10 research outputs found

    Lack of association between apolipoprotein C3 gene polymorphisms and risk of coronary heart disease in a Han population in East China

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    <p>Abstract</p> <p>Background</p> <p>Several polymorphisms in the apolipoprotein C3 (APOC3) gene have been found association with hypertriglyceridemia(HTG), but the link with coronary heart disease(CHD) risk between ethnicities was still controversial. Among them, reseachers paid more attentions to the promoter polymorphisms T-455C and C-482T because both of them located in insulin-responsive element (IRE) and insulin was thought to exert its action by down-regulating APOC3 gene expression. The aim of this study was to investigate the association of the two polymorphisms of APOC3 with CHD in a Han population in East China.</p> <p>Methods</p> <p>TaqMan SNP Genotyping Assays were carried out to detect the genotypes of APOC3 gene, including the T-455C and C-482T, in 286 subjects with CHD and 325 controls without CHD. The levels of serum lipid profiles were also detected by biochemical methods.</p> <p>Results</p> <p>There was no difference of genotype frequencies and allele frequencies between the CHD population and the controls(P > 0.05). Compared with the most common genotype -455TT or -482CC, the variants had neither significantly increased CHD risk, nor the lipid variables showed any statistically relevant differences in the research population. The adjusted OR of CHD were 5.67 [0.27-18.74] and 0.75 [0.20-2.73] in carriers of the APOC3 -455C and -482T variants, respectively(P > 0.05). There was also no significant difference in APOC3 haplotype distribution in CHD and controls, but there was a strong linkage disequilibrium between T-455C and C-482T with D' = 0.9293, 0.8881, respectively(P < 0.0001).</p> <p>Conclusions</p> <p>Our data did not support a relationship between the two polymorphisms of APOC3 gene and risk of CHD in the Han population in East China.</p

    Interactions of the apolipoprotein C-III 3238C>G polymorphism and alcohol consumption on serum triglyceride levels

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    <p>Abstract</p> <p>Background</p> <p>Both apolipoprotein (Apo) C-III gene polymorphism and alcohol consumption have been associated with increased serum triglyceride (TG) levels, but their interactions on serum TG levels are not well known. The present study was undertaken to detect the interactions of the ApoC-III 3238C>G (rs5128) polymorphism and alcohol consumption on serum TG levels.</p> <p>Methods</p> <p>A total of 516 unrelated nondrinkers and 514 drinkers aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoC-III 3238C>G was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Interactions of the ApoC-III 3238C>G genotype and alcohol consumption was assessed by using a cross-product term between genotypes and the aforementioned factor.</p> <p>Results</p> <p>Serum total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C), ApoA-I and ApoB levels were higher in drinkers than in nondrinkers (<it>P </it>< 0.05-0.001). There was no significant difference in the genotypic and allelic frequencies between the two groups. Serum TG levels in nondrinkers were higher in CG genotype than in CC genotype (<it>P </it>< 0.01). Serum TC, TG, low-density lipoprotein cholesterol (LDL-C) and ApoB levels in drinkers were higher in GG genotype than in CC or CG genotype (<it>P </it>< 0.01 for all). Serum HDL-C levels in drinkers were higher in CG genotype than in CC genotype (<it>P </it>< 0.01). Serum TC, TG, HDL-C and ApoA-I levels in CC genotype, TC, HDL-C, ApoA-I levels and the ratio of ApoA-I to ApoB in CG genotype, and TC, TG, LDL-C, ApoA-I and ApoB levels in GG genotype were higher in drinkers than in nondrinkers (<it>P </it>< 0.05-0.01). But the ratio of ApoA-I to ApoB in GG genotype was lower in drinkers than in nondrinkers (<it>P </it>< 0.01). Multivariate logistic regression analysis showed that the levels of TC, TG and ApoB were correlated with genotype in nondrinkers (<it>P </it>< 0.05 for all). The levels of TC, LDL-C and ApoB were associated with genotype in drinkers (<it>P </it>< 0.01 for all). Serum lipid parameters were also correlated with age, sex, alcohol consumption, cigarette smoking, blood pressure, body weight, and body mass index in both groups.</p> <p>Conclusions</p> <p>This study suggests that the ApoC-III 3238CG heterozygotes benefited more from alcohol consumption than CC and GG homozygotes in increasing serum levels of HDL-C, ApoA-I, and the ratio of ApoA-I to ApoB, and lowering serum levels of TC and TG.</p

    Genetics of metabolic syndrome and related traits

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    In this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that obesity is the most important trigger of metabolic impairment, the MetS definition in this thesis was chosen to include the obesity measure waist circumference as an essential component. In the study described in chapter 2, the heritability of the metabolic syndrome was addressed and compared to the heritability of its individual components. Since the individual components of MetS were shown to be more heritable than MetS itself, the studies described in chapter 3 and 4 focused on the genetics of the individual MetS component plasma TG. For this purpose, a candidate gene approach was employed using HTG patients and healthy controls. The involvement of a series of candidate genes was confirmed. The study described in chapter 5 followed a similar approach to that used in the studies described in chapter 3 and 4. Several candidate genes were studied in patients suffering from hyperlipoproteinemia (HLP) type III, which is characterized by elevated levels of total plasma cholesterol and plasma TG. HLP type III is characterized by APOE2 homozygosity. Contributing genetic factors in the (metabolically stressed) APOE2/2 environment were confirmed. Plasma adiponectin, an adipose tissue secreted hormone (adipokine), has been suggested to be a biomarker for MetS. In chapter 6 we describe a study which particularly aimed to determine the effect of menopause on the discriminating accuracy of adiponectin to predict MetS. Especially low levels of plasma adiponectin in postmenopausal women were found to be a risk for MetS. However, the discriminating accuracy of adiponectin for the presence of MetS was exceeded by BMI in men and pre __and post menopausal women. Since plasma adiponectin levels are very well correlated with MetS components or related traits, the study described in chapter 7 addressed the question whether these correlations are caused by a genetic overlap (genetic correlation). The genetic correlation was mono-laterally validated with regard to the adiponectin gene (ADIPOQ). Chapter 8 describes a study towards finding novel loci associated with adiponectin or loci that are possibly involved in the genetic overlap between adiponectin and MetS components or related traits. This study followed a genome-wide association (GWA) approach. The results of this GWA were used in a joined analysis with two other cohorts in a meta-analysis. In addition, a selected proportion of SNPs was submitted for replication in several cohorts. Chapter 9 provides a general discussion by reviewing all previous chapters in the thesis. Furthermore, chapter 9 includes suggestions and proposals for future analyses towards unraveling genetic and environmental factors involved in the expression and manifestation of metabolic risk factors.UBL - phd migration 201


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    Dyslipidemia has a complex pathophysiology consisting of various genetic, lifestyle, and environmental factors. It has many adverse health impacts, notably in the development of chronic non-communicable diseases. Significant ethnic differences exist due to the prevalence and types of lipid disorders. While elevated serum total- and LDL-cholesterol are the main concern in Western populations, in other countries hypertriglyceridemia and low HDL-cholesterol are more prevalent. The latter types of lipid disorders are considered as components of the metabolic syndrome. The escalating trend of obesity, as well as changes in lifestyle and environmental factors will make dyslipidemia a global medical and public health threat, not only for adults but for the pediatric age group as well. Several experimental and clinical studies are still being conducted regarding the underlying mechanisms and treatment of dyslipidemia. The current book is providing a general overview of dyslipidemia from diverse aspects of pathophysiology, ethnic differences, prevention, health hazards, and treatment

    Development and validation of gold nanoprobes for human SNP detection towards commercial application

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    Conventional molecular techniques for detection and characterization of relevant nucleic acid (i.e. DNA) sequences are, nowadays, cumbersome, expensive and with reduced portability. The main objective of this dissertation consisted in the optimization and validation of a fast and low-cost colorimetric nanodiagnostic methodology for the detection of single nucleotide polymorphisms (SNPs). This was done considering SNPs associated to obesity of commercial interest for STAB VIDA, and subsequent evaluation of other clinically relevant targets. Also, integration of this methodology into a microfluidic platform envisaging portability and application on points-of-care (POC) was achieved. To warrant success in pursuing these objectives, the experimental work was divided in four sections: i) genetic association of SNPs to obesity in the Portuguese population; ii) optimization and validation of the non-cross-linking approach for complete genotype characterization of these SNPs; iii) incorporation into a microfluidic platform; and iv) translation to other relevant commercial targets. FTO dbSNP rs#:9939609 carriers had higher body mass index (BMI), total body fat mass, waist perimeter and 2.5 times higher risk to obesity. AuNPs functionalized with thiolated oligonucleotides (Au-nanoprobes) were used via the non-cross-linking to validate a diagnostics approach against the gold standard technique - Sanger Sequencing - with high levels of sensitivity (87.50%) and specificity (91.67%). A proof-of-concept POC microfluidic device was assembled towards incorporation of the molecular detection strategy. In conclusion a successful framework was developed and validated for the detection of SNPs with commercial interest for STAB VIDA, towards future translation into a POC device

    Insulin pathway and its correlation with ageing and longevity

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    Ageing is unavoidable and leads to the reduction of the ability to adapt to the environment, involving the organism at all levels. Approximately 25% of the overall variation in human lifespan can be attributed to genetic factors, which become more relevant for extreme longevity. A \u201cfavourable\u201d genetic background is essential to live longer. Longevity depends on the survival after reproduction and genes that lead to longevity are \u201csurvival genes\u201d rather than \u201clongevity genes\u201d. But human population is very heterogeneous because of the different genetic background and different environmental stimuli thus it has not been yet possible to identify a clear panel of biomarkers of ageing and longevity. However, the correlation between nutritional, hormonal and immune-inflammatory pathways is particularly evident. The aim of my PhD was to explore the mechanisms that drive ageing and longevity focusing the attention on the role of insulin/IGF-1 pathway and of inflammatory mechanisms. In particular, the attention was focused on IGF-1, IGF-1 receptor, Forkhead box O (FOXO) 3A, Silent mating type information regulation 1, KLOTHO and SHIP2, all molecules directly or indirectly involved in the above mentioned pathway. Through reviews we explored the literature to summarize the existing data up to date. With systematic reviews and meta-analyses we identified some genetic variants associated with ageing and longevity . Moreover, we conducted a case-control study to verify the association of two SNPs of SHIP2 with T2DM and AD. The results confirmed previous studies about the association between FOXOA3A, IGF-1R and longevity but no association was reported between IGF-1 and SIRT1 (for the analyzed SNPs). This would be consistent with the hypothesis that most longevity genes have modest or small effect sizes. Moreover, we observed sex-specific differences in the association of the genetic variation with survival during old age. About KLOTHO, the KL-VS variant was associated with healthy ageing and longevity. This association was limited to KL-VS heterozygous people because the KL-VS homozygous undergoes to a detrimental effect of the polymorphism indicating a possible association mechanism not related to the gene dose. We also found an association of an insertion/deletion of 28 base pairs in INPPL1 that encodes for SHIP2 with ageing, both successfully and unsuccessfully. Moreover, it could be speculated that a reduction in insulin signaling may reduce the activation of NF-kB thus slow down the transcription of inflammatory genes. Hence, we agreed that a down regulation of this pathway can increase lifespan in human leading to \u201chealthspan\u201d and healthy longevity. Moreover, we agreed that inflammatory pathways have a crucial role, as well. Indeed, as previously discussed for the Sicilian population, there was an association between SNPs responsible for a low production of inflammatory mediators and longevity

    Identification of novel loci affecting human disorders of iron homeostasis and their effect on lipid metabolism

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    2013/2014Il ferro è un elemento fondamentale per molti processi di cellule e tessuti ma è potenzialmente tossico e un eccesso può danneggiare diversi componenti cellulari. A livello fisiologico il ferro circolante è regolato da segnali da pathway che lo consumano e da cellule che lo forniscono. Il principale ormone regolatore epcidina agisce insieme al recettore cellulare ferroportina nel controllare l’assorbimento con la dieta, l’immagazzinamento e la distribuzione del ferro nel flusso sanguigno. Disturbi genetici che colpiscono i componenti del pathway così altamente regolato possono causare serie malattie nell’uomo come l’emocromatosi ereditaria e l’anemia sideropenia refrattaria al ferro (IRIDA) principalmente causate da mutazioni note nei geni HFE e TMPRSS6. Gli studi descritti in questa tesi hanno lo scopo di evidenziare varianti nuove e causative che hanno un ruolo nella regolazione del pathway di ecpidina-ferroportina per spiegare l’effetto delle variazioni di ferro e le basi molecolari dell’insorgenza dei disturbi genetici del ferro nell’uomo. Studi di associazione sull’intero genoma (GWAS) sono stati condotti sui valori quantitativi di epcidina, parametri del ferro e tratti eritroidi misurati nell’ampia popolazione della Val Borbera che include 1785 individui genotipizzati da un isolato genetico italiano. Il principale risultato mostra che l’associazione di HFE e TMPRRS6 ai tratti eritroidi dipendono in maggior parte dal totale di ferro disponibile e non da un effetto diretto di HFE e TMPRSS6. I livelli di epcidina sono stati associati alle variazioni in HFE e TMPRSS6 e una prima ampia meta-analisi condotta su circa 6,000 individui VBI e olandesi ha evidenziato 2 nuovi loci associati significativamente (p<5x10-8) all’epcidina: il primo sul cromosoma 10 vicino al gene FOXI2 e il secondo sul cromosoma 2 nel gene EML6 e vicino a SPTBN1 (alias ELF). SPTBN1 è un gene interessante in quanto essenziale nel signaling TGF-β mediante le proteine SMAD, una delle quali svolge un ruolo anche nella regolazione della trascrizione dell’epcidina. Per identificare ulteriori loci che hanno un ruolo nell’omeostasi del ferro è stata condotta un’ampia meta-analisi sui marcatori clinici dello stato del ferro su 48,000 individui di origine europea in collaborazione con il consorzio australiano per lo studio genetico del ferro (GIS): lo studio mostra associazioni più significative ed effetto pleiotropico dei geni noti del ferro HFE, TF, TFR2 and TMPRSS6 e cinque nuovi geni associati a livello Bonferroni (ABO, ARNTL, FADS2, NAT2, TEX14). In particolare la trasferrina è associata a NAT2 precedentemente associato a disturbi dei lipidi e a rischio cardiovascolare e FADS2 le cui variazioni hanno un effetto su diversi fenotipi come gli acidi grassi, il glucosio nel sangue e gli enzimi del fegato. I risultati mostrano una forte correlazione tra omeostasi del ferro e metabolismo dei lipidi nell’uomo e quindi il ferro potrebbe avere un ruolo nell’insorgenza dei disturbi cardiovascolari. I risultati confermano che l’isolato della Val Borbera ha costituito un modello della popolazione generale adatto a studi genetici su malattie comuni. Per aumentare la possiblità di trovare varianti rare e causative sfruttando i vantaggi e le caratteristiche delle popolazioni isolate, la coorte della Val Borbera e gli altri isolati genetici italiani si sono riuniti in un progetto che utilizza le tecniche innovative di sequenziamento dell’intero genoma allo scopo di creare un pannello di riferimento ricco di sequenze italiane rare e di altà qualità per ulteriori studi genetici sul ferro, epcidina e altri tratti di rischio.Iron is a key element for cellular and tissue processes. It is also potentially toxic and excess iron can damage various cellular components. At physiological levels circulating iron is regulated by signals from pathways that use iron and from cells that supply iron. The main iron-regulatory hormone hepcidin and its receptor iron channel ferroportin play a critical role controlling the dietary absorption, storage, and tissue distribution of iron through the bloodstream. Genetic disorders that affect the components of the tightly regulated hepcidin-ferroportin pathway could cause severe pathologies in humans as hereditary hemocromatosis and iron-refractory iron-deficiency anemia or IRIDA mainly caused respectively by mutation in two known loci, HFE and TMPRSS6. The studies described in this thesis aimed at highlighting novel and causative variants in loci that have a role in the regulation of hepcidin-iron pathway to explain the effect of unbalanced iron in humans and the molecular basis of the onset of genetic iron disorders. First, genome-wide association studies (GWAS) have been carried out on quantitative hepcidin, iron parameters and erythrocyte traits measured in the population of Val Borbera (VBI) that includes 1785 genotyped individuals from an Italian genetic isolate. The main result showed that association of HFE and TMPRSS6 to erythroid traits is mostly dependent on the amount of iron available and not a direct effect of HFE and TMPRSS6 variants. Hepcidin levels have been associated to HFE and TMPRSS6 variations and a first large meta-analysis, performed on 6,000 VBI and Dutch individuals, revealed two novel loci associated to hepcidin at genome-wide significance (p<5x10-8): the first on chromosome 10, near the gene FOXI2 and the second signal on chromosome 2 in the EML6 gene and near SPTBN1 (alias ELF). SPTBN1 is an interesting gene as it is essential in TGF-β signaling by SMAD proteins and one of the SMADs is involved in hepcidin transcription regulation. To identify additional loci affecting iron homeostasis, a large international meta-analysis on the serum biomarkers commonly used to determine the clinical iron status has been carried out in 48,000 European ancestry individuals in collaboration with Australian Genetic Iron Status (GIS) Consortium: the study showed more significant associations and pleiotropic effect for known loci as HFE, TF, TFR2 and TMPRSS6 and five novel associated loci at significant levels (ABO, ARNTL, FADS2, NAT2, TEX14). In particular, transferrin is associated to NAT2, previously associated to lipids affections and cardiovascular risk, and to FADS2 that affects several phenotypes as lipids fatty acids, fasting glucose and liver enzyme. The results highlighted a strong correlation between iron homeostasis and lipid metabolism in humans that could have implication on the onset of cardiovascular disorders. The Val Borbera genetic isolate has represented a suitable model for genetic study on common disease. To increase the power of detection of rare and causative variants and to take advantage of the characteristics of genetic isolates, VBI and other Italian isolated populations are now involved in an innovative whole-genome sequencing (WGS) project with the aim to create an Italian specific panel enriched in lower-frequency high-quality variants to be used in further genetic analysis on iron parameters, hepcidin and other traits.XXVII Ciclo198

    Abdominal obesity and hyperglycemia mask the effect of a common APOC3 haplotype on the risk of myocardial infarction

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    Background: Plasma apolipoprotein (apo) C-III strongly predicts myocardial infarction (MI) and directly activates atherogenic processes in vascular cells. Genetic variation in the insulin response element of the APOC3 promoter is associated with an increased risk of MI. Objective: The objective was to determine whether the APOC3 promoter variation affects plasma apo C-III concentrations and MI only when insulin sensitivity is normal. Design: The APOC3*222 haplotype, defined by the minor alleles of the single nucleotide polymorphisms 3238C→G, −455T→C, and −482C→T, was studied in 1703 matched nonfatal case-control pairs with MI in the Central Valley of Costa Rica. We used fasting hyperglycemia and abdominal obesity as surrogates for insulin sensitivity. Results: The APOC3*222 haplotype was associated with higher apo C-III concentrations only in those with the lowest waist circumference or fasting glucose concentration. The association between the APOC3*222 haplotype and nonfatal MI, previously reported in this population, was strongly influenced by fasting hyperglycemia and abdominal obesity. The odds ratios for MI for the APOC3*222 haplotype were 1.72 (95% CI: 1.16, 2.54) and 1.84 (1.31, 2.59) in subjects in the lowest quintiles of abdominal obesity and fasting hyperglycemia, respectively, and were 0.75 (0.54, 1.05) and 1.16 (0.85, 1.59) in subjects in the highest quintiles, respectively (P for interaction <0.05). Conclusion: The results support the concept that mutations in the APOC3 promoter inhibit the down-regulation of APOC3 expression by insulin. This cardioprotective system becomes dysfunctional in abdominal obesity and hyperglycemia.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Centro Centroamericano de Población (CCP

    Antioxidant and DPPH-Scavenging Activities of Compounds and Ethanolic Extract of the Leaf and Twigs of Caesalpinia bonduc L. Roxb.

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    Antioxidant effects of ethanolic extract of Caesalpinia bonduc and its isolated bioactive compounds were evaluated in vitro. The compounds included two new cassanediterpenes, 1α,7α-diacetoxy-5α,6β-dihydroxyl-cass-14(15)-epoxy-16,12-olide (1)and 12α-ethoxyl-1α,14β-diacetoxy-2α,5α-dihydroxyl cass-13(15)-en-16,12-olide(2); and others, bonducellin (3), 7,4’-dihydroxy-3,11-dehydrohomoisoflavanone (4), daucosterol (5), luteolin (6), quercetin-3-methyl ether (7) and kaempferol-3-O-α-L-rhamnopyranosyl-(1Ç2)-β-D-xylopyranoside (8). The antioxidant properties of the extract and compounds were assessed by the measurement of the total phenolic content, ascorbic acid content, total antioxidant capacity and 1-1-diphenyl-2-picryl hydrazyl (DPPH) and hydrogen peroxide radicals scavenging activities.Compounds 3, 6, 7 and ethanolic extract had DPPH scavenging activities with IC50 values of 186, 75, 17 and 102 μg/ml respectively when compared to vitamin C with 15 μg/ml. On the other hand, no significant results were obtained for hydrogen peroxide radical. In addition, compound 7 has the highest phenolic content of 0.81±0.01 mg/ml of gallic acid equivalent while compound 8 showed the highest total antioxidant capacity with 254.31±3.54 and 199.82±2.78 μg/ml gallic and ascorbic acid equivalent respectively. Compound 4 and ethanolic extract showed a high ascorbic acid content of 2.26±0.01 and 6.78±0.03 mg/ml respectively.The results obtained showed the antioxidant activity of the ethanolic extract of C. bonduc and deduced that this activity was mediated by its isolated bioactive compounds