocytes and significantly decreases intracellular triglyceride content. In the present study, endocytosis of apoA5 by adipocytes under different conditions, and the underlying mechanism by which apoA5 regulates cellular triglyceride storage, was investigated. The results revealed that the apoA5 protein was detected in human subcutaneous abdominal adipose tissues. In addition, the uptake of apoA5 was attenuated in human obese adipose tissues and in cultured adipocytes with hypertrophy or insulin resistance. Low‑density lipoprotein receptor protein 1 (LRP1) knockdown in adipocytes resulted in a decrease in internalized apoA5 content, suggesting that LRP1 serves a role in apoA5 uptake. Treatment of adipocytes with apoA5 decreased the expression of the lipid droplet‑associated proteins such as cidec and perilipin. ApoA5‑treated adipocytes demonstrated an increase in lipolysis activity and expression of uncoupling protein 1, which is the molecular effector of thermogenesis in brown adipocytes. These results suggested that decreased triglyceride accumulation in adipocytes induced by apoA5 may be associated with enhanced lipolysis and energy expenditure, which may result from reduced expression of cidec and perilipin. In conclusion, the present study demonstrated a novel role of apoA5 in regulating the intracellular triglyceride metabolism of adipocytes. The results of the present study suggested that apoA5 may serve as a potential therapeutic target for the treatment of obesity and its related disorders. [ABSTRACT FROM AUTHOR]

Background and Objectives: Apolipoprotein A5 (APOA5) gene is important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. Mutation in this gene affected plasma triglyceride level. We looked for possible associations of the APOA5 gene polymorphism S19W with coronary heart disease (CHD) in a sample of Iranian population. Materials and Methods: A total of 73 CHD patients and 55 controls were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) for this single nucleotide polymorphism. Serum lipids and Fast Blood Sugar concentrations were measured in all subjects with enzymatic method. Results: Allele frequencies observed in our population were 0.041 for the W allele and 0.959 for the S allele which are similar to other populations (p>0.05). There is no evidence that APOA5 S19W, is a risk factor of CHD in our sample (p>0.05). In addition, we observed no association between the APOA5 W allele and elevated plasma TG levels (p>0.05) in the CHD group. This result was also present in the control group (p>0.05). Conclusion: The APO A5 gene polymorphism in S19W gene has no association with the high susceptibility to CHD.

Background and Objectives: Apolipoprotein A5 (APOA5) gene is important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. Mutation in this gene affected plasma triglyceride level. We looked for possible associations of the APOA5 gene polymorphism S19W with coronary heart disease (CHD) in a sample of Iranian population. Materials and Methods: A total of 73 CHD patients and 55 controls were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) for this single nucleotide polymorphism. Serum lipids and Fast Blood Sugar concentrations were measured in all subjects with enzymatic method. Results: Allele frequencies observed in our population were 0.041 for the W allele and 0.959 for the S allele which are similar to other populations (p>0.05). There is no evidence that APOA5 S19W, is a risk factor of CHD in our sample (p>0.05). In addition, we observed no association between the APOA5 W allele and elevated plasma TG levels (p>0.05) in the CHD group. This result was also present in the control group (p>0.05). Conclusion: The APO A5 gene polymorphism in S19W gene has no association with the high susceptibility to CHD.

We determined the contribution of the combination of FEN1 10154G>T with the most significant association in the analysis of plasma arachidonic acid (AA, 20:4ω6) and the APOA5-1131T>C on phospholipid ω6PUFA and coronary artery disease (CAD). Patients with CAD (n = 807, 27–81 years of age) and healthy controls (n = 1123) were genotyped for FEN1 10154G>T and APOA5-1131T>C. We found a significant interaction between these two genes for CAD risk (P = 0.007) adjusted for confounding factors. APOA5-1131C allele carriers had a higher CAD risk [odds ratio (OR):1.484, 95% confidence interval (CI):1.31–1.96; P = 0.005] compared with APOA5-1131TT individuals in the FEN1 10154GG genotype group but not in the FEN1 10154T allele group (OR:1.096, 95%CI:0.84–1.43; P = 0.504). Significant interactions between these two genes were also observed for the AA proportion (P = 0.04) and the ratio of AA/linoleic acid (LA, 18:2ω6) (P = 0.004) in serum phospholipids of controls. The APOA5-1131C allele was associated with lower AA (P = 0.027) and AA/LA (P = 0.014) only in controls carrying the FEN1 10154T allele. In conclusion, the interaction between these genes suggests that the FEN1 10154T variant allele decreases AA and AA/LA in the serum phospholipids of carriers of the APOA5-1131C allele, but contributes no significant increase in CAD risk for this population subset despite their increased triglylcerides and decreased apoA5.

BACKGROUND AND OBJECTIVE: Apolipoprotein A5 gene plays an important role in plasma lipid regulation. Protein deficiency of apolipoprotein A5 gene causes an increase in plasma triglyceride. The aim of this study was to assay the effect of apolipoprotein A5-1131T>C polymorphism associated with lipid profile in Babol population.METHODS: This case-control study was performed on 199 people in Babol. They were divided into two groups under supervision of the specialist and with regard to their medical history and files: low triglyceride group (99 persons with triglyceride< 103 mg/dl) and high triglyceride group (100 persons with triglyceride> 150 mg/dl) and their biochemistry and anthropometric parameter were measured. The apolipoprotein A5 gene was amplified by PCR method and polymorphism was revealed by the use of MseI enzyme with RFLP method and then compared.FINDINDS: Allele C frequency in people with high triglyceride was 0.21 and in people with low triglyceride was 0.11 that these differences were statistically significant (p=0.02). Also, significant association was found between serum triglyceride (p=0.016) and C allele in low and high triglyceride groups. Being carrier allele C versus TT genotype increased the chance of high triglyceride OR=1.97 times (95% CI=1.35-3.68).CONCLUSION: Our study confirms the association of the APOA5 -1131T>C polymorphism with triglyceride levels in humans. Therefore, genetically evaluation of subjects with high triglyceride recommends to determine allele and diagnosis of cardiovascular patient.

The prevalence of hypertriglyceridemia, considered to be an independent risk factor for the development of cardiovascular disease, is high in Taiwanese aborigines. This study was undertaken to examine the effect of the -1131T > C polymorphism in the apolipoprotein A5 gene on serum triglyceride levels in female Taiwanese aborigines. This was a cross-sectional study, and a total of 316 unrelated female Taiwanese aborigines were genotyped at the -1131T > C polymorphism in apolipoprotein A5 using the polymerase chain reaction-restriction fragment length polymorphism method. Serum triglyceride ≥150 mg/dL was defined as the hypertriglyceridemia group and triglyceride < 150 mg/dL was considered to be the control group. The frequency of the minor C allele was significantly higher in the hypertriglyceridemia group (0.53) than in the control group (0.35) (p < 0.001). The frequency of this rare allele was comparable to that in Japanese and Han Chinese, but was higher than that in Caucasians. In a multiple logistic model adjusted for possible confounders, C allele-containing variants were independently associated with greater risks (CT genotype: OR = 3.28, 95% CI = 1.43–7.56; CC genotype: OR = 5.86, 95% CI = 2.15–15.99) of hyper-triglyceridemia than the TT genotype (p < 0.01), notably with the CC homozygote exhibiting the greatest risks. The genotype polymorphisms were also associated with serum triglyceride concentrations in a linear fashion (for trend, p < 0.05). Our results indicate that the -1131T > C polymorphism of the Apo A5 gene influences serum triglyceride levels in female Taiwanese aborigines, and that differences exist in the frequency of the C allele among people of various ethnicities.

Background: Apolipoprotein A5 (APOA5) is involved in serum triglyceride (TG) regulation. Several studies have reported that the rs651821 locus in the APOA5 gene is associated with serum TG levels in the Chinese population. However, no research has been performed regarding the association between the variants of rs651821 and the risk of hyperlipidemic acute pancreatitis (HLAP). Methods: A case-control study was conducted and is reported following the STROBE guidelines. We enrolled a total of 88 participants in this study (60 HLAP patients and 28 controls). APOA5 was genotyped using PCR and Sanger sequencing. Logistic regression models were conducted to calculate odds ratios and a 95% confidence interval. Results: The genotype distribution of the rs651821 alleles in both groups follow the Hardy-Weinberg distribution. The frequency of the "C" allele in rs651821 was increased in HLAP patients compared to controls. In the recessive model, subjects with the "CC" genotype had an 8.217-fold higher risk for HLAP (OR = 8.217, 95% CI: 1.023-66.01, p  = 0.046) than subjects with the "TC+TT" genotypes. After adjusting for sex, the association remained significant (OR = 9.898, 95% CI: 1.176-83.344, p  = 0.035). Additionally, the "CC" genotype was related to an increased TG/apolipoprotein B (APOB) ratio and fasting plasma glucose (FPG) levels. Conclusions: Our findings suggest that the C allele of rs651821 in APOA5 increases the risk of HLAP in persons from Southeastern China.

Background: Apolipoprotein A5 (APOA5) 1131 is one of the most investigated gene polymorphisms in association with cardiovascular diseases (CVD) for its roles in epigenetics pathways. Objectives: The major objective of this metaprediction study was to comprehensively examine the association of polymorphism risk subtypes of APOA5 1131 gene and potential contributing factors of CVD risks in global populations. Methods: This study is a meta-analysis to determine APOA5 gene polymorphisms as risk factors for CVDs. Following the guidelines of meta-analyses, we applied big data analytics including the recursive partition tree, nonlinear association curve fit, and heat maps for data visualization--in addition to the conventional pooled analyses. Results: A total of 17,692 CVD cases and 23,566 controls from 50 study groups were included. The frequency of APOA51131 CC and TC polymorphisms in Asian populations (22.2%-52.6%) were higher than that in other populations, including Caucasians and Eurasians (10.0%-25.0%). The homozygous CC and heterozygous TC genotypes (both p < .0001) were associated with increased risks for CVD and were higher in many Western nations, including Canada, Spain, the Czech Republic, Hungary, Turkey, Egypt, France, and Iran. The CC genotype was associated with greater risks (RR > 2.00, p < .0001) for dyslipidemia and myocardial infarction, whereas RR > 1.00 was associated with metabolic syndrome, coronary artery disease, and stroke. Air pollution was significantly associated with APOA5 1131 CC and TC polymorphisms. Discussion: The findings of this study provided novel insight to further understand the associations among APOA5 1131 polymorphisms, air pollution, and the development of CVDs. Methylation studies are needed to examine epigenetic factors associated with APOA5 1131 polymorphisms and CVD and to suggest potential prevention strategies for CVD. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the correlation between serum levels of serum apolipoprotein M (ApoM), A5 (ApoA5), and high-density lipoprotein (HDL) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and study the effects of nasal continuous positive airway pressure treatment on these serum biomarkers. Methods: Thirty OSAHS patients and 15 non-OSAHS probands as control were selected for the study. Serum HDL, ApoM, and ApoA5 levels in two groups were detected; differences and association among them were analyzed. Patients with moderate and severe OSAHS underwent 3-month auto-continuous positive airway pressure treatment, and a comparative study was conducted to investigate the changes in blood lipids, serum ApoM, and ApoA5. Results: In comparison to the control group, the HDL, ApoM, and ApoA5 serum levels were lower ( P < 0.05). HDL was positively correlated to ApoM and ApoA5 ( P < 0.001), and ApoM was positively correlated to ApoA5 ( r = 0.536, P < 0.001). HDL, ApoM, and ApoA5 were significantly increased in the patients of moderate and severe OSAHS after auto-continuous positive airway pressure treatment for 3 months ( P < 0.05). Conclusions: The HDL level was significantly lower in OSAHS patients. The decrease in serum ApoM and ApoA5 in OSAHS patients was correlated to the severity of OSAHS and HDL levels. Auto-continuous positive airway pressure treatment increased serum levels of ApoM, ApoA5, and HDL in OSAHS patients. [ABSTRACT FROM AUTHOR]

Apolipoprotein A5 (APOA5) is a small protein, expressed predominantly in the liver. In plasma, it is located on triglyceride rich lipoprotein particles (chylomicrones and VLDL) and on HDL. Plasma concentration of apolipoprotein A5 is very low, suggesting rather regulatory (activation of lipoprotein lipase, …) than structural function. APOA5 is an important determinant of plasma triglyceride concentration; this effect has been confirmed both on animal models, as well as on human studies. Minor alleles of three commonly analysed variants within this gene (rs662799, rs3135506, rs2075291) are associated with higher plasma TG values and increased risk of myocardial infarction, with some important interethnic differences observed. Further roles of APOA5; determination of BMI, diabetes and last but not least nutri- and pharmaco-genetic interactions are suggested, but without the definitive conclusions. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) infection causes lipid metabolism disorders. Apolipoprotein A5 (ApoA5) is a new apolipoprotein family member that plays an important role in the regulation of lipid metabolism. The present study was to investigate the impact of HBV on ApoA5 expression and its regulatory mechanism. Methods: Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to measure ApoA5 mRNA and protein expression in HepG2 and HepG2.2.15 cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum ApoA5 levels in healthy individuals and HBV patients. HBV infectious clone pHBV1.3 or individual plasmids expressing the HBV genome was cotransfected with the ApoA5 promoter pGL3-Apo5-LUC plasmid into HepG2 cells to assess the luciferase activity. RT-PCR and western blotting methods were used to detect Apo5 mRNA and protein expression, respectively. Results: The ApoA5 mRNA and protein expression levels were decreased in HepG2.2.15 cells compared with the control HepG2 cells. The serum ApoA5 levels were 196.4 ± 28.7 μg/L in the healthy individuals and 104.5 ± 18.3 μg/L in the HBV patients, statistical analysis showed that the ApoA5 levels were significantly lower in HBV patients than in the healthy individuals (P < 0.05). pHBV1.3 and its core gene inhibited ApoA5 promoter activity and mRNA and protein expression in HepG2 cells. Conclusion: HBV inhibits ApoA5 expression at both the transcriptional and translational levels through its core gene. [ABSTRACT FROM AUTHOR]

Introduction Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotriglyceridemic actions. Methods Two obese mouse models, including high-fat diet-induced obese mice and ob/ob obese mice, were adopted. The effects of low- and high-dose metformin were determined on plasma and hepatic TG and apoA5 of these obese mice. Besides, the effects of metformin on TG and apoA5 were also detected in mouse and human hepatocytes in vitro . Results (1) Plasma apoA5 levels in the obese mice were markedly elevated and positively correlated with TG. Hepatic TG contents and apoA5 expressions were also remarkably increased in the obese mice. (2) Metformin dose-dependently decreased hepatic and plasma TG and apoA5 in the obese mice. Similarly, metformin dose-dependently reduced cellular TG contents and apoA5 expressions in hepatocytes in vitro . Compared to APOA5 knock-down (KD), metformin plus APOA5 KD resulted in more TG reduction of hepatocytes. Conclusion Increased hepatic and plasma apoA5 could be a result of obesity-associated hypertriglyceridemia, and metformin displays hypotriglyceridemic effects on obese mice partly via the apoA5 pathway. [ABSTRACT FROM AUTHOR]

Singapore comprises three ethnic groups: Chinese (76.7%), Malays (14%), and Asian-Indians (7.9%). Overall, Singaporeans experience coronary heart disease rates similar to those found in the United States. However, there is a dramatic interethnic gradient, with Asian-Indians having significantly higher risk than Chinese and Malays. These differences are associated with HDL cholesterol levels and cannot be solely explained by environmental exposure, and may be driven by genetic factors. The gene encoding apolipoprotein A-V (APOA5) has been located on chromosome 11, and it is emerging as an important candidate gene for lipoprotein metabolism. We investigated associations between APOA5 polymorphisms and plasma lipids in 3,971 Singaporeans to establish whether they accounted for some of the ethnic differences in plasma lipids. We found significant associations between the minor alleles at each of four common polymorphisms and higher plasma triglycerides (TGs) across ethnic groups. Haplotype analyses showed significant associations with TGs, explaining 6.9%, 5.2%, and 2.7% of the TG variance in Malays, Asian-Indians, and Chinese, respectively. Conversely, we observed significant inverse associations between the minor alleles and HDL cholesterol concentrations for Chinese and Malays.These data suggest that APOA5 plays a role in the ethnic differences observed for plasma TG and HDL cholesterol concentrations.

Objective: Apolipoprotein A5 (lipoprotein lipase activator) and cholesterol 7α-hydroxylase (microsomal cytochrome P450) are almost exclusively expressed in liver tissue. Variants within the regulatory parts of these genes (rs662799 and rs3135506 within APOA5 and rs3808607 within CYP7A1) can probably affect levels of plasma lipids and may influence the success of the treatment of dyslipidaemia. Methods: In order to conduct a primary analysis of whether the effect of the variants is mediated through gene expression, we collected and analysed 25 anonymous samples of human liver tissue. Results: APOA5 expression levels of hepatic mRNA were lower in carriers of at least one less common APOA5 allele than in common alleles homozygotes, but the difference was not significant (p = 0.19), mainly due to the huge expression range in different samples. Similarly, CYP7A1 expression was also not significantly influenced by the promoter variant, regardless of the type of statistical model used (all p > 0.31). In our study, we have detected a huge inter-individual variation in the hepatic transcript levels of APOA5 and CYP7A1. These inter-individual variations were the main reasons why having even twice as high levels of expression between the compared groups with different genotypes was not significant. Conclusions: The results of our pilot study did not confirm a possible effect of promoter variants on the expression of APOA5 and CYP7A1 genes. The relatively small sample size could have affected our results. A central facility based on international collaboration that collects liver resection material may help increase the number of samples to provide meaningful results. [ABSTRACT FROM AUTHOR]

Background: 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). Methods: 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. Results: 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). Conclusion: APOA5 -1131 T > C and APOC3 -455 T > C SNPs may play potent roles in the development and progression of CHD. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between apolipoprotein A5 (apoA5) gene and metabolic syndrome (MS). Methods Polymerase chain reaction and technique of restriction fragment length polymorphism were used to determine the genotypes of apoA5 -1131T>C (rs662799) and 1259T>C (rs2266788) in 110 patients with MS and 110 healthy control subjects. Results The levels of BMI and TG of subjects with apoA5-1131CC genotype were higher than those of subjects with TC and CC genotype (P<0.05). The levels of TG and HBA1C of subjects with apoA5 1259CC genotype were higher than those of subjects with TC and CC genotype (P<0.05). The risk of MS in subjects with apoA5-1131CC genotype was 4.5 times higher than that in subjects with TT genotype (OR=4.504, 95% CI: 1.766-11.490, P=0.002). Conclusion The genetic polymorphism of apoA5 -1131T>C (rs662799) may contribute to an increased risk of MS while that of apoA5 1259T>C(rs2266788) has no obvious relationship with the occurrence of MS. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a common disorder which is a constellation of clinical features including abdominal obesity, increased level of serum triglycerides (TGs) and decrease of serum high-density lipoprotein-cholesterol (HDL-C), elevated blood pressure, and glucose intolerance. The apolipoprotein A5 (APOA5) is involved in lipid metabolism, influencing the level of plasma TG and HDL-C. In the present study, we aimed to investigate the associations between four INDEL variants of APOA5 gene and the MetS risk. Materials and Methods: In this case–control study, we genotyped 116 Iranian children and adolescents with/without MetS by using Sanger sequencing method for these INDELs. Then, we explored the association of INDELs with MetS risk and their clinical components by logistic regression and one-way analysis of variance analyses. Results: We identified a novel insertion polymorphism, c. *282–283 insAG/c. *282–283 insG variant, which appears among case and control groups. rs72525532 showed a significant difference for TG levels between various genotype groups. In addition, there were significant associations between newly identified single-nucleotide polymorphism (SNP) and rs72525532 with MetS risk. Conclusions: These results show that rs72525532 and the newly identified SNP may influence the susceptibility of the individuals to MetS.

Background We report a case of a 33-year-old man who presented with immunoglobulin (Ig)G4-related disease (IgG4-RD) forming a pseudotumor in the left paratesticular region during oral administration of corticosteroid for Wells syndrome, which involves cellulitis with eosinophilia. Case presentation The patient was introduced to our institution from a private hospital with a 3-month history of asymptomatic left scrotal mass. A 5-cm diameter nodule was palpable in the left scrotum. Tumor lesion in the left paratestis involving the epididymis and spermatic cord was observed on computed tomography and magnetic resonance imaging. Blood testing showed no abnormalities other than a minimal increase in C-reactive protein levels. Urine examination likewise revealed no significant findings. Left radical orchidectomy was performed under a diagnosis of left paratesticular neoplasm suspected as malignant tumor. The tumor was pathologically identified as IgG4-RD of the left paratestis involving the epididymis and spermatic cord. Conclusions We present a first description of IgG4-RD in a patient with Wells syndrome and the ninth case of IgG4-RD in a scrotal organ, and discuss this very rare entity with reference to the literature. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_225 [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to evaluate the relationships of the T-1131C (rs662799) polymorphism variants of apolipoprotein A5 (Apo A5) gene and variants of apolipoprotein E (Apo E) gene common polymorphism (rs429358, rs7412) to selected hemostatic markers. Study design and methods We examined 590 asymptomatic dyslipidemic patients, subsequently divided into MetS + (n = 146) and MetS - (n = 444) groups according to the criteria for identification of the metabolic syndrome (MetS). We compared variant frequencies and differences in levels of hemostatic markers according to Apo A5, Apo E and Apo A5/Apo E common variants. Results The - 1131C Apo A5 minor variant was associated with elevated tissue plasminogen activator (tPA) in comparison to TT genotype (p < 0.001), but not in the MetS + group. The analysis of Apo A5/Apo E common variants in all subjects revealed that the presence of - 1131C minor allele has always been associated with higher levels of tPA in comparison with T allele, regardless of Apo E genotype. Also the presence of minor Apo E2 allele led to elevated tPA concentrations in both T and C carriers. In addition, common - 1131C/E2 variant was associated with the highest tPA levels. Conclusion We demonstrated a remarkable association especially between the - 1131C Apo A5 variant and increased tPA levels in asymptomatic dyslipidemic patients. [ABSTRACT FROM AUTHOR]

Background Although the association between the apolipoprotein A5 (APOA5) genetic variants and hypertriglyceridemia has been extensively studied, there have been few studies, particularly in children and adolescents, on the association between APOA5 genetic variants and obesity or non-high-density lipoprotein cholesterol (non-HDL-C) levels. The objective of this study was to examine whether APOA5 gene polymorphisms affect body mass index (BMI) or plasma non-HDL-C levels in Chinese child population. Methods This was a case-control study. Single nucleotide polymorphisms (SNPs) were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry for an association study in 569 obese or overweight and 194 healthy Chinese children and adolescents. Results Genotype distributions for all polymorphisms in both cohorts were in accordance with the Hardy-Weinberg distribution. The frequencies of the risk alleles in rs662799 and rs651821 SNPs in APOA5 gene were all increased in obese or overweight patients compared to the controls. After adjusted for age and sex, C carriers in rs662799 had a 1.496-fold [95% confidence interval (CI): 1.074-2.084, P = 0.017] higher risk for developing obesity or overweight than subjects with TT genotype, while C carriers in rs651821 had a 1.515-fold higher risk than subjects with TT genotype (95% CI: 1.088-2.100, P = 0.014). Triglyceride (TG) and non-HDL-C concentrations were significantly different among rs662799 variants and both were higher in carriers of minor allele than in noncarriers for TG (1.64 ± 0.96 vs. 1.33 ± 0.67 mmol/L) (P < 0.001), and for non-HDL-C (3.23 ± 0.92 vs. 3.02 ± 0.80 mmol/L) (P = 0.005), respectively. There was also a trend towards increased TG and non-high-density lipoprotein cholesterol levels for rs651821 C carriers (P < 0.001 and P = 0.002, respectively). Furthermore, to confirm the independence of the associations between APOA5 gene and TG or non-HDL-C levels, multiple linear regression analysis was performed and the relationships were not eliminated by adjustment for age, sex and BMI. Conclusions These findings suggest the TG-raising genetic variants in the APOA5 gene may influence the susceptibility of the individual to obesity, which may also contribute to an increased risk of high non-HDL-C levels in Chinese obese children and adolescents. [ABSTRACT FROM AUTHOR]

Context: Type I hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme hypertriglyceridemia that fails to respond to lipid-lowering agents, predisposing to frequent attacks of acute pancreatitis. Mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), lipase maturation factor 1 (LMF1), glycosyl-phosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and apolipoprotein AV (APOA5) cause T1HLP, but we lack data on phenotypic variations among the different genetic subtypes. Objective: To study genotype-phenotype relationships among subtypes of T1HLP patients. Design/Intervention: Genetic screening for mutations in LPL, APOC2, GPIHBP1, LMF1, and APOA5. Setting: Tertiary referral center. Patients: Ten patients (7 female, 3 male) with chylomicronemia, serum triglyceride levels about 2000 mg/dL, and no secondary causes of hypertriglyceridemia. Main Outcome Measures: Genotyping and phenotypic features. Results: Four patients harbored homozygous or compound heterozygous mutations in LPL, 3 had homozygous mutations in GPIHBP1, and 1 had a heterozygous APOA5 mutation. We failed to fully identify the genetic etiology in 2 cases: 1 had a heterozygous LPL mutation only and another did not have any mutations. We identified 2 interesting phenotypic features: the patient with heterozygous APOA5 mutation normalized triglyceride levels with weight loss and fish oil therapy, and all 7 female patients were anemic. Conclusions: Our data suggest the possibility of novel loci for T1HLP. We observed that heterozygous APOA5 mutation can cause T1HLP but such patients may unexpectedly respond to therapy, and females with T1HLP suffer from anemia. Further studies of larger cohorts may elucidate more phenotype-genotypes relationships among T1HLP subtypes. [Copyright &y& Elsevier]