Déficit familial de la LCAT au Québec : description d’une première mutation et contribution du génotype de l’APO E sur le phénotype lipoprotéique

Le déficit familial de LCAT (FLD) est une maladie caractérisée par un défaut de l’activité de l’enzyme lecithin:cholesterol acyltransferase (LCAT). Ce défaut résulte en une concentration plasmatique de C-HDL extrêmement basse, des opacités cornéennes prématurées, la présence d’anémie, de protéinurie et d’insuffisance rénale. Nous avons identifié les premiers patients canadiens-français atteints de déficit familial de LCAT. Deux frères, présentant les signes classiques de FLD étaient homozygotes pour une nouvelle mutation du gène de la LCAT: la mutation c.102delG. Cette mutation se traduit au niveau protéique par un changement du cadre de lecture au niveau du codon His35 et l’insertion d’un codon stop en position 61 entraînant une abolition de l’activité LCAT in vitro et in vivo. La présence de cette mutation cause une réduction importante du C-HDL chez les hétérozygotes (22%) et les homozygotes (88%) ainsi qu’une baisse du C-LDL chez les hétérozygotes (35%) et les homozygotes (58%). De plus, le profil lipidique différait de manière importante entre les deux frères atteints de FLD qui présentaient des génotypes APOE différents. Nous suggérons que APOE est un gène qui modifie le phénotype du FLD et pourrait expliquer l’hétérogénéité des profils lipidiques chez les patients atteints de FLD. Nos résultats suggèrent également que l’association du génotype LCAT-/- a un allèle APOE ε2 est un nouveau mécanisme conduisant à la dysbétalipoproteinemie. Finalement nous avons montré des différences importantes dans les sous-populations des HDL chez les deux sujets atteints de FLD. Le porteur de l’allèle APOE ε2 présentait une proportion beaucoup plus importante de HDL immatures (preβ discoïdaux) par rapport a son frère (77.9% vs. 31.0%).Familial LCAT deficiency (FLD) is a disease characterized by a defect in the enzyme lecithin:cholesterol acyltransferase (LCAT) resulting in low HDL-C, premature corneal opacities, anaemia as well as proteinuria and renal failure. We have identified the first French Canadian kindred with familial LCAT deficiency. Two brothers, presenting classical signs of FLD, were shown to be homozygous for a novel LCAT mutation. This c.102delG mutation occurs at the codon for His35 and causes a frameshift that stops transcription at codon 61 abolishing LCAT enzymatic activity both in vivo and in vitro. It has a dramatic effect on the lipoprotein profile, with an important reduction of HDL-C in both heterozygotes (22%) and homozygotes (88%) and a significant decrease in LDL-C in heterozygotes (35%) as well as homozygotes (58%). Furthermore, the lipoprotein profile differs markedly between the two affected brothers who had different APOE genotypes. We propose that APOE could be an important modifier gene explaining heterogeneity in lipoprotein profiles observed among FLD patients. Our results suggest that a LCAT-/- genotype associated with an APOE ε2 allele could be a novel mechanism leading to dysbetalipoproteinemia. Finally we have identified major differences in the HDL sub-populations of both subjects affected by FLD. The carrier of the APOE ε2 allele presented a much higher proportion of immature HDL particles (discoid preβ) compared to his brother (77.9% vs. 31.0%)

L’influence des relations familiales et sociales sur la consommation de médicaments psychotropes chez les personnes âgées

Les psychotropes occupent le deuxième rang dans la consommation de médicaments chez les personnes âgées. L'objectif de cette étude est de vérifier un modèle explicatif de la consommation de psychotropes dans cette population. Notre principale hypothèse est que la qualité des relations qu'entretient une personne âgée avec autrui, et particulièrement avec ses enfants, a une influence directe sur son bien-être psychologique, lequel a une influence directe sur la non-consommation de psychotropes. Une enquête a été réalisée auprès d'un échantillon de 500 personnes âgées de 65 à 84 ans, vivant à domicile. Au cours des trois mois précédant l'entrevue, 31,8 % des répondants ont consommé des psychotropes. Les données empiriques n'ayant pas permis de vérifier le modèle théorique retenu, des analyses multivariées ont conduit à l'élaboration d'un modèle explicatif de la consommation qui met en évidence que le bien-être psychologique et la santé sont les meilleurs prédicteurs de cette consommation. Un bien-être psychologique élevé diminue la consommation alors qu'un mauvais état de santé l'augmente. Les relations sociales influencent directement le bien-être psychologique alors que les relations familiales ont un effet de moindre importance. Le modèle explicatif proposé explique 13 % du phénomène de la consommation de psychotropes chez les personnes âgées.Psychotropic drugs are the second most commonly used medication by Quebec's elderly. The objective of this study is to test a theoretical model of psychotropic drug use in the elderly. The principal hypothesis is that the quality of relationships the elderly person has with others, particularly with his or her children, has a direct influence on his or her psychological well-being, which, in turn, directly affects the consumption of psychotropic agents. A survey was conducted on a sample of 500 elderly people, aged 65-84 years, living at home. 31.8% of the respondents used psychotropic drugs during the three-month period preceding the interview. Path analysis led to the elaboration of a modified model for the consumption of psychotropic drugs by the elderly which indicates that the best predictors of consumption are both the psychological well-being and the state of health of the individual. More elevated is the psychological well-being, less is the consumption of psychotropic drugs, whereas poor health condition increases it. The quality of an individual's social relationships has a direct influence on his or her psychological well-being, whereas family relationships are of lesser importance. Our model accounts for 13% of the predictors of psychotropic consumption by the elderly

A Role for Cdc42 in Macrophage Chemotaxis

Three members of the Rho family, Cdc42, Rac, and Rho are known to regulate the organization of actin-based cytoskeletal structures. In Bac1.2F5 macrophages, we have shown that Rho regulates cell contraction, whereas Rac and Cdc42 regulate the formation of lamellipodia and filopodia, respectively. We have now tested the roles of Cdc42, Rac, and Rho in colony stimulating factor-1 (CSF-1)–induced macrophage migration and chemotaxis using the Dunn chemotaxis chamber. Microinjection of constitutively activated RhoA, Rac1, or Cdc42 inhibited cell migration, presumably because the cells were unable to polarize significantly in response to CSF-1. Both Rho and Rac were required for CSF-1–induced migration, since migration speed was reduced to background levels in cells injected with C3 transferase, an inhibitor of Rho, or with the dominant-negative Rac mutant, N17Rac1. In contrast, cells injected with the dominant-negative Cdc42 mutant, N17Cdc42, were able to migrate but did not polarize in the direction of the gradient, and chemotaxis towards CSF-1 was abolished

Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor

The translocation of fluorescently tagged PLC gamma and requirements for this process in cells stimulated with EGF were analyzed using real time fluorescence microscopy applied for the first time to monitor growth factor receptor-effector interactions. The translocation of PLC gamma to the plasma membrane required the functional Src homology 2 domains and was not affected by mutations in the pleckstrin homology domain or inhibition of phosphatidylinositol (PI) 3-kinase. An array of domains specific for PLC gamma isoforms was sufficient for this translocation. The dynamics of translocation to the plasma membrane and redistribution of PLC gamma, relative to localization of the EGF receptor and PI 4,5-biphosphate (PI 4,5-P(2)), were shown. Colocalization with the receptor was observed in the plasma membrane and in membrane ruffles where PI 4,5-P(2) substrate could also be visualized. At later times, internalization of PLC gamma, which could lead to separation from the substrate, was observed. The data support a direct binding of PLC gamma to the receptor as the main site of the plasma membrane recruitment. The presence of PLC gamma in membrane structures and its access to the substrate appear to be transient and are followed by a rapid incorporation into intracellular vesicles, leading to downregulation of the PLC activity

Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study

Background: Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia. Methods: This worldwide cross-sectional study used individual-level data from the EAS FHSC registry and included adults older than 18 years with a clinical or genetic diagnosis of heterozygous familial hypercholesterolaemia who had data available on age, BMI, and diabetes status. Those with known or suspected homozygous familial hypercholesterolaemia and type 1 diabetes were excluded. The main outcome was prevalence of type 2 diabetes overall and by WHO region, and in relation to obesity (BMI ≥30·0 kg/m2) and lipid-lowering medication as predictors. The study population was divided into 12 risk categories based on age (tertiles), obesity, and receiving statins, and the risk of type 2 diabetes was investigated using logistic regression. Findings: Among 46 683 adults with individual-level data in the FHSC registry, 24 784 with heterozygous familial hypercholesterolaemia were included in the analysis from 44 countries. 19 818 (80%) had a genetically confirmed diagnosis of heterozygous familial hypercholesterolaemia. Type 2 diabetes prevalence in the total population was 5·7% (1415 of 24 784), with 4·1% (817 of 19 818) in the genetically diagnosed cohort. Higher prevalence of type 2 diabetes was observed in the Eastern Mediterranean (58 [29·9%] of 194), South-East Asia and Western Pacific (214 [12·0%] of 1785), and the Americas (166 [8·5%] of 1955) than in Europe (excluding the Netherlands; 527 [8·0%] of 6579). Advancing age, a higher BMI category (obesity and overweight), and use of lipid-lowering medication were associated with a higher risk of type 2 diabetes, independent of sex and LDL cholesterol. Among the 12 risk categories, the probability of developing type 2 diabetes was higher in people in the highest risk category (aged 55–98 years, with obesity, and receiving statins; OR 74·42 [95% CI 47·04–117·73]) than in those in the lowest risk category (aged 18–38 years, without obesity, and not receiving statins). Those who did not have obesity, even if they were in the upper age tertile and receiving statins, had lower risk of type 2 diabetes (OR 24·42 [15·57–38·31]). The corresponding results in the genetically diagnosed cohort were OR 65·04 (40·67–104·02) for those with obesity in the highest risk category and OR 20·07 (12·73–31·65) for those without obesity. Interpretation: Adults with heterozygous familial hypercholesterolaemia in most WHO regions have a higher type 2 diabetes prevalence than in Europe. Obesity markedly increases the risk of diabetes associated with age and use of statins in these patients. Our results suggest that heterozygous familial hypercholesterolaemia does not protect against type 2 diabetes, hence managing obesity is essential to reduce type 2 diabetes in this patient population. Funding: Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron

Abstract 15805: PCSK9 R46L, Lower LDL and Cardiovascular Disease Risk in Familial Hypercholesterolemia

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a down-regulator of the low density lipoprotein receptor (LDLR). Familial hypercholesterolemia (FH) is a autosomal monogenic disease associated with high LDL-C concentration and cardiovascular risk. Hypothesis: This study aimed to examine whether the PCSK9 R46L loss of function mutation found in a cohort of FH patients will be associated with lower LDL-C and cardiovascular risk. Methods: We studied FH patients attending the IRCM Lipid Clinic and whose DNA genotyping was positive for LDLR mutations. The presence of the PCSK9 loss of function R46L missense mutation was determined among a cohort of 582 FH patients by sequencing. Results: Frequency of the R46L variant was 3%. Comparison of their lipid profile showed that carriers had significantly reduced LDL-C (11%, p&lt;0.001), TC (9%, p&lt;0.01), ApoB (10%, p&lt;0.01) and non-HDL (12%, p&lt;0.001) concentrations compared to non-carriers. The analysis of physical xanthomata among both groups, showed a decreased average number of xanthoma per individual in R46L carriers (0.33 and 0.76 respectively, p&lt;0.001). Importantly, the R46L mutation was associated with a significant 66% (p=0.05) lower risk of cardiovascular events compared to non-carriers. Conclusion: Our study showed that the presence of the PCSK9 loss of function R46L mutation in the genotype of FH patients is beneficial for the lipid homeostasis and down-regulate the effect of the LDLR mutation in terms of accumulation of LDL-C, ApoB , total cholesterol, non-HDL and thereby, lowers the coronary heart disease risk of PCSK9 LOF mutation carriers. It is therefore very likely that anti-PCSK9 therapy will be useful in reducing cardiovascular risk in FH patients. </jats:p

Déficit familial de la LCAT au Québec : description d’une première mutation et contribution du génotype de l’APO E sur le phénotype lipoprotéique

Le déficit familial de LCAT (FLD) est une maladie caractérisée par un défaut de l’activité de l’enzyme lecithin:cholesterol acyltransferase (LCAT). Ce défaut résulte en une concentration plasmatique de C-HDL extrêmement basse, des opacités cornéennes prématurées, la présence d’anémie, de protéinurie et d’insuffisance rénale. Nous avons identifié les premiers patients canadiens-français atteints de déficit familial de LCAT. Deux frères, présentant les signes classiques de FLD étaient homozygotes pour une nouvelle mutation du gène de la LCAT: la mutation c.102delG. Cette mutation se traduit au niveau protéique par un changement du cadre de lecture au niveau du codon His35 et l’insertion d’un codon stop en position 61 entraînant une abolition de l’activité LCAT in vitro et in vivo. La présence de cette mutation cause une réduction importante du C-HDL chez les hétérozygotes (22%) et les homozygotes (88%) ainsi qu’une baisse du C-LDL chez les hétérozygotes (35%) et les homozygotes (58%). De plus, le profil lipidique différait de manière importante entre les deux frères atteints de FLD qui présentaient des génotypes APOE différents. Nous suggérons que APOE est un gène qui modifie le phénotype du FLD et pourrait expliquer l’hétérogénéité des profils lipidiques chez les patients atteints de FLD. Nos résultats suggèrent également que l’association du génotype LCAT-/- a un allèle APOE ε2 est un nouveau mécanisme conduisant à la dysbétalipoproteinemie. Finalement nous avons montré des différences importantes dans les sous-populations des HDL chez les deux sujets atteints de FLD. Le porteur de l’allèle APOE ε2 présentait une proportion beaucoup plus importante de HDL immatures (preβ discoïdaux) par rapport a son frère (77.9% vs. 31.0%).Familial LCAT deficiency (FLD) is a disease characterized by a defect in the enzyme lecithin:cholesterol acyltransferase (LCAT) resulting in low HDL-C, premature corneal opacities, anaemia as well as proteinuria and renal failure. We have identified the first French Canadian kindred with familial LCAT deficiency. Two brothers, presenting classical signs of FLD, were shown to be homozygous for a novel LCAT mutation. This c.102delG mutation occurs at the codon for His35 and causes a frameshift that stops transcription at codon 61 abolishing LCAT enzymatic activity both in vivo and in vitro. It has a dramatic effect on the lipoprotein profile, with an important reduction of HDL-C in both heterozygotes (22%) and homozygotes (88%) and a significant decrease in LDL-C in heterozygotes (35%) as well as homozygotes (58%). Furthermore, the lipoprotein profile differs markedly between the two affected brothers who had different APOE genotypes. We propose that APOE could be an important modifier gene explaining heterogeneity in lipoprotein profiles observed among FLD patients. Our results suggest that a LCAT-/- genotype associated with an APOE ε2 allele could be a novel mechanism leading to dysbetalipoproteinemia. Finally we have identified major differences in the HDL sub-populations of both subjects affected by FLD. The carrier of the APOE ε2 allele presented a much higher proportion of immature HDL particles (discoid preβ) compared to his brother (77.9% vs. 31.0%).Le déficit familial de LCAT (FLD) est une maladie caractérisée par un défaut de l’activité de l’enzyme lecithin:cholesterol acyltransferase (LCAT). Ce défaut résulte en une concentration plasmatique de C-HDL extrêmement basse, des opacités cornéennes prématurées, la présence d’anémie, de protéinurie et d’insuffisance rénale. Nous avons identifié les premiers patients canadiens-français atteints de déficit familial de LCAT. Deux frères, présentant les signes classiques de FLD étaient homozygotes pour une nouvelle mutation du gène de la LCAT: la mutation c.102delG. Cette mutation se traduit au niveau protéique par un changement du cadre de lecture au niveau du codon His35 et l’insertion d’un codon stop en position 61 entraînant une abolition de l’activité LCAT in vitro et in vivo. La présence de cette mutation cause une réduction importante du C-HDL chez les hétérozygotes (22%) et les homozygotes (88%) ainsi qu’une baisse du C-LDL chez les hétérozygotes (35%) et les homozygotes (58%). De plus, le profil lipidique différait de manière importante entre les deux frères atteints de FLD qui présentaient des génotypes APOE différents. Nous suggérons que APOE est un gène qui modifie le phénotype du FLD et pourrait expliquer l’hétérogénéité des profils lipidiques chez les patients atteints de FLD. Nos résultats suggèrent également que l’association du génotype LCAT-/- a un allèle APOE ε2 est un nouveau mécanisme conduisant à la dysbétalipoproteinemie. Finalement nous avons montré des différences importantes dans les sous-populations des HDL chez les deux sujets atteints de FLD. Le porteur de l’allèle APOE ε2 présentait une proportion beaucoup plus importante de HDL immatures (preβ discoïdaux) par rapport a son frère (77.9% vs. 31.0%).Familial LCAT deficiency (FLD) is a disease characterized by a defect in the enzyme lecithin:cholesterol acyltransferase (LCAT) resulting in low HDL-C, premature corneal opacities, anaemia as well as proteinuria and renal failure. We have identified the first French Canadian kindred with familial LCAT deficiency. Two brothers, presenting classical signs of FLD, were shown to be homozygous for a novel LCAT mutation. This c.102delG mutation occurs at the codon for His35 and causes a frameshift that stops transcription at codon 61 abolishing LCAT enzymatic activity both in vivo and in vitro. It has a dramatic effect on the lipoprotein profile, with an important reduction of HDL-C in both heterozygotes (22%) and homozygotes (88%) and a significant decrease in LDL-C in heterozygotes (35%) as well as homozygotes (58%). Furthermore, the lipoprotein profile differs markedly between the two affected brothers who had different APOE genotypes. We propose that APOE could be an important modifier gene explaining heterogeneity in lipoprotein profiles observed among FLD patients. Our results suggest that a LCAT-/- genotype associated with an APOE ε2 allele could be a novel mechanism leading to dysbetalipoproteinemia. Finally we have identified major differences in the HDL sub-populations of both subjects affected by FLD. The carrier of the APOE ε2 allele presented a much higher proportion of immature HDL particles (discoid preβ) compared to his brother (77.9% vs. 31.0%)

History of Early Education in Victoria, Texas

No abstract prepared.Curriculum and Instructio