Apolipoprotein C3 Gene Research Articles

Apolipoprotein C3 gene variants are not related to isolated low HDL cholesterol in South Asians: The Ethnic-Echocardiographic Heart of England Screening study (E-ECHOES)

Apolipoprotein C3 gene variants are not related to isolated low HDL cholesterol in South Asians: The Ethnic-Echocardiographic Heart of England Screening study (E-ECHOES)

Visceral obesity modulates the impact of apolipoprotein C3 gene variants on liver fat content

It has not been solved whether subjects carrying the minor alleles of the -455T>C or -482C>T single nucleotide polymorphisms (SNPs) in the apolipoprotein-C3-gene (APOC3) have an increased risk for developing fatty liver and insulin resistance. We investigated the relationships of the SNPs with hepatic APOC3 expression and hypothesized that visceral obesity may modulate the effects of these SNPs on liver fat and insulin sensitivity (IS). APOC3 mRNA expression and triglyceride content were determined in liver biopsies from 50 subjects. In a separate group (N=330) liver fat was measured by (1)H-magnetic resonance spectroscopy. IS was estimated during an oral glucose tolerance test (OGTT) and the euglycemic, hyperinsulinemic clamp (N=222). APOC3 mRNA correlated positively with triglyceride content in liver biopsies (r=0.29, P=0.036). Carriers of the minor alleles (-455C and -482T) tended to have higher hepatic APOC3 mRNA expression (1.80 (0.45-3.56) vs 0.77 (0.40-1.64), P=0.09), but not higher triglyceride content (P=0.76). In 330 subjects the genotype did not correlate with liver fat (P=0.97) or IS (OGTT: P=0.41; clamp: P=0.99). However, a significant interaction of the genotype with waist circumference in determining liver fat was detected (P=0.02) in which minor allele carriers had higher liver fat only in the lowest tertile of waist circumference (P=0.01). In agreement, during a 9-month lifestyle intervention the minor allele carriers of the SNP -482C>T in the lowest tertile also had less decrease in liver fat (P=0.04). APOC3 mRNA expression is increased in fatty liver and is regulated by SNPs in APOC3. The impact of the APOC3 SNPs on fatty liver is small and depends on visceral obesity.

Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground

Nonalcoholic fatty liver disease (NAFLD) is becoming an important chronic liver disorder in Asia. Prevalence figures show regional variations but at least 10% of the general population in Asia have fatty liver. Fatty liver can develop with relatively small changes in weight (2-3 kg), often with increasing central adiposity. The metabolic syndrome may precede or follow NAFLD. Overt diabetes is present in one-third of cases but when oral glucose tolerance tests are performed, a further third of individuals have impaired glucose tolerance or diabetes. Natural history data are still scarce but cases of advanced hepatic fibrosis and hepatocellular carcinoma are now regularly reported. Many cases of cryptogenic cirrhosis are also attributable to NAFLD. Histological progression has been demonstrated for patients with NASH as well as for those with hepatic steatosis alone. Genetic factors may in part contribute to the rise in NAFLD. Polymorphisms within apolipoprotein C3 (APOC3) gene have been linked to NAFLD in lean Indian men. Although a number of other polymorphisms involving genes controlling adipose distribution, insulin signalling, adipokine responses and hepatic fibrosis have been reported, these studies have been underpowered. Transient elastography could help in detecting and monitoring hepatic fibrosis but further refinements in technique are necessary for obese individuals. Of the biomarkers, hyaluronic acid and cytokeratin-18 fragment testing show promise as markers of hepatic fibrosis and NASH, respectively. Lifestyle alterations including dietary changes and increased physical activity remain the cornerstone of management. Attention should be paid to prevention through public education of campaigns addressing the increase in both adult and childhood obesity.

Regulation of Hepatic ApoC3 Expression by PGC-1β Mediates Hypolipidemic Effect of Nicotinic Acid

Peroxisome proliferator-activated receptor (PPAR) γ coactivator-1β (PGC-1β) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1β is regulated by free fatty acids. Here we show that PGC-1β regulates plasma triglyceride metabolism through stimulating apolipoprotein C3 (APOC3) expression and elevating APOC3 levels in circulation. Remarkably, liver-specific knockdown of APOC3 significantly ameliorates PGC-1β-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1β and APOC3 is reduced in response to acute and chronic treatments with nicotinic acid, a widely prescribed drug for lowering plasma triglycerides. Adenoviral-mediated knockdown of PGC-1β or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1β transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRα and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1β as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects.

Influence of genetic variants in the apolipoprotein A5 and C3 gene on lipids, lipoproteins, and its association with coronary artery disease in Indians

Indians worldwide demonstrate a triad of elevated triglyceride (TG) with high low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol levels. In the present study, we aim to investigate the effect of -1131T > C, -3A > G, c.56C > G, and c.553G > T SNPs in the apolipoprotein A5 (APOA5) gene and 1100C > T and 3238C > G in the apolipoprotein C3 (APOC3) on plasma lipid and lipoprotein levels and risk of coronary artery disease (CAD) in Indians. Genotyping and lipid assays were carried out using standard protocols in a study population that included 150 controls and 90 cases with CAD. Significant associations between minor alleles and higher TG levels were seen for -1131T > C (P < 0.001), -3A > G (P < 0.001), c.56C > G (P = 0.026), and c.553G > T (P = 0.003) SNPs in the APOA5 gene and 1100C > T (P = 0.001) and 3238C > G (P = 0.009) in the APOC3 gene. The haplotypes 11211, 22111, 11112, and 22112 were significantly associated with TG levels (P = 0.025, P = 0.017, P = 0.027, and P < 0.001, respectively) and very-low-density lipoprotein cholesterol levels (P = 0.025, P = 0.017, P < 0.001, and P = 0.002) in males. The 22111, 11112, and 22112 were associated with elevated TG (P = 0.030, P = 0.036, and P = 0.024) but not VLDL-C levels in females. No association with other lipid parameters was seen. In the logistic regression model, the rare S2 allele was a significant risk factor (P = 0.030, 95% CI 1.186-31.432) along with smoking (P < 0.0001, 95% CI 2.018-10.397) for CAD. The APOA5 and APOC3 locus is a strong determinant of plasma TG levels in Indians. The APOC3 3238G is a risk factor for CAD and a higher frequency was also seen with type 2 diabetes mellitus.

Update on nonalcoholic fatty liver disease: genes involved in nonalcoholic fatty liver disease and associated inflammation

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases worldwide. Advanced age, extensive overweight and a number of features of the metabolic syndrome are associated with NAFLD severity. The cause of NAFLD is considered multifactorial with a substantial genetic component. Family members of children with NAFLD demonstrate a higher risk for NAFLD. Whereas such an association only suggests that familial factors are major determinants of whether or not an individual will develop NAFLD, recent genome-wide association studies were able to identify first candidate genes. An allele in patatin-like phospholipase 3, encoding a protein of unknown function with homology to lipid acyl hydrolases, is strongly associated with increased hepatic fat and inflammation. Apolipoprotein C3 gene variants are also associated with NAFLD and insulin resistance. Several other genetic variants have been identified, although with less convincing evidence. These genetic variants involve molecules regulating insulin signaling, lipid metabolism, oxidative stress or fibrogenesis. Furthermore, genetic variants of several cytokines and adipocytokines have been associated with NAFLD. Several genetic factors such as patatin-like phospholipase 3 or apolipoprotein C3 have been recently characterized in NAFLD. Further studies to identify their interaction with environmental factors are eagerly warranted.

The Effect of APOC3 Promoter Polymorphisms on the Risk of Hypertriglyceridemia in Chinese Han Population With or Without Type 2 Diabetes Mellitus

Background: Promoter polymorphisms in the apolipoprotein C3 (APOC3) gene are associated with hypertriglyceridemia (HTG), which is a complication of Type 2 Diabetes Mellitus (T2DM). Because there is a strong insulin resistance in T2DM, it is essential to investigate whether the APOC3 promoter variation affects plasma lipid profiles in the population with or without T2DM. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect the genotypes of APOC3. The levels of serum lipid profiles were also studied by biochemical methods. Results: In the control group, the prevalence of the −455CC or −482TT variants was higher in persons with HTG compared to those with normal triglyceride (NTG). Compared with the most common genotype, −455TT or −482CC, the variants had a significantly increased HTG risk in this population. However, a similar association was not found in the T2DM group. Conclusions: There was no relationship between promoter rare allele −455C or −482T of APOC3 gene and HTG in T2DM, but both the rare alleles contributed to an increased risk of HTG in the control group without T2DM.

Association of APOA5 and APOC3 gene polymorphisms with plasma apolipoprotein A5 level in patients with metabolic syndrome

Apolipoprotein A5 gene (APOA5) variants are associated with increased plasma triglycerides, a risk factor for the metabolic syndrome (MS), but a correlation with apolipoprotein C3 (APOC3) genotypes is controversial. We investigated the correlation of APOA5 genotypes with plasma apoA5 levels and APOC3 genotypes in MS patients from a Romanian population. APOA5 (−1131T>C, c.56C>G) and APOC3 (−482C>T, −455T>C) genotypes and plasma apoA5 concentration were determined in MS patients and healthy subjects. Results showed higher apoA5 levels in plasma and high density lipoproteins (HDL) from MS patients, carriers of the APOA5 c.56G allele, as compared to MS carriers of APOA5 −1131C allele or the common genotype. ApoA5 levels in plasma and HDL fraction from MS carriers of −1131C and c.56G alleles correlated positively with plasma triglycerides levels and negatively with HDL-cholesterol in MS carriers of c.56G allele. Higher frequencies of APOC3 −482T and −455C alleles were detected in MS patients compared with healthy subjects. We demonstrated the association of APOC3 −482T and −455C with APOA5 −1131C allele, but not with c.56G allele in MS patients. We propose APOA5c.56C>G as a functional polymorphism, whereas APOA5 −1131T>C is not an independent risk factor, being effective only when associated with APOC3 −482T or −455C alleles.

Apolipoprotein C3 Polymorphisms, Cognitive Function and Diabetes in Caribbean Origin Hispanics

BackgroundApolipoprotein C3 (APOC3) modulates triglyceride metabolism through inhibition of lipoprotein lipase, but is itself regulated by insulin, so that APOC3 represents a potential mechanism by which glucose metabolism may affect lipid metabolism. Unfavorable lipoprotein profiles and impaired glucose metabolism are linked to cognitive decline, and all three conditions may decrease lifespan. Associations between apolipoprotein C3 (APOC3) gene polymorphisms and impaired lipid and glucose metabolism are well-established, but potential connections between APOC3 polymorphisms, cognitive decline and diabetes deserve further attention.MethodsWe examined whether APOC3 single nucleotide polymorphisms (SNPs) m482 (rs2854117) and 3u386 (rs5128) were related to cognitive measures, whether the associations between cognitive differences and genotype were related to metabolic differences, and how diabetes status affected these associations. Study subjects were Hispanics of Caribbean origin (n = 991, aged 45–74) living in the Boston metropolitan area.ResultsCognitive and metabolic measures differed substantially by type II diabetes status. In multivariate regression models, APOC3 m482 AA subjects with diabetes exhibited lower executive function (P = 0.009), Stroop color naming score (P = 0.014) and Stroop color-word score (P = 0.022) compared to AG/GG subjects. APOC3 m482 AA subjects with diabetes exhibited significantly higher glucose (P = 0.032) and total cholesterol (P = 0.028) compared to AG/GG subjects. APOC3 3u386 GC/GG subjects with diabetes exhibited significantly higher triglyceride (P = 0.004), total cholesterol (P = 0.003) and glucose (P = 0.016) compared to CC subjects.ConclusionsIn summary, we identified significant associations between APOC3 polymorphisms, impaired cognition and metabolic dysregulation in Caribbean Hispanics with diabetes. Further research investigating these relationships in other populations is warranted.

Apolipoprotein CIII and Atherosclerosis

The prevailing concept of mechanisms responsible for the development of atherosclerotic lesions largely focuses on the accumulation and retention of low-density lipoproteins in the arterial intima and their subsequent oxidative modification. This oxidation leads to activation of the endothelium, and particularly, expression of adhesion molecules that mediate leukocyte adherence and chemokines which initiate the inflammation reaction that is widely accepted as being responsible for the development and progression of atherosclerotic lesions.1,2 There is also a strong body of evidence to indicate that elevated triacylglycerides (triglycerides) are an independent risk factor for atherosclerosis.3–5 Article p 731 One mechanism that can contribute to elevated triglycerides involves apolipoprotein CIII (apoCIII). apoCIII is a small protein that resides on the surface of very-low-density lipoproteins (VLDLs), low-density lipoproteins, chylomicrons, and high-density lipoproteins (Figure). It exists as multiple species, as either a nonglycosylated isoform (apoCIIIo) or a glycosylated isoform (apoCIII1 or apoCIII2); all three isoforms have similar plasma half-lives and probably have very similar physiological functions. Increased apoCIII production is a characteristic feature of patients with hypertriglyceridemia,6 and plasma apoCIII levels have been positively correlated with plasma triacylglycerol concentrations and also have been associated with severity of hypertriglyceridemia.7 Elevated plasma apoCIII concentration and, specifically, accumulation of apoCIII in triacylglycerol-rich lipoproteins is casually related to hypertriglyceridemia in patients with metabolic syndrome and has also been associated with insulin resistance.8 apoCIII is a major regulator of lipolysis, as it noncompetitively inhibits endothelial-bound lipoprotein lipase, the enzyme that hydrolyzes triacylglycerols in …

Genetic profiling in healthy subjects from the Stanislas cohort based on 24 polymorphisms: effects on biological variables

The association of genetic profiles with biological or clinical assessments is not clearly established especially among apparently healthy subjects. A multivariate statistical analysis was performed on 24 polymorphisms related to the main metabolic pathways involved in cardiovascular diseases (CVDs). They were collected among 1551 healthy subjects of the Stanislas cohort to obtain genetic profiles. Association with biological variables was then studied at baseline (t0) and 5 years later (t5). Six genetic clusters were identified with relevant profiles and five polymorphisms from the selectin, apolipoprotein C3 and lipoprotein lipase genes (SELE-98G/T, APOC3-3175C/G, APOC3-482C/T, APOC3-1100C/T, LPL-93T/G) were sufficiently characteristic to associate 99.6% of the subjects with their corresponding cluster. A 5-year follow-up showed that clinical and biological measurements in relation to CVD risk factors already differ with triglyceride (p=0.009 for t0 and p=0.005 for t5) and high-density lipoprotein cholesterol (p=0.014 for t0 and p=0.003 for t5) for these previous genetic clusters. This study presents the hypothesis that SELE could be protective, whereas APOC3 could be associated with risk. It remains to be seen whether these polymorphisms will be predictive of CVD events among the selected clusters of different metabolic subtypes after a 10-year follow-up.

APOA5 polymorphisms influence plasma triglycerides in young, healthy African Americans and whites of the CARDIA Study

Genetic variation in the apolipoprotein A-V gene (APOA5) has been associated with variation in plasma triglyceride (TG) levels in African American and white females and males older than 40 years and/or at increased risk of coronary artery disease. We have examined whether plasma TG levels are associated with 16 APOA5 polymorphisms in young (18-30 years) African American (1,075 females and 783 males) and white (1,041 females and 932 males) individuals of the Coronary Artery Risk Development in Young Adults (CARDIA) Study selected without regard to health. Plasma TG was significantly (P < 0.01) associated with markers 27376 and 28837 (-3A/G) in both white females and males, with 27709 (-1131T/C) and 29085 in white males, with 29009 (S19W) in African American females and white males, and with 30966 in African American females. No statistically significant associations were observed in African American males. These six single-nucleotide polymorphisms individually accounted for 0-0.78% of lnTG variation among white females, 0-2.46% among white males, and 0-0.69% among African American females. The results of our study suggest a small but replicable context-dependent influence of the APOA5 gene region on plasma TG levels in young, healthy individuals.

Genetic effect of two polymorphisms in the apolipoprotein A5 gene and apolipoprotein C3 gene on serum lipids and lipoproteins levels in a Chinese population.

Two polymorphisms, apolipoprotein A5 (APOA5) -1131T>C and apolipoprotein C3 (APOC3) -482C>T, were examined in a healthy Chinese group. Analysis of covariance (ancova) showed that both -1131T>C and -482C>T minor alleles were associated with triglyceride (TG)-raising effects (p < 0.001 and p = 0.012, respectively) after adjustment of sex, age, and body mass index (BMI). Moreover, -1131T>C minor alleles were also found to be associated with total cholesterol (TC)-raising effects (p = 0.045). However, the relationship between -482C>T minor alleles and TC-raising effects was not observed after adjustment of sex, age, and BMI. By contrast, significant inverse associations were noted between minor alleles (-1131T>C and -482C>T) and high-density lipoprotein cholesterol (HDL-C) concentrations (p = 0.021 and p = 0.021, respectively). Linear regression analysis showed that the effects of -1131T>C and -482C>T polymorphisms on TG and HDL-C (0.001 and 0.008; 0.041 and 0.005, respectively) are independent and additive and that -1131T>C can seriously affect the levels of TG (0.001 vs 0.008). The additive effect of the two polymorphisms was confirmed further by haplotype analysis. Our results strongly support that the two single nucleotide polymorphisms, -1131T>C in APOA5 and -482C>T in APOC3, are related to the levels of serum TG and HDL-C and those of other several lipids and lipoproteins in the Chinese population.

The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects.

The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 (APOC3) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23-q24. Polymorphisms of these genes have been extensively investigated in lipoprotein disorders and cardiovascular diseases, but poorly investigated in healthy ageing. The aim of this study was to describe possible modifications of the APOA1, APOC3, and APOA4 gene pool by cross-sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato-chemical parameters in the norm). APOA1-MspI-RFLP (-75 nt from the transcription starting site), APOC3-SstI-RFLP (3'UTR, 3238 nt), and APOA4-HincII-RFLP (Asp127/Ser127) were analysed according to age and sex. A significant age-related variation of the APOA1 gene pool was observed in males. An analysis of the allele average effect exerted by APOA1-MspI-RFLP A/P alleles (Absence/Presence of the restriction site) on lipidemic parameters in 46-80 year old males showed that allele A decreased, while allele P significantly increased, serum LDL-cholesterol. Unexpectedly, the P allele was over-represented in the group of the oldest old subjects, thus giving evidence of another "genetic paradox of centenarians".