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Les anomalies du métabolisme des lipoprotéines riches en triglycérides (LRTG), les chylomicrons et les VLDL exposent à des hypocholestérolémies lors d'un défaut de sécrétion et à des hypertriglycéridémies (HTG) majeures entraînant un risque athéromateux et de pancréatites aigües lors de l'altération de leur clairance. Nous avons diagnostiqué des patients présentant un défaut génétique de sécrétion des LRTG au décours de maladie de rétention des chylomicrons, d'abetalipoprotéinémie et d'hypobetalipoprotéinémie homozygote, causées respectivement par des mutations sur les gènes SAR1B, MTTP et APOB. Nous avons étudié le phénotype des 158 patients publiés avec mutation délétère et mis en évidence des différences portant principalement sur la stéatose hépatique, l'insulinorésistance et l'obésité. Nous avons également mis au point une méthode d'évaluation de l'activité post héparinique de la lipoprotéine lipase (LPL) par mesure de la lipolyse des triglycérides des VLDL in vitro, permettant l'exploration phénotypique des patients présentant une HTG sévère. Nous avons mis en évidence des activités LPL augmentées chez des patients présentant pourtant des antécédents d'HTG sévère et des déficits chez des patients ne présentant pas de mutation identifiable du gène LPL, laissant supposer l'existence de facteurs additionnels modulant l'expression ou l'activité de la LPL. Enfin des interrelations des multiples gènes impliqués dans le métabolisme des triglycérides modulent le phénotype. Elles soulèvent l'intérêt de l'exploration simultanée des principaux gènes impliqués dans les dyslipidémies, telle qu'elle sera effectuée par NGS, pour une meilleure compréhension de leur physiopathologie / Abnormal metabolism of triglyceride-rich lipoproteins (LRTG), chylomicrons and VLDL, can result in hypocholesterolemia in case of impaired secretion, or severe hypertriglyceridemia (HTG) and increased risk of atheroma and acute pancreatitis if clearance is affected. We explored patients suffering from genetic defect in the LRTG secretion (chylomicron retention disease, abetalipoproteinemia and homozygous hypobetalipoproteinemia) and identified mutations on respectively SAR1B, and MTTP and APOB gene. Then, we analysed the phenotype of 158 previously published patients with deleterious mutation (i.e. reported cases added to our cohort) and were able to highlight some specific differences like hepatic steatosis, insulin resistance and obesity. Furthermore we developed an assay to evaluate the lipoprotein lipase (LPL) functionality by measuring the triglyceride-VLDL lipolysis in vitro, and provide a reliable phenotypic exploration for patients with past history of severe hypertriglyceridemia. We found an increased LPL activity in some patients with severe hypertriglyceridemia but conversely showed deficits in other patients free from mutation on LPL gene. These results lead to hypothesize that additional factors might contribute to modulate the expression or the activity of LPL. Finally multiple genes of triglycerides metabolism interact together to additionally modulate phenotype. Of high interest is therefore the simultaneous exploration of the key genes involved in dyslipidemia, as provided by the new generation sequencing (NGS), for better understanding of all pathophysiological mechanisms

INTRODUCTION : Il a été démontré que le nombre de lipoprotéines apolipoprotéine B (apoB) est un prédicteur du développement du diabète de type 2 (DT2), mais le mécanisme est inconnu. La résistance à l'insuline (RI) et l'hyperinsulinémie compensatoire (HI) entraînent l’épuisement des cellules β et la progression vers le DT2. De plus, l'activation du système de l'interleukine -1β (IL- 1β) est impliquée dans la pathophysiologie du DT2. Notre objectif était donc d'étudier si l’apoB est associé à la RI et à l’HI chez les humains et si cette corrélation est médiée par l’activation du système IL-1β. MÉTHODOLOGIE : 47 femmes ménopausées, non diabétiques, obèses ou en surpoids et 28 hommes, âgés de 45 à 74 ans ont été recrutés. La sécrétion d'insuline (SI) et la sensibilité à l'insuline ont été mesurées par un clamp Botnia modifié. La 1ère et 2ème phase de SI furent mesurées lors d'un test de tolérance au glucose intraveineux (IVGTT) d’une heure, suivi d’un clamp hyperinsulinémique euglycémique (HEIC) de 3 heures (taux de perfusion d'insuline de 75 mU/m2/min) pour mesurer la sensibilité à l'insuline lors des 30 dernières minutes du clamp (état d'équilibre). La sensibilité à l'insuline est exprimée comme étant le taux de perfusion de glucose (GIR) seul ou divisé par le taux d’insuline à l’état d’équilibre (M/I). RÉSULTATS : Chez les femmes, l’apoB à jeun corrélait avec une augmentation de la 2e phase de SI, la SI totale et la sécrétion totale de C-peptide (r=0,202; r=0,168; r=0,204) et avec une diminution de la sensibilité à l'insuline (GIR r=-0,299; M/I r=-0,180) indépendamment de l'adiposité. L’IL-1Ra à jeun (indicateur de l’activation du système IL-1β) corrélait positivement avec la 2e phase, la SI totale et la sécrétion totale de C-peptide (r=0,217; r=0,154; r=0,198) et négativement avec la sensibilité à l'insuline (GIR r=-0,304; M/I r=-0,214). L’IL-1Ra était également corrélée avec l'apoB (r=0,352). Une fois corrigé pour l'IL-1Ra, toutes les associations entre l'apoB et les indices de sensibilité à l'insuline et de SI ont été perdues. Malgré des glycémies similaires, il n’y avait pas de corrélation de l’apoB avec les indices mesurés chez les hommes. CONCLUSION : L’apoB est associé à l’HI et la RI chez les femmes non diabétiques obèses et en surpoids, potentiellement via l'activation du système IL-1β. Ces différences sexuelles doivent être prises en compte dans l'exploration de la physiopathologie du DT2. / INTRODUCTION: The number of plasma apolipoprotein B lipoproteins (apoB) is reported to predict the development of type 2 diabetes (T2D); however the underlying mechanism is unknown. Insulin resistance (IR) and compensatory hyperinsulinemia (HI) are believed to promote β-cell exhaustion and progression to T2D. Moreover, the activation of the interleukin-1β (IL-1β) system is implicated in the pathophysiology of T2D. Our aim was thus to investigate whether plasma apoB associates with IR and HI in humans and whether this is mediated through the IL-1β system. METHODOLOGY: 47 non-diabetic overweight and obese postmenopausal women and 28 men, 45-74 years old were recruited. Insulin secretion (IS) and insulin sensitivity were examined by a modified Botnia clamp. 1st and 2nd phase IS were measured during a 1 hour intravenous glucose tolerance test (IVGTT), followed by a 3 hour hyperinsulinemic-euglycemic clamp (HEIC, insulin infusion rate of 75 mU/m2/min) to measure insulin sensitivity during the last 30 minutes of the clamp (steady state). Insulin sensitivity was expressed as steady state glucose infusion rate (GIR) alone or divided over steady state plasma insulin (M/I). RESULTS: In women, fasting plasma apoB correlated positively with increased 2nd phase and total IS and with total C-peptide secretion (r=0.202; r=0.168; r=0.204 respectively) and negatively with insulin sensitivity (r: GIR= -0.299 and M/I =-0.180) independent of adiposity. Similar to plasma apoB, fasting plasma IL-Ra (indicator of activated IL-1β system) correlated positively with 2nd phase and total IS and with total C-peptide secretion (r=0.217; r=0.154; r=0.198 respectively) and negatively with insulin sensitivity (GIR r=-0.304; M/I r=-0.214). Fasting plasma IL-Ra also correlated with apoB r=0.352). Once corrected for IL-1Ra, the associations between apoB and the indexes of insulin sensitivity and IS were all lost. Despite similar fasting glucose, plasma apoB did not correlate with any indices of insulin secretion or sensitivity in men. CONCLUSION: ApoB is associated with HI and IR in non-diabetic overweight and obese women, which may be mediated through activation of the IL-1β system. Gender differences may need to be considered in exploring the pathophysiology of T2D in humans.

Made available in DSpace on 2017-07-21T19:59:57Z (GMT). No. of bitstreams: 1 Lucia Hoffmann.pdf: 1860358 bytes, checksum: d1a047a5d9cc402bd848a17fc42409b4 (MD5) Previous issue date: 2012-12-14 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Apolipoprotein B (apoB) is the principal protein from low density lipoprotein (LDL) involved in cholesterol metabolism and transport. Single nucleotide polymorphisms (SNPs) in the human apoB gene have been associated with cardiovascular disease risk, such as Coronary Artery Disease (CAD), dyslipidemia and atherosclerosis. These multifactorial diseases are generated by interaction between environmental and genetic factors. Previous works investigated the genetic causative components of these diseases and focused mainly on polymorphisms that occur in genes encoding structural proteins and enzymes related to lipid profile. The present study aimed to investigate the MspI polymorphism in the apoB gene association with cardiovascular risk factors in a case-control patients group from the Campos Gerais region (Paraná, Brazil) population, moreover to determine this polymorphism allele and genotype frequencies, and also to associate the obtained genetic data with cardiac risk related variables by using correlation analysis. We evaluated 66 patients, from which 55 patients formed the cardiovascular risk group, and 11 others composed the group without risk – control. The patients mean age was 60 ± 10.0 years in the group with risk and 53 ± 14.0 years in the control group. The MspI polymorphism (exon 26) on apoB gene was characterized by PCR-RFLP and, after restriction, DNA fragments were identified by electrophoresis using agarose gel. The normal allele was named M1 and the mutated allele was called M2. The obtained values for MspI polymorphism genotypic frequencies were 0.82, 0.09, 0.09 for the control group, and 0.76, 0.24, 0.00 for the CAD risk group, respectively for genotypes M1M1, M1M2, M2M2. It was showed that the M1M1 homozygous was dominant in the genotype distribution for both groups. There was no significant difference between the allele and genotype frequencies for MspI polymorphism in the apoB gene (2 = 5.90, P > 0.05; Contingency Test) when comparing the two groups. Therefore, the distribution of the studied polymorphism in the Campos Gerais region population presented to be in Hardy-Weinberg equilibrium both for the control group and for the CAD risk patients group, keeping stable the polymorphism, what was already previously reported for Chinese and Korean populations. The Pearson correlation analysis performed between the risk variables (age, diabetes mellitus, high LDL, high triglycerides, low HDL, hypothyroidism, weight, body mass index) showed correlation between the most of the variables for M1M1 and M1M2 genotypes. But for the total population (n = 66), the association of the apoB gene polymorphism was not correlated with cardiac risk variables. In the end, this research presented data for understanding the association of apoB gene polymorphism with lipid metabolism disorder in the development of risk factors for cardiovascular disease in the population of Campos Gerais (PR). / A apolipoproteína B (apoB) é a principal proteína da lipoproteína de baixa densidade (LDL) que está envolvida no transporte e metabolismo do colesterol. Polimorfismos de único nucleotídeo (SNPs) no gene da apoB humana têm sido associados ao risco para doenças cardiovasculares, como a Doença Arterial Coronariana (DAC), as dislipidemias e a aterosclerose. Estas doenças são caracterizadas como multifatoriais, causadas pela interação entre fatores ambientais e genéticos. Estudos de investigação dos componentes genéticos causadores destas doenças têm focado principalmente em polimorfismos nos genes que codificam proteínas estruturais e enzimas relacionadas ao perfil lipídico. Este trabalho teve como objetivo investigar a associação do polimorfismo MspI no gene da apoB com os fatores de risco cardiovascular em um grupo de pacientes caso-controle na população da Região dos Campos Gerais (Paraná, Brasil), além de determinar as frequências alélicas e genotípicas deste polimorfismo, e associar os dados genéticos obtidos com as variáveis relacionadas aos riscos cardíacos através da análise de correlação. Foram avaliados 66 pacientes, dos quais 55 compuseram o grupo com risco cardiovascular, e os 11 demais formaram o grupo sem risco – controle. A idade média dos pacientes foi de 60 ± 10,0 anos no grupo com risco e 53 ± 14,0 anos no grupo controle. O polimorfismo MspI (exon 26) no gene da apoB foi caracterizado por PCR-RFLP, sendo os fragmentos de DNA, após a restrição, identificados por eletroforese em gel de agarose. O alelo normal foi denominado M1 e o alelo mutado M2. As frequências genotípicas encontradas para o polimorfismo MspI foram 0,82, 0,09 e 0,09 para o grupo controle; e 0,76, 0,24 e 0,00 para o grupo de pacientes com risco, respectivamente para os genótipos M1M1, M1M2 e M2M2. O homozigoto M1M1 foi predominante na distribuição genotípica para ambos os grupos. Não houve diferença significativa entre as frequências genotípicas e alélicas do polimorfismo MspI no gene da apoB (2 = 5,90; P > 0,05; Teste de Contingência), quando comparados os 2 grupos em estudo. Assim, a distribuição do polimorfismo estudado na população da região dos Campos Gerais (PR) se mostrou no equilíbrio de Hardy-Weinberg, tanto no grupo controle quanto no grupo de pacientes com risco cardíaco, mantendo o polimorfismo estável, sendo estes resultados também relatados para as populações chinesa e coreana. Na análise de correlação de Pearson entre as variáveis de risco (idade, diabetes mellitus, LDL alto, triglicerídios alto, HDL baixo, hipotireoidismo, peso, índice de massa corporal), observou-se que a maioria das variáveis analisadas se correlacionaram para os genótipos M1M1 e M1M2. Já para a população total estudada (n = 66), a associação do polimorfismo gênico da apoB não apresentou correlação com as variáveis de risco cardíaco. Enfim, esta pesquisa apresentou dados para o entendimento da associação do polimorfismo do gene da apoB com o distúrbio de metabolismo lipídico no desenvolvimento de fatores de risco para doenças cardiovasculares na população dos Campos Gerais (PR).

Abdominal aortic aneurysm (AAA) is a devastating disease that exhibits permanent lumen expansion typically in the infrarenal aorta. AAA is prevalent among aged population, especially in males. Despite the incidence in women is lower, studies indicate the tortuosity is more severe and aortic rupture risk is higher in women. In most patients, AAA remains asymptomatic until it ruptures leading to sudden and fatal hemorrhage. To date, there is no proven medical therapy that can prevent the expansion or rupture. Human observational studies implicate the presence of AAA is associated with both high plasma low-density lipoprotein-cholesterol (HDL-C) and low plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. To examine the role of specific lipoproteins in development of AAA, angiotensin (Ang) II-induced AAA was firstly determined in apolipoprotein AI deficient (apoAI -/-) mice in both C57BL/6 and LDL receptor deficient (LDL receptor -/-) backgrounds. The deletion of apoAI led to a significant decrease of HDL-C concentrations. However, we were unable to define any exacerbation of AngII-induced AAA in either normo- or hyperlipidemic mice with apoAI deficiency. Next we compared AngII-induced AAA formation using multiple mouse strains with dietary manipulation to generate different severities of hypercholesterolemia. We demonstrated the apolipoprotein B (apoB)-containing lipoproteins promoted the development of AngII-induced AAA. Moreover, ezetimibe administration significantly reduced both apoB-containing lipoproteins and AAA formation. Together, our studies demonstrate that elevated apoB-containing lipoproteins, contribute to the development of AngII-induced AAA. To investigate the role of apoB-containing lipoproteins on established AAA, male LDL receptors -/- mice fed a Western diet were infused with AngII for 4 weeks to induced AAA. Then mice with AAA were stratified into either a group maintained on western diet or switched to a normal diet. AngII infusion was continued for an additional 8 weeks. The diet switch resulted in significantly reduced plasma cholesterol concentrations, which was attributable to the decrease of apoB-containing lipoproteins. We found a profound inhibition of aneurysm progression in diet switched mice associated with attenuated macrophage accumulation and medial thickening. Collectively, our data demonstrate that apoB-containing lipoproteins promote the progression of established AAA.

Les marqueurs de risque cardio-vasculaire peuvent être améliorés par des recommandations nutritionnelles à l’échelle d’une population, mais la réponse à ces régimes varie entre les individus, variabilité partiellement due aux polymorphismes génétiques. Les objectifs de ce travail étaient d’étudier l’association entre la réponse à un régime suivi pendant 3 mois et certains polymorphismes des gènes de l’apolipoprotéine B (-516C/T) et de l’apolipoprotéine E (epsilon et -219G/T).Le régime alimentaire (diminution des lipides totaux et remplacement des acides gras saturés par des acides gras mono- et poly-insaturés) a été suivi par 69 hommes et 100 femmes (âge moyen 51±10 ans) dont le risque cardio-vasculaire était modéré (Score de Framingham 5,93 ± 3,17).Dans ce travail, nous montrons que, après 3 mois de régime, les marqueurs de risque cardio-vasculaire ont été améliorés dans la population totale, mais que la réponse au régime variait en fonction du polymorphisme -516C/T d’ApoB des sujets étudiés. En effet, les sujets homozygotes pour l’allèle T ne modifiaient pas les taux plasmatiques de cholestérol et de glucose ainsi que les paramètres postprandiaux, déjà bas à l’inclusion.De son côté, les 2 polymorphismes de l’ApoE ne modulaient pas la réponse au régime mais étaient associés à l’insulinorésistance des sujets dès l’inclusion. En effet, les sujets porteurs de l’allèle epsilon 4 et de l’allèle -219T présentaient une insulinémie à jeun 70 % plus élevée que les sujets homozygotes pour l’allèle epsilon 3 et pour l’allèle T.Ce travail montre que le terrain génétique pourrait expliquer en partie la variabilité de réponse aux régimes recommandés. / Cardiovascular risk markers have been obviously improved at the population level by the widespread use of public dietary guidelines. Nevertheless a large variability, questionably linked to genetic polymorphism, is observed between individual responses. The aim of this study was to evaluate the influence of a polymorphism at the apolipoprotein B locus (-516C/T) and 2 polymorphisms at the apolipoprotein E locus (epsilon and -219G/T) on cardiovascular risk markers in response to a dietary intervention targeted at reducing total fat intake together with a partial replacement of saturated FA by mono/polyunsaturated FA.69 men and 100 women (mean age 51±10 y), displaying at baseline a moderate cardiovascular risk (Framingham score 5,93 ± 3,17), followed this diet for 3 months and improved biological markers for cardiovascular risk. But individual responses to the diet differed according to genotype concerning ApoB-516C/T polymorphism. While most individuals greatly improved biological risk markers, homozygous subjects for the T allele did not modify cholesterol, glucose and post-prandial parameters, parameters that were already low at the inclusion.Concerning the ApoE locus, we showed that both polymorphims did not modify the response to the diet, but were associated with insulin resistance measured at the inclusion. Indeed, subjects carrying both the epsilon 4 and the -219T allele, displayed a 70% higher insulinemia than subjects homozygous for the epsilon 3 and for the -219T allele.In conclusion, this work shows that the genetic background may at least in part account for the individual variability that is observed in the response to a diet.

No description available.

Dislipidemia é uma desordem multifatorial causada pela interação entre fatores ambientais e genéticos. A identificação dos componentes genéticos responsáveis por essas características tem sido intensamente investigada nos últimos anos. Esses estudos têm enfocado principalmente polimorfismos nos genes que codificam proteínas estruturais e enzimas relacionadas ao metabolismo dos lipídios. Sendo assim, este trabalho teve como objetivos avaliar as freqüências dos polimorfismos EcoRI, TaqI, S447X, -250G>A dos genes APOB, CETP, LPL e LIPC e investigar a interação desses polimorfismos com dados clínicos, bioquímicos e antropométricos em 119 pacientes dislipidêmicos, de uma amostra da população de Porto Alegre. Para analisar os genótipos de cada polimorfismo e sua possível influência sobre a eficácia ao tratamento com estatinas foram analisados 48 pacientes dislipidêmicos. As medidas dos níveis lipídicos foram verificadas ao longo do estudo. Utilizou-se a técnica de PCRRFLP para a realização das análises de biologia molecular. O polimorfismo -250G>A foi associado significativamente com os níveis de HDL-C. Para análises não ajustadas, os portadores do alelo G aumentaram mais o nível de HDL-C (P=0,004) que os indivíduos homozigotos AA, considerando que o genótipo AA apresentou níveis de TG mais elevados (P=0,017) que os indivíduos com genótipo GG ou GA. Para níveis de TG esses resultados mantiveram-se para análises ajustadas, com elevados níveis de TG para indivíduos com genótipo AA em comparação aos indivíduos com genótipo GG ou GA (P=0,073). Diferenças entre os genótipos no percentual de variação nos níveis lipídicos foram observadas para os polimorfismos LIPC e LPL. Depois de ajustadas por covariáveis, os indivíduos com genótipo GA ou AA apresentaram uma redução maior do nível de CT, comparados com os indivíduos com o genótipo GG (-26,4% ± 15,5 vs. -18,2% ± 11,8, P=0,034). Para análises não ajustadas, os indivíduos com o alelo G do polimorfismo LPL S447X mostraram um aumento dos níveis de HDL-C comparados com os indivíduos com o genótipo CC (13,8% VS. 3,3%, P=0,047). Depois de ajustadas por covariáveis, a significância do efeito desse polimorfismo foi observada para o nível de CT. O percentual da média de redução no nível de CT foi maior nos indivíduos homozigotos CC que os indivíduos com o alelo G (-26,6% ± 13,6 vs -20,5% ±13,6, P=0,046). Nossos dados sugerem uma associação do polimorfismo LIPC -250G>A com níveis de HDL-C e TG, para análises não ajustadas, mas para análises não ajustadas por covariáveis a associação manteve-se para níveis de TG. Nós também encontramos associação significante dos polimorfismos LIPC -250G>A e LPL S447X na resposta ao tratamento com estatinas. Esses resultados podem ser explicados através de vários fatores, tais como: gênero, estrogênio, IMC e outras variáveis que possam interferir no efeito dos polimorfismos sobre os níveis lipídicos e resposta ao tratamento. / Dyslipidemia is a multifactorial disorder caused by an interaction between genetic and environmental factors. The identification of the genetic component of this traits have been intensively investigated in the last year. These studies focused mainly on polymorphism in genes coding for structural proteins and enzymes related to lipid metabolism. Therefore, in the present study, we investigated the frequencies of the polymorphisms EcoRI, TaqIB, S447X and (-250G>A) of the APOB, CETP, LPL and LIPC genes with clinical, biochemical, anthropometrics data of the one hundred and nineteen patients with dyslipidemia in a sample of Southern Brazilian population. To determine the genotype association with response to statin treatment, only 48 individuals were enrolled for analysis. Plasma lipids and lipoproteins were measured before and throughout the study. PCR-RFLP method was used for molecular biology analysis. Plasma lipids and lipoproteins were measured before and throughout the study. Baseline lipid and lipoprotein parameters were compared among APOB EcoRI, CETP TaqIB, LPL S447X (G>C) and LIPC -250G>A genotypes after genotyping by PCR and restriction mapping. Data from forty-eight patients with statin treatment were used to pharmacogenetic statistical analyses. The LIPC -250G>A polymorphism was significantly associated with HDL-C. For unadjusted levels, carriers of the G allele had higher HDL-C concentrations (P=0.004) than AA homozygotes, whereas AA genotype had higher TG concentrations (P=0.073) than GG and GA genotypes. For TG levels the same results were observed for adjusted data, with higher TG concentrations in AA homozygotes than GG and GA genotypes (P=0.017). Differences among genotypes in the percentage variation in lipid and lipoprotein concentrations for LIPC and LPL polymorphism were observed. After adjustment for covariates, GA and AA carriers genotypes showed a greater reduction in total cholesterol compared than GG genotype (-26.4% ± 15.5 vs. -18.2% ± 11.8, P=0.034). For unadjusted data, G allele carriers for LPL S447X gene polymorphism showed a greater HDLcholesterol increase compared to CC subjects (13.8% vs. 3.3%, P = 0.047). After adjustment for covariates, a significant effect of this polymorphism was observed for change in TC levels. The mean percent reduction in TC was greater in CC homozygotes than in G carriers (-26.6% ± 13.6 vs. -20.5% ± 13.6, P=0.046). Our data suggest an association of LIPC -250G>A gene polymorphism with HDL-C and TG concentrations for unadjusted data, but not after adjustment for covariates. For TG concentrations the associations was maintained after adjustment. We also found a significant effect dependent of covariates of LIPC and LPL polymorphisms on statin treatment response. These results can be explained on the basis of there being several factors such as gender, estrogens, BMI and other variables that can modulate the effect of gene polymorphisms on the lipid in lipoprotein concentration and treatment response.

Dislipidemia é uma desordem multifatorial causada pela interação entre fatores ambientais e genéticos. A identificação dos componentes genéticos responsáveis por essas características tem sido intensamente investigada nos últimos anos. Esses estudos têm enfocado principalmente polimorfismos nos genes que codificam proteínas estruturais e enzimas relacionadas ao metabolismo dos lipídios. Sendo assim, este trabalho teve como objetivos avaliar as freqüências dos polimorfismos EcoRI, TaqI, S447X, -250G>A dos genes APOB, CETP, LPL e LIPC e investigar a interação desses polimorfismos com dados clínicos, bioquímicos e antropométricos em 119 pacientes dislipidêmicos, de uma amostra da população de Porto Alegre. Para analisar os genótipos de cada polimorfismo e sua possível influência sobre a eficácia ao tratamento com estatinas foram analisados 48 pacientes dislipidêmicos. As medidas dos níveis lipídicos foram verificadas ao longo do estudo. Utilizou-se a técnica de PCRRFLP para a realização das análises de biologia molecular. O polimorfismo -250G>A foi associado significativamente com os níveis de HDL-C. Para análises não ajustadas, os portadores do alelo G aumentaram mais o nível de HDL-C (P=0,004) que os indivíduos homozigotos AA, considerando que o genótipo AA apresentou níveis de TG mais elevados (P=0,017) que os indivíduos com genótipo GG ou GA. Para níveis de TG esses resultados mantiveram-se para análises ajustadas, com elevados níveis de TG para indivíduos com genótipo AA em comparação aos indivíduos com genótipo GG ou GA (P=0,073). Diferenças entre os genótipos no percentual de variação nos níveis lipídicos foram observadas para os polimorfismos LIPC e LPL. Depois de ajustadas por covariáveis, os indivíduos com genótipo GA ou AA apresentaram uma redução maior do nível de CT, comparados com os indivíduos com o genótipo GG (-26,4% ± 15,5 vs. -18,2% ± 11,8, P=0,034). Para análises não ajustadas, os indivíduos com o alelo G do polimorfismo LPL S447X mostraram um aumento dos níveis de HDL-C comparados com os indivíduos com o genótipo CC (13,8% VS. 3,3%, P=0,047). Depois de ajustadas por covariáveis, a significância do efeito desse polimorfismo foi observada para o nível de CT. O percentual da média de redução no nível de CT foi maior nos indivíduos homozigotos CC que os indivíduos com o alelo G (-26,6% ± 13,6 vs -20,5% ±13,6, P=0,046). Nossos dados sugerem uma associação do polimorfismo LIPC -250G>A com níveis de HDL-C e TG, para análises não ajustadas, mas para análises não ajustadas por covariáveis a associação manteve-se para níveis de TG. Nós também encontramos associação significante dos polimorfismos LIPC -250G>A e LPL S447X na resposta ao tratamento com estatinas. Esses resultados podem ser explicados através de vários fatores, tais como: gênero, estrogênio, IMC e outras variáveis que possam interferir no efeito dos polimorfismos sobre os níveis lipídicos e resposta ao tratamento. / Dyslipidemia is a multifactorial disorder caused by an interaction between genetic and environmental factors. The identification of the genetic component of this traits have been intensively investigated in the last year. These studies focused mainly on polymorphism in genes coding for structural proteins and enzymes related to lipid metabolism. Therefore, in the present study, we investigated the frequencies of the polymorphisms EcoRI, TaqIB, S447X and (-250G>A) of the APOB, CETP, LPL and LIPC genes with clinical, biochemical, anthropometrics data of the one hundred and nineteen patients with dyslipidemia in a sample of Southern Brazilian population. To determine the genotype association with response to statin treatment, only 48 individuals were enrolled for analysis. Plasma lipids and lipoproteins were measured before and throughout the study. PCR-RFLP method was used for molecular biology analysis. Plasma lipids and lipoproteins were measured before and throughout the study. Baseline lipid and lipoprotein parameters were compared among APOB EcoRI, CETP TaqIB, LPL S447X (G>C) and LIPC -250G>A genotypes after genotyping by PCR and restriction mapping. Data from forty-eight patients with statin treatment were used to pharmacogenetic statistical analyses. The LIPC -250G>A polymorphism was significantly associated with HDL-C. For unadjusted levels, carriers of the G allele had higher HDL-C concentrations (P=0.004) than AA homozygotes, whereas AA genotype had higher TG concentrations (P=0.073) than GG and GA genotypes. For TG levels the same results were observed for adjusted data, with higher TG concentrations in AA homozygotes than GG and GA genotypes (P=0.017). Differences among genotypes in the percentage variation in lipid and lipoprotein concentrations for LIPC and LPL polymorphism were observed. After adjustment for covariates, GA and AA carriers genotypes showed a greater reduction in total cholesterol compared than GG genotype (-26.4% ± 15.5 vs. -18.2% ± 11.8, P=0.034). For unadjusted data, G allele carriers for LPL S447X gene polymorphism showed a greater HDLcholesterol increase compared to CC subjects (13.8% vs. 3.3%, P = 0.047). After adjustment for covariates, a significant effect of this polymorphism was observed for change in TC levels. The mean percent reduction in TC was greater in CC homozygotes than in G carriers (-26.6% ± 13.6 vs. -20.5% ± 13.6, P=0.046). Our data suggest an association of LIPC -250G>A gene polymorphism with HDL-C and TG concentrations for unadjusted data, but not after adjustment for covariates. For TG concentrations the associations was maintained after adjustment. We also found a significant effect dependent of covariates of LIPC and LPL polymorphisms on statin treatment response. These results can be explained on the basis of there being several factors such as gender, estrogens, BMI and other variables that can modulate the effect of gene polymorphisms on the lipid in lipoprotein concentration and treatment response.

Dislipidemia é uma desordem multifatorial causada pela interação entre fatores ambientais e genéticos. A identificação dos componentes genéticos responsáveis por essas características tem sido intensamente investigada nos últimos anos. Esses estudos têm enfocado principalmente polimorfismos nos genes que codificam proteínas estruturais e enzimas relacionadas ao metabolismo dos lipídios. Sendo assim, este trabalho teve como objetivos avaliar as freqüências dos polimorfismos EcoRI, TaqI, S447X, -250G>A dos genes APOB, CETP, LPL e LIPC e investigar a interação desses polimorfismos com dados clínicos, bioquímicos e antropométricos em 119 pacientes dislipidêmicos, de uma amostra da população de Porto Alegre. Para analisar os genótipos de cada polimorfismo e sua possível influência sobre a eficácia ao tratamento com estatinas foram analisados 48 pacientes dislipidêmicos. As medidas dos níveis lipídicos foram verificadas ao longo do estudo. Utilizou-se a técnica de PCRRFLP para a realização das análises de biologia molecular. O polimorfismo -250G>A foi associado significativamente com os níveis de HDL-C. Para análises não ajustadas, os portadores do alelo G aumentaram mais o nível de HDL-C (P=0,004) que os indivíduos homozigotos AA, considerando que o genótipo AA apresentou níveis de TG mais elevados (P=0,017) que os indivíduos com genótipo GG ou GA. Para níveis de TG esses resultados mantiveram-se para análises ajustadas, com elevados níveis de TG para indivíduos com genótipo AA em comparação aos indivíduos com genótipo GG ou GA (P=0,073). Diferenças entre os genótipos no percentual de variação nos níveis lipídicos foram observadas para os polimorfismos LIPC e LPL. Depois de ajustadas por covariáveis, os indivíduos com genótipo GA ou AA apresentaram uma redução maior do nível de CT, comparados com os indivíduos com o genótipo GG (-26,4% ± 15,5 vs. -18,2% ± 11,8, P=0,034). Para análises não ajustadas, os indivíduos com o alelo G do polimorfismo LPL S447X mostraram um aumento dos níveis de HDL-C comparados com os indivíduos com o genótipo CC (13,8% VS. 3,3%, P=0,047). Depois de ajustadas por covariáveis, a significância do efeito desse polimorfismo foi observada para o nível de CT. O percentual da média de redução no nível de CT foi maior nos indivíduos homozigotos CC que os indivíduos com o alelo G (-26,6% ± 13,6 vs -20,5% ±13,6, P=0,046). Nossos dados sugerem uma associação do polimorfismo LIPC -250G>A com níveis de HDL-C e TG, para análises não ajustadas, mas para análises não ajustadas por covariáveis a associação manteve-se para níveis de TG. Nós também encontramos associação significante dos polimorfismos LIPC -250G>A e LPL S447X na resposta ao tratamento com estatinas. Esses resultados podem ser explicados através de vários fatores, tais como: gênero, estrogênio, IMC e outras variáveis que possam interferir no efeito dos polimorfismos sobre os níveis lipídicos e resposta ao tratamento. / Dyslipidemia is a multifactorial disorder caused by an interaction between genetic and environmental factors. The identification of the genetic component of this traits have been intensively investigated in the last year. These studies focused mainly on polymorphism in genes coding for structural proteins and enzymes related to lipid metabolism. Therefore, in the present study, we investigated the frequencies of the polymorphisms EcoRI, TaqIB, S447X and (-250G>A) of the APOB, CETP, LPL and LIPC genes with clinical, biochemical, anthropometrics data of the one hundred and nineteen patients with dyslipidemia in a sample of Southern Brazilian population. To determine the genotype association with response to statin treatment, only 48 individuals were enrolled for analysis. Plasma lipids and lipoproteins were measured before and throughout the study. PCR-RFLP method was used for molecular biology analysis. Plasma lipids and lipoproteins were measured before and throughout the study. Baseline lipid and lipoprotein parameters were compared among APOB EcoRI, CETP TaqIB, LPL S447X (G>C) and LIPC -250G>A genotypes after genotyping by PCR and restriction mapping. Data from forty-eight patients with statin treatment were used to pharmacogenetic statistical analyses. The LIPC -250G>A polymorphism was significantly associated with HDL-C. For unadjusted levels, carriers of the G allele had higher HDL-C concentrations (P=0.004) than AA homozygotes, whereas AA genotype had higher TG concentrations (P=0.073) than GG and GA genotypes. For TG levels the same results were observed for adjusted data, with higher TG concentrations in AA homozygotes than GG and GA genotypes (P=0.017). Differences among genotypes in the percentage variation in lipid and lipoprotein concentrations for LIPC and LPL polymorphism were observed. After adjustment for covariates, GA and AA carriers genotypes showed a greater reduction in total cholesterol compared than GG genotype (-26.4% ± 15.5 vs. -18.2% ± 11.8, P=0.034). For unadjusted data, G allele carriers for LPL S447X gene polymorphism showed a greater HDLcholesterol increase compared to CC subjects (13.8% vs. 3.3%, P = 0.047). After adjustment for covariates, a significant effect of this polymorphism was observed for change in TC levels. The mean percent reduction in TC was greater in CC homozygotes than in G carriers (-26.6% ± 13.6 vs. -20.5% ± 13.6, P=0.046). Our data suggest an association of LIPC -250G>A gene polymorphism with HDL-C and TG concentrations for unadjusted data, but not after adjustment for covariates. For TG concentrations the associations was maintained after adjustment. We also found a significant effect dependent of covariates of LIPC and LPL polymorphisms on statin treatment response. These results can be explained on the basis of there being several factors such as gender, estrogens, BMI and other variables that can modulate the effect of gene polymorphisms on the lipid in lipoprotein concentration and treatment response.