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Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA(2) activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA(2) activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA(2) activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6 x 10(-24)); CELSR2/PSRC1 on chromosome 1 (p = 3 x 10(-15)); SCARB1 on chromosome 12 (p = 1x10(-8)) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4 x 10(-8)). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA(2) mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA(2) activity and mass. Show less

To assess the relationships and possible interactions between polymorphisms related to HDL levels and alcohol consumption. Cross-sectional population-based study including 2863 women and 2546 men aged 35-75 years (CoLaus study). Alcohol intake was assessed by the reported alcohol consumption of the last 7 days. Nineteen candidate genes known to influence HDL levels were studied. Alcohol consumption increased HDL cholesterol levels in both genders. After multivariate adjustment for gender, age, body mass index, smoking, hypolipidaemic drug treatment, physical activity and alcohol consumption, APOA5, CETP, LIPC and LPL gene polymorphisms were significantly (10(-5) threshold) related with HDL cholesterol levels, while no genexalcohol intake interaction was found for all SNPs studied. ABCA1 polymorphisms were related to HDL cholesterol levels on bivariate analysis but the relationship was no longer significant after multivariate analysis. Our data confirm the association of alcohol consumption and of APOA5, CETP, LIPC and LPL gene polymorphisms with HDL cholesterol levels. Conversely, no genexalcohol consumption interactions were found, suggesting that the effect of alcohol consumption on HDL cholesterol levels is not mediated via a modulation of HDL related genes. Show less

Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG > or = 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-epsilon4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG. Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the epsilon4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia. Show less

The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community. Show less

Several polymorphisms in the ApoA5 gene emerged as important candidate genes in triglyceride metabolism. The aim of this study was to determine the associations between ApoA5 polymorphisms, plasma triglyceride concentrations and the presence of cardiovascular disease (CVD) in three ethnic origins. Genotypes for 15 single nucleotide polymorphisms (SNPs) were determined in 659 older adults (mean age 71+/-7 years) who immigrated to Israel or whose ancestors originated from East Europe (Ashkenazi), North Africa, Asia (Sephardic) or Yemen (Yemenite). The minor alleles of the four common SNPs (rs662799, rs651821, rs2072560 and rs2266788) are associated with an increase of 27-38% in triglyceride concentration among Ashkenazi and Yemenite Jews compared with the major alleles, but not among those of Sephardic origin. Conversely, among the Sephardic group, the presence of the minor allele in SNP rs3135506 compared with the major allele was associated with an increase of 34% in triglyceride concentration. The four SNPs were in significant linkage disequilibrium (D'=0.96-0.99), resulting in three haplotypes H1, H2 and H3, representing 98-99% of the population. Haplotype H2 was significantly associated with triglyceride concentration among Ashkenazi and Yemenite but not among Sephardic Jews. Conversely, haplotype H3 was associated with triglyceride concentration in Sephardic but not in Ashkenazi and Yemenite Jews. Ashkenazi carriers of H2 haplotype had a CVD odds ratio of 2.19 (95% CI: 1.05-4.58) compared with H1 (the most frequent), after adjustment for all other risk factors. These results suggest that different SNPs in ApoA5 polymorphisms may be associated with triglyceride concentration and CVD in each of these ethnic origins. Show less

We aimed to determine the influence of apolipoprotein A5 gene (APOA5)-1131T>C single nucleotide polymorphism on the effects of dietary intervention and regular exercise (DIRE) targeting ApoA5 and triglyceride (TG) concentrations. Hypertriglyceridemia patients (TG, 150-500mg/dL, n=283) undertook a 12-week DIRE (replacing 1/3 of refined rice in their diets with legumes, increasing vegetable intake, and regular walking). Pre-treatment, no genotype-related differences were detected in ApoA5, TG, or HDL cholesterol levels; however, post-treatment, subjects homozygous (T/T) for the T allele had lower serum TG (P=0.009) and higher HDL cholesterol (P=0.036) than other subjects. In T/T subjects, after adjustments for age, sex and weight changes (r1) or initial TG levels (r2), changes in ApoA5 levels negatively correlated with TG changes (r1=-0.29, P=0.05, r2=-0.28, P<0.1) and positively correlated with changes in HDL cholesterol (r1=0.30, P<0.05, r2=0.32, P<0.05) and free fatty acid (r1=0.38, P<0.01, r2=0.40, P<0.01). In those with moderate hypertriglyceridemia (TG, 200-500mg/dL, n=130), APOA5-1131T/T carriers achieved significantly lower TG (P=0.007) and higher HDL cholesterol (P<0.001) than -1131C allele carriers. Additionally, statistically significant interactions between the -1131T>C and the compliance of DIRE were found for the change in TG (P=0.002) and HDL cholesterol (P=0.039). In good compliance group, T/T subjects showed greater reduction of TG and higher increase of HDL cholesterol than other subjects. On the other hand, non-good compliance group had no significant improvement in these variables. APOA5-1131T/T carriers may benefit more from the DIRE than C allele carriers. These effects were remarkable in patients with moderate hypertriglyceridemia and the individuals with good compliance. Show less

As a newly described member of the apolipoprotein gene family, apolipoprotein A5 (APOA5) has been suggested to play a key role in the triglyceride metabolism in both human and mice. The aim of this study was to identify the porcine (Sus scrofa) APOA5 gene, determine its mRNA and its mutations that are associated with lipid accumulation. The porcine APOA5 cDNA was amplified by reverse transcriptase polymerase chain reaction using the information of the mouse or other mammals. It had been determined that the open reading frame of the porcine APOA5 gene consists of 1092 bp, which encodes a predicted protein composed of 363 amino acids with a similarity to bovine (80.43%) and to human (78.47%). The expression analysis indicated that the porcine APOA5 gene was expressed in hypophysis, fat and liver. Twelve single nucleotide polymorphisms (SNPs), including 4 SNPs in the 5' end, 1 SNP in second intron, 1 SNP in third exon and 6 SNPs in the 3' end, were identified in the porcine APOA5 gene and genotyped on the Jinhua × Pietrain F2 reference population, it had revealed that the SNP of C1834T was significantly associated with average backfat thickness and leaf fat weight (P < 0.01 and P < 0.05, respectively). In conclusion, this study has got basic information of the porcine APOA5 gene and provides evidence that the APOA5 gene could be a potential candidate gene for fat deposition. Show less

Apolipoprotein A5 (APOA5) -1131C allele is associated with higher triglyceride, an independent cardiovascular risk factor and a commonly recognized lipid abnormality in diabetes mellitus (DM). We investigated the association of APOA5 -1131T>C or S19W with DM. Study subjects were all women and categorized into metabolically healthy controls (n = 2033) and DM subjects (n = 304). Association of APOA5 -1131T>C with DM was calculated by odds ratio (OR). Anthropometric parameters, fasting glucose, and lipid profiles were measured. C carriers, particularly those with CC homozygote, had higher triglyceride and lower high-density lipoprotein cholesterol in both healthy controls (P < .001 and P < .001) and DM patients (P = .002 and P = .006) after the adjustment for age, body mass index, menopause, smoking, and drinking. APOA5 -1131C allele was associated with an increased risk of DM (OR, 1.61 [95% confidence interval {CI}, 1.23-2.10]; P < .001) after adjustment for the above confounders. Further adjustment for fasting triglyceride or/and high-density lipoprotein cholesterol attenuated a little bit, but still significantly increased the risk of DM in C carriers (OR(2), 1.36 [95% CI, 1.02-1.80]; P = .035 and OR(3), 1.36 [95% CI, 1.032-1.79]; P = .029, respectively). Interestingly, C allele carriers in DM patients showed a positive correlation between fasting glucose and triglyceride after the adjustment (r = 0.172, P = .035). On the other hand, this significant correlation was not observed in healthy women. Regarding S19W, minor allele was not found in our study population from prescreening test. In conclusion, APOA5 -1131C allele may contribute to the increased susceptibility of DM in Korean women. In addition, positive correlation between fasting glucose and triglyceride in C carriers of DM patients suggested that C allele in hyperglycemic states may be more susceptible to the risk of cardiovascular disease. Show less

Although epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have not been included in any of the previously reported genome-wide association studies for lipids. We investigated 6 single-nucleotide polymorphisms associated with triglycerides, 7 with high-density lipoprotein cholesterol, and 1 with both triglycerides and high-density lipoprotein cholesterol in recent Caucasian genome-wide association studies in Mexican familial combined hyperlipidemia families and hypertriglyceridemia case-control study samples. These variants were within or near the genes ABCA1, ANGPTL3, APOA5, APOB, CETP, GALNT2, GCKR, LCAT, LIPC, LPL (2), MMAB-MVK, TRIB1, and XKR6-AMAC1L2. We performed a combined analysis of the family-based and case-control studies (n=2298) using the Z method to combine statistics. Ten of the single-nucleotide polymorphisms were nominally significant and 5 were significant after Bonferroni correction (P=2.20 x 10(-3) to 2.6 x 10(-11)) for the number of tests performed (APOA5, CETP, GCKR, and GALNT2). Interestingly, our strongest signal was obtained for triglycerides with the minor allele of rs964184 (P=2.6 x 10(-11)) in the APOA1/C3/A4/A5 gene cluster region that is significantly more common in Mexicans (27%) than in whites (12%). It is important to confirm whether known loci have a consistent effect across ethnic groups. We show replication of 5 Caucasian genome-wide association studies lipid associations in Mexicans. The remaining loci will require a comprehensive investigation to exclude or verify their significance in Mexicans. We also demonstrate that rs964184 has a large effect (odds ratio, 1.74) and is more frequent in the Mexican population, and thus it may contribute to the high predisposition to dyslipidemias in Mexicans. Show less

Apolipoprotein A-V (apoA-V), secreted solely by the liver, is a low abundance protein that strongly influences plasma triglyceride (TG) levels. In vitro, in transfected hepatoma cell lines apoA-V is largely retained within the cell in association with cytosolic lipid droplets (LD). To evaluate if this is true in vivo, in the present study the amount of apoA-V in the plasma compartment versus liver tissue was determined in APOA5 transgenic (Tg) mice. The majority of total apoA-V ( approximately 80%) was in the plasma compartment. Injection of APOA5 Tg mice with heparin increased plasma apoA-V protein levels by approximately 25% indicating the existence of a heparin-releasable pool. Intrahepatic apoA-V was associated with LD isolated from livers of wild type (WT) and APOA5 Tg mice. Furthermore, livers from APOA5 Tg mice contained significantly higher amounts of TG than livers from WT or apoa5 knockout mice suggesting that apoA-V influences intrahepatic TG levels. Show less

Apolipoprotein A-V (apo A-V) exerts a potent triglyceride (TG)-lowering effect through enhanced intravascular TG-hydrolysis with increased uptake of TG-derived free fatty acids into muscle and adipose tissue. Genetic variants in the APOA5 gene were strongly associated with plasma TG concentrations. The aim of this study was to examine whether APOA5 genetic variation was associated with obesity. We genotyped the missense c.553 G>T polymorphism (p.G185C) in the APOA5 gene in 1,085 Chinese (333 obese subjects and 752 nonobese controls). We analyzed the association between the c.553 G>T polymorphism and obesity and related metabolic phenotypes. The T allele at the c.553 G>T polymorphism was associated with higher plasma TG concentrations. Each additional T allele was associated with an increased TG concentration of 53.5 mg/dl (95% confidence interval (CI) 29.6-76.0, P < 0.0001). However, the T allele was associated lower risk of obesity (odds ratio (OR), 0.48; 95% CI 0.32-0.73, P = 0.0004). Each additional copy of the T allele was associated with a BMI decrease of 0.73 kg/m(2) (95% CI 0.26-1.16, P = 0.002), equivalent to 2.11 kg in a person 1.7 m tall. We may then conclude that the TG-raising APOA5 genetic variant was associated with a decrease in BMI and reduced risk of obesity in the Chinese population. Show less

The orphan nuclear receptor Nur77 (NR4A1) has been reported to play a crucial role in the modulation of diverse metabolic processes in liver. Here, we reported the identification of human apolipoprotein A5 (ApoA5), which implicated in lowering plasma triglyceride levels, as a novel target gene of Nur77. Nur77 induced the human ApoA5 promoter activity. Using 5'-deletion and mutagenesis of human ApoA5 promoter analysis and chromatin immunoprecipitation assays, it was shown that Nur77 directly regulated human ApoA5 gene expression by binding to a Nur77 response element (AAAGGTCA) located in the proximal human ApoA5 promoter region. In addition, we demonstrated that blocking of Nur77 transcriptional activity via overexpression of dominant negative Nur77 suppressed human ApoA5 promoter activity and mRNA expression in human hepatoma cells, HepG2. Taken together, our results demonstrated that Nur77 is a novel regulator of human ApoA5 gene expression and provide a new insight into the role of this orphan nuclear receptor in lipoprotein metabolism and triglyceride homeostasis. Show less

Hypertriglyceridemia is associated insulin resistance in obese people. Recently identified apolipoprotein A5 (apoA5) is involved in triglyceride (TG) metabolism. This study was to investigate the role of apoA5 in insulin resistance-related hypertriglyceridemia in obesity. 682 participants including 340 non-obese individuals and 342 obese individuals were recruited in this study. Plasma apoA5 levels were measured. The insulin resistance in participants was assessed by homeostasis model assessment of insulin resistance (HOMA-IR). An insulin resistant and hypertriglyceridemic rat model was established by high-fructose diet with obese Zucker rats as positive controls. Besides, two insulin resistant models in vitro were induced by insulin and tumor necrosis factor-alpha (TNFalpha) in HepG2 cells. Obese participants had lower plasma apoA5 levels. Plasma apoA5 levels were inversely correlated with TG, body mass index and HOMA-IR in humans. Furthermore, hepatic and plasma apoA5 reduced in fructose-fed rats whereas no significant changes of apoA5 were observed in obese Zucker rats. In addition, treatment of HepG2 cells with insulin and TNFalpha decreased apoA5 expression and increased TG content. Thus, decreased apolipoprotein A5 is implicated in insulin resistance-related hypertriglyceridemia in obesity. Show less

To analyze single nucleotide polymorphisms (SNP) of primary open angle glaucoma- and metabolic syndrome-related genes in primary open angle glaucoma (POAG), in order to elucidate the roles of metabolic syndrome as a risk factor in POAG progress. SNP genotypes and alleles of interleukin-6 (IL-6), IL-6 receptor (IL-6R), dopamine D(2) receptor (DRD(2)), beta-fibrinogen (FGB), peroxisome proliferator-activated receptor-γ2 (PPARG), transforming growth factor-β1 (TGF-β1), E-selectin (E-Sel), apolipoprotein A-5 (APOA5), C-reactive protein (CRP), ectonueleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), hepatic lipase (LIPC), adiponectin (ADIPOQ), paraoxonase 1 (PON1) and serine protease inhibitor E (SERPINE1) genes in POAG (n=37) and normal control (n=100) groups were measured with ABI Prism 7900HT Fluorescence Quantitative PCR and TaqMan SNP Genotyping fluorescence probe kit. Genotypes and allele frequencies of IL-6R, IL-6, FGB, CRP, ENPP1, LIPC, ADIPOQ, PON1, and SERPINE1 in total POAG group were significantly different compared to the control group. Metabolic syndrome as a risk factor for POAG may be associated with genotypes and allele frequencies of the related genes. The corresponding gene expression and function can affect POAG progress, including roles of SERPINE1 in extracellular matrix, ENPP1 in insulin inhibition, IL-6 in endogenous neuroprotection, IL-6, IL-6R and E-Sel in autoimmune response, LIPC and FGB in blood hyperviscosity syndrome, ADIPOQ in NOS/NO production, PON1 in vascular endothelial protection. Show less

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. Show less

USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined. We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated. Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects. Show less

Both the natural variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein gene (GCKR) have been shown to associate with increased fasting triglyceride levels. Here, we investigated the possible association of the functional variants of these two genes with non-fasting triglyceride levels and their susceptibility nature in ischemic stroke. A total of 513 stroke patients and 172 healthy controls were genotyped. All the APOA5 variants (T-1131C, IVS3 + G476A, C56G, and T1259C) were associated with increased triglyceride levels in all stroke patients and controls; except for T1259C, they all conferred risk for the disease. No such association was found for the examined GCKR rs1260326 (C1337T) variant. Furthermore, we examined the effects of specific combinations of the GCKR rs1260326 and APOA5 polymorphisms. Our findings confirmed the previous results regarding the association of APOA5 variants with triglyceride-level increase and stroke susceptibility of these alleles. By contrast, we could not detect any association of the studied GCKR allele with triglyceride levels or with the susceptibility of stroke in the same cohort of patients. In addition, the effect of APOA5 did not change significantly when specific combinations of the two genes were present. Show less

In recent studies, the T-1131C variant of apolipoprotein A5 (APOA5) gene was found to confer a risk for metabolic syndrome (MS). Here we determined four haplotype-tagging polymorphisms (T-1131C, IVS3+G476A, T1259C, and C56G), and studied the distribution of the naturally occurring major haplotype profiles in MS. A total of 343 MS patients and 284 controls were genotyped using PCR-RFLP methods. Both in MS and control groups, we confirmed the already known association of -1131C, IVS3+473A and 1259C minor alleles with elevated triglyceride levels. The prevalence of the APOA5*2 haplotype (the combination of T-1131C, IVS3+G476A and T1259C SNPs) was 13.1% in MS patients, and 4.9% in controls (p<0.001); multiple logistic regression analysis revealed that this haplotype confers risk for the development of MS (OR=2.880; 95% CI: 1.567-5.292; p=0.001). We also observed a gender effect: in males a more prominent degree of susceptibility was found. Contrary to the APOA5*2 haplotype, the prevalence rate of APOA5*4 (determined by the T-1131C SNP alone) did not differ between MS patients and controls. We identified a novel haplotype, designated here as APOA5*5 (1259C allele alone); which appears to be protective against MS. Our results refined the role of SNP T-1131C in the development of MS. The susceptibility nature of this SNP is limited to the APOA5*2 haplotype, while in APOA5*4 haplotype it did not confer a risk for the disease. In addition, as our current data suggest, the novel APOA5*5 haplotype can confer protection against MS. Show less

Apolipoprotein A5 (APOA5) and lipoprotein lipase (LPL) proteins interact functionally to regulate lipid metabolism, and single-nucleotide polymorphisms (SNPs) for each gene have also been associated independently with obesity risk. Evaluating gene combinations may be more effective than single SNP analyses in identifying genetic risk, but insufficient minor allele frequency (MAF) often limits evaluations of potential epistatic relationships. Populations with multiple ancestral admixtures may provide unique opportunities for evaluating genetic interactions. We examined relationships between LPL m107 (rs1800590) and APOA5 S19W (rs3135506) and lipid and anthropometric measures in Caribbean origin Hispanics (n = 1,019, aged 45-75 years) living in the Boston metropolitan area. Significant interaction terms between LPL m107 and APOA5 S19W were observed for BMI (P = 0.003) and waist circumference (P = 0.019). Higher BMI (P = 0.001), waist (P = 0.011) and hip (P = 0.026) circumference were observed in minor allele (G) carriers for LPL m107 who also carried the APOA5 S19W minor allele (G). Additionally, extreme obesity (BMI > or = 40 kg/m(2)) risk was higher (odds ratio = 4.02; 95% confidence interval: 1.81-8.91; global P = 0.008) for minor allele carriers for both SNPs (LPL TG+GG, APOA5 CG+GG) compared to major allele carriers for both SNPs. In summary, we identified significant interactions for APOA5 S19W and LPL m107 for obesity in Caribbean Hispanics. Population-specific MAFs increase the difficulties of replicating gene-gene interactions, but may support the hypothesis that combinations of frequencies in selected genes could heighten obesity susceptibility in a given population. Analyses of gene-gene interactions may improve understanding of genetically based obesity risk, and underscore the need for further study of groups with multiple ancestral admixtures. Show less

To provide phenotypic and functional data in new patients with APOA5 mutations and to identify genetic and metabolic factors influencing their phenotypic expression. By sequencing APOA5 gene in a cohort of 286 hyperchylomicronemic subjects, free of LPL or APOC2 mutations, we identified 4 unrelated carriers of the Q97X mutation (3 heterozygotes and 1 homozygote) and one heterozygote with a new L242P mutation. Postheparin LPL activity level was reduced by about 50% in Q97X heterozygotes and more than 90% in the Q97X homozygote, but was normal in the L242P patient after resolution of hyperchylomicronemia. Plasma apoAV was undetectable in the Q97X homozygote and in the normal range in the L242P and Q97X heterozygous carriers. In Western blot studies, the association of apoAV with plasma lipoproteins was altered in Q97X heterozygous carriers but not in the L242P carrier. Hyperchylomicronemic heterozygotes for both mutations carried an additional APOA5 variant haplotype and/or APOE variant (E2 or E4). Type 2 diabetes or metabolic syndrome were not a major phenotypic determinant. The L242P mutation was present in a hyperchylomicronemic proband but its causal involvement remains to be established. The Q97X mutation was clearly involved in hyperchylomicronemia with evidence of concomitant altered intravascular lipolysis, and a complete apoAV deficiency in the homozygote. The phenotypic expression variability of APOA5 mutations was mostly influenced by compound heterozygosity with APOA5 variant haplotypes plus additional genetic factors, and in a lesser extent by the metabolic environment. Show less

The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5. We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55-74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an additive model adjusting for age and sex and the definition for metabolic syndrome from the National Cholesterol Education Program's Adult Treatment Panel III (NCEP (AIII)) including medication. The overall prevalence for metabolic syndrome was 41%. Two SNP combinations showed a nominal gene-gene interaction (p values 0.024 and 0.047). The effect of one SNP was modified by the other SNP, with a lower risk for the metabolic syndrome with odds ratios (ORs) between 0.33 (95% CI = 0.13-0.83) and 0.40 (95% CI = 0.15-1.12) when the other SNP was homozygous for the minor allele. Nevertheless, none of the associations remained significant after correction for multiple testing. Thus, there is an indication of an interaction between APOA5 and USF1 on the risk for metabolic syndrome. Show less

APOA5 -1131T > C and S19W single nucleotide polymorphisms (SNP) have been consistently associated with plasma lipid concentration and metabolic syndrome (MetS), alone and in modulation by dietary factors. Puerto Ricans have a high prevalence of metabolic conditions and high minor allele frequency for these SNP, suggesting a possible role in disease for this population. We aimed to determine the association of APOA5 -1131T > C and S19W with plasma lipids and markers of MetS, alone and in interaction with total fat intake, as a percent of total energy intake, in Puerto Ricans. Anthropometric and demographic data, FFQ, and blood samples were collected at baseline from participants in the Boston Puerto Rican Health Study (n = 802, 45-75 y). APOA5 S19W was associated with plasma HDL cholesterol (HDL-C) (P = 0.044); minor allele carriers had lower HDL-C [1.12 +/- 0.03 (mean +/- SE)] than those with the common variant (1.18 +/- 0.01 mmol/L), even after adjustment for plasma triglycerides (TG) (P = 0.012). Neither polymorphism was associated with TG or other lipids. Interaction of the -1131T > C SNP with total fat energy intake was observed for plasma TG (P = 0.032) and total cholesterol (P = 0.034). APOA5 S19W interacted with total fat intake in association with systolic (P = 0.002) and diastolic (P = 0.007) blood pressure. Neither SNP was associated with MetS in the overall analysis or after stratifying by total energy intake as fat. In conclusion, Puerto Ricans present a distinctive lipid profile in association with APOA5 polymorphisms. Dietary fat intake seems to modulate these associations. The results contribute to the understanding of health disparities in this population. Show less

The N-terminal 146 residues of apolipoprotein (apo) A-V adopt a helix bundle conformation in the absence of lipid. Because similarly sized truncation mutants in human subjects correlate with severe hypertriglyceridemia, the lipid binding properties of apoA-V(1-146) were studied. Upon incubation with phospholipid in vitro, apoA-V(1-146) forms reconstituted high density lipoproteins 15-17 nm in diameter. Far UV circular dichroism spectroscopy analyses of lipid-bound apoA-V(1-146) yielded an alpha-helix secondary structure content of 60%. Fourier transformed infrared spectroscopy analysis revealed that apoA-V(1-146) alpha-helix segments align perpendicular with respect to particle phospholipid fatty acyl chains. Fluorescence spectroscopy of single Trp variant apoA-V(1-146) indicates that lipid interaction is accompanied by a conformational change. The data are consistent with a model wherein apoA-V(1-146) alpha-helices circumscribe the perimeter of a disk-shaped bilayer. The ability of apoA-V(1-146) to solubilize dimyristoylphosphatidylcholine vesicles at a rate faster than full-length apoA-V suggests that N- and C-terminal interactions in the full-length protein modulate its lipid binding properties. Preferential association of apoA-V(1-146) with murine plasma HDL, but not with VLDL, suggests that particle size is a determinant of its lipoprotein binding specificity. It may be concluded that defective lipoprotein binding of truncated apoA-V contributes to the hypertriglyceridemia phenotype associated with truncation mutations in human subjects. Show less

Lipase maturation factor 1 (LMF1) gene is a novel candidate gene in severe hypertriglyceridemia. Lmf1 is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in endoplasmic reticulum. To date only one patient with severe hypertriglyceridemia and related disorders was found to be homozygous for a nonsense mutation in LMF1 gene (Y439X). The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded. The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G>A substitution in exon 9 (c.1395G>A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The proband's son, heterozygous for the W464X, shows normal plasma triglyceride levels. We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described. Show less

Combining statin and fibrate in clinical practice provides a greater reduction of triglycerides than either drug given alone, but the mechanism for this effect is poorly understood. Apolipoprotein AV (apoAV) has been implicated in triglyceride metabolism. This study was designed to investigate the effect of the combination of statin and fibrate on apoAV and the underlying mechanism(s). Hypertriglyceridaemia was induced in rats by giving them 10% fructose in drinking water for 2 weeks. They were then treated with atorvastatin, fenofibrate or the two agents combined for 4 weeks, and plasma triglyceride and apoAV measured. We also tested the effects of these two agents on triglycerides and apoAV in HepG2 cells in culture. Western blot and reverse transcription polymerase chain reaction was used to measure apoAV and peroxisome proliferator-activated receptor-alpha (PPARalpha) expression. The combination of atorvastatin and fenofibrate resulted in a greater decrease in plasma triglycerides and a greater increase in plasma and hepatic apoAV than either agent given alone. Hepatic expression of the PPARalpha was also more extensively up-regulated in rats treated with the combination. A similar, greater increase in apoAV and a greater decrease in triglycerides were observed following treatment of HepG2 cells pre-exposed to fructose), with the combination. Adding an inhibitor of PPARalpha (MK886) abolished the effects of atorvastatin on HepG2 cells. A combination of atorvastatin and fenofibrate increased apoAV and decreased triglycerides through up-regulation of PPARalpha. Show less

To explore the relationship between serum apolipoprotein A5 (ApoA5) and lipid profile or high sensitive C-reactive protein (hs-CRP) in patients with acute coronary syndrome (ACS). Serum apoA5 and hs-CRP levels were measured by ELISA and immunoturbidimetry in control subjects (n = 232), patients with stable angina (SA, n = 127), unstable angina (UA, n = 116) and acute myocardial infarction (AMI, n = 112). Triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were also measured. Compared with controls [(108.7 +/- 23.2) microg/L] and SA patients [(78.3 +/- 20.2) microg/L], serum ApoA5 level was significantly increased in UA [(340.6 +/- 63.5) microg/L] and AMI patients [(373.2 +/- 73.8) microg/L] (all P < 0.05). ApoA5 was positively correlated with TG (r = 0.63 and 0.67, respectively, all P < 0.05) and hs-CRP (r = 0.57 and 0.55, respectively, all P < 0.05) in UA and AMI patients but there were no significant correlations between ApoA5 and TC, HDL-C and LDL-C in ACS patients (all P > 0.05). Increased serum apoA5 level and the positive correlation between ApoA5 and serum TG and hs-CRP in ACS patients might reflect increased inflammation responses in ACS patients. Show less

Common polymorphism of the apolipoprotein A5 gene (APOA5, c.553G>T) related to metabolic syndrome components, insulin resistance, and carotid atherosclerosis remains unclear. We investigated the associations of the APOA5 c.553G>T gene with various metabolic syndrome components and carotid artery atherosclerosis among family members. A total of 661 participants who provided complete genotyping and carotid artery measures were included in this study. Participants with APOA5 c.553T carrier (GT and TT) were more likely to have higher levels of triglycerides and apolipoprotein B, as well as lower levels of high-density lipoprotein (HDL) cholesterol, than participants with the GG genotype. Individuals who carried T alleles had an increased risk of a high level of triglycerides (multivariate odds ratio [OR], 3.86; 95% confidence interval [CI], 1.98-7.55; P<0.0001) and low levels of HDL cholesterol (OR, 2.32; 95% CI, 1.40-3.86; P=0.0012) compared with those without T alleles. The age was an effect modifier for the association between APOA5 genotype and smoking, alcohol drinking, obesity, and lipid profiles, including total, HDL, and low-density lipoprotein (LDL) cholesterol; triglycerides; and apolipoproteins. In addition, the association between APOA5 genotype and hypertriglyceridemia was significant only in adult groups (OR, 3.53; 95% CI, 1.79-6.94), and the association between APOA5 genotype and low HDL cholesterol was stable in young adolescents (OR, 2.39; 95% CI, 1.19-4.78) and adults (OR, 2.20; 95% CI, 1.17-4.15). Our findings indicated that the APOA5 c.553G>T polymorphism is associated with high triglycerides and low HDL cholesterol but not with other metabolic syndrome components or carotid atherosclerosis in this ethnic Chinese population. Show less

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie--to an apparently even greater degree--susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples. Show less

The effects of dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), on lipid metabolism were examined. Young male Wistar rats were fed diets containing paprika powder, paprika organic solvent extract, residue of paprika extract, and purified capsanthin. Administration of purified capsanthin for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P < 0.05) without detectable differences in plasma total cholesterol and TAG concentrations. A statistically significant correlation (r 0.567; P < 0.001) was found between dietary capsanthin concentrations and plasma HDL-cholesterol concentrations. Animals receiving diets containing two different capsanthin concentrations exhibited dose-dependent increases in plasma HDL-cholesterol (r 0.597; P < 0.005). While capsanthin was absent in the liver of animals fed the basal diet, it increased markedly in capsanthin-fed animals (P < 0.001). Quantitative analyses of hepatic mRNA levels revealed that capsanthin administration resulted in up-regulation of mRNA for apoA5 and lecithin cholesterol acyltransferase (LCAT), without significant differences in other mRNA levels related to HDL-cholesterol metabolism. These results suggest that capsanthin had an HDL-cholesterol-raising effect on plasma, and the potential to increase cholesterol efflux to HDL particles by increasing apoA5 levels and/or enhancement of LCAT activity. Show less