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CARDIOVASCULAR GENE ONTOLOGY INITIATIVE
Poster Sessions PO24 Genetic polymorphisms and cardiovascular risk protection factor for obesity onset in the analysed population, whereas other analysed polymorphisms are not. PO24-342
CARDIOVASCULAR GENE ONTOLOGY INITIATIVE
R. Lovering 1 , P. Scambler 2 , M. Hubank 3 , R. Apweiler 4 , P.J. Talmud 1 . of Medicine, University College London, London, UK; Molecular Medicine Unit, Institute of Child Health, London, UK; 3 Molecular Haematology, Institute of Child Health, London, UK; 4 European Bioinformatics Institute, Cambridge, UK 1 Department 2
PO24-343
SCREENING FOR LDLR GENE MUTATIONS RESPONSIBLE FOR HYPERCHOLESTEROLEMIA IN RUSSIAN POPULATION
M.I. Voevoda, E.V. Shakhtshneider, I.V. Kulikov, V.N. Maksimov, I.V. Pilipenko, I.P. Tereshchenko, Yu.I. Ragino, A.G. Romashchenko, Yu.P. Nikitin. Institute of Internal Medicine SB RAMS, Novosibirsk, Russia Background and aims: The present study was aimed at the identification of the spectrum of mutations in low-density lipoproteins receptor (LDLR) gene in a population sample of Russian patients with hypercholesterolemia. Methods: The patients included in the analyses were selected based on total cholesterol level from population sample surveyed in frame of HAPIEE project (∼9000 participants, aged 45-69). Totally 10 men and 10 women aged 45-49 with highest total cholesterol level in this age group were included in the analyses. The plasma lipid levels were determined by standard enzymatic assays. All patients were of Caucasian origin. For each patient all exons of LDLR gene were sequenced. Results: Seven different heretofore undeclared mutations in exon 9 (R410G; M412V) and exon 12 (Y/Y576; N/N591; L605V; L605R; A612G) and twelve previously described mutations in exon 2 (C/C27), exon 5 (C261F; E240X), exon 6 (E288K), exon 8 (A391T), exon 9 (E418G; L432R; D433E), exon 11 (G/G549; E558K; L/L568), exon 12 (G592E) in twenty unrelated patients were identified; thirteen of the detected mutations being missence mutations and one, a nonsense mutation. Only 1 of these mutations was previously described in clinically selected Russian patients with familial hypercholesterolemia. Conclusions: Population sample of Russian patients with hypercholesterolemia significantly differs from clinically selected patients with familial hypercholesterolemia by the spectrum of mutations in LDLR gene. This work was supported by Program of Grants of Federal Agency of Science of Russia B-02.442.11.7515, 2006.
THE DIFFERENTIAL EFFECT OF SOD ALA16VAL POLYMORPHISM ON OXIDIZED LDL-C LEVELS IN YOUNGER AND OLDER ADULTS
G.V. Dedoussis 1 , S. Kanoni 1 , D.B. Panagiotakos 1 , E. Louizou 1 , E. Grigoriou 1 , C. Chrysohoou 2 , C. Pitsavos 2 , C. Stefanadis 2 . 1 Department of Dietetics and Nutrition, Harokopio University; 2 First Cardiology Clinic, School of Medicine, University of Athens, Ippocration Hospital Background and aims: Superoxide dismutase (SOD) is part of a fundamental system, developed to prevent oxidative damage, with potential impact on the atherosclerotic and the ageing process. We sought to examine the effect of superoxide dismutase (SOD) Ala16Val polymorphism on the levels of ox-LDL-C in two Greek cohorts of middle-aged and elderly participants. Methods: We obtained sociodemographic, genotype and biochemical data from 495 middle-aged (n=127 females: 43.2±13 years, n=268 males: 43.3±14 years) Caucasian Greek subjects and 88 elderly (n=44 females: 81.7±5 years; n=44 males: 81.4±4 years). Results: Multiple linear regression analysis, stratified by gender and adjusted for age, smoking habits and body mass index as covariates, showed higher ox-LDL-C levels for the middle aged men with the Val/Val genotype, compared to the other allele (Ala/Ala and Ala/Val) carriers (65.9±25.7 vs. 55.7±20.5 mg/dl; standardized β coefficient=0.192, P=0.012). On the contrary, elderly women with the Ala/Ala or Ala/Val genotype occurred with higher ox-LDL-C levels compared to the Val/Val genotype (77.3±16.1 vs. 66.4±15.8 mg/dl; standardized β coefficient=0.324, P=0.044). Additionally, middle aged men with the Val/Val genotype had higher HDL-C levels compared to the Ala allele carriers, while elderly men and women with the Ala/Ala or Ala/Val genotype presented higher triglycerides levels compared to Val/Val (women: 165.0±77.2 vs. 108.5±24.7 mg/dl, P=0.001; men: 143.2±65.7 vs. 101.9±36.8 mg/dl, P=0.015). Conclusions: The results suggest that SOD Ala16Val polymorphism is an age-dependent modulator of ox-LDL-C levels in middle-aged men and elderly women. PO24-345
PCSK9, FROM GENE AND VARIANTS TO PROTEIN AND PHENOTYPE
M. Abifadel 1,2 , L. Bernier 3 , J. Bonneau 1 , A. Marques 1 , M. Marduel 1 , M. Devillers 1 , D. Erlich 1 , J.-P. Rabes 1,4 , M. Varret 1 , J. Davignon 3 , C. Boileau 1,4 . 1 INSERM U781, hospital Necker, 149-161 rue de Sevres, 75743 Paris cedex 15; 2 Faculty of Pharmacy, University Saint-Joseph, Beirut, Lebanon; 3 Institut de Recherche Clinique, Montreal, Canada; 4 Laboratoire de Biochimie, Genetique Moleculaire, CHU Ambroise Pare Autosomal Dominant Hypercholesterolemia (ADH) is a very frequent human inherited disorder. Until 2003, mutations in the LDLR and the APOB genes had been clearly implicated in the disease. We were the first to identify the PCSK9 gene (Proprotein Convertase Subtilisin Kexin 9) as the third gene involved in ADH by positional cloning in French non LDLR/non APOB families. Several hypercholesterolemic mutations of PCSK9 have been reported: p.S127R, p.F216L, p.D374Y. Two non sense variations p.Y142X and p.C679X were associated with a reduction of LDL-cholesterol levels and of CHD. The p.R46L variation (frequency of 3.2% in white Americans) is associated with a reduction of LDL-cholesterol of 15% and 47% of CHD. We studied the frequency of 2 variations in 600 Caucasian subjects (400 hypercholesterolemic and 200 normolipemic). p.R46L was found only in the control population with a frequency of 2%. p.A443T was found in a woman with mild hypercholesterolemia. This variation was not found in 340 Caucasian controls and it turns out to be a rare polymorphism in whites, more frequent in blacks, associated with lower plasma levels of LDL-C but which has been found in both low and high LDL-C subjects in the Dallas Heart Study. Finally, a third variation, found in two Canadian families, segregates with a lipid alteration previously unknown to be associated with variations in the PCSK9 gene. PCSK9 is an attractive therapeutic target for LDL-C lowering but further investigations of natural variants are required to understand its precise role in cholesterol homeostasis and to identify its inhibitors.
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
POSTER SESSIONS
Background and aim: Gene Ontology (GO) is the established standard for the functional annotation of gene products (www.geneontology.org/). GO provides a systematic language, or ontology, for the description of attributes of genes and gene products in three key domains shared by all organisms: molecular function, biological process and cellular component. Funded by the British Heart Foundation and in association with the EBI, our aim is to provide a unique public resource for the cardiovascular community, both in the UK and internationally, by providing comprehensive functional annotation for genes implicated in heart development and cardiovascular processes and disease. Methods: Manual annotation will be undertaken. This requires time and care but yields a far more detailed and accurate set of GO annotations for particular genes than any other annotation approach. These annotations will be made in accordance with GOC annotation standards and will be contributed to the GOC open source database via existing pipelines. Results: This project is in its infancy but over the next 5 years we will create a comprehensive list of genes associated with cardiovascular processes by drawing on the knowledge and expertise available in the cardiovascular community and the international advisory panel. At the end of the five year initiative the manual annotation of 1500 well-known genes relevant to the cardiovascular system will be completed. Conclusions: The functional annotation of genes associated with the cardiovascular system will enable the accumulated knowledge of heart disease and cardiovascular processes to be effectively utilised by high-throughput technologies, such as microarray.
PO24-344
101
CARDIOVASCULAR GENE ONTOLOGY INITIATIVE
R. Lovering 1 , P. Scambler 2 , M. Hubank 3 , R. Apweiler 4 , P.J. Talmud 1 . of Medicine, University College London, London, UK; Molecular Medicine Unit, Institute of Child Health, London, UK; 3 Molecular Haematology, Institute of Child Health, London, UK; 4 European Bioinformatics Institute, Cambridge, UK 1 Department 2
PO24-343
SCREENING FOR LDLR GENE MUTATIONS RESPONSIBLE FOR HYPERCHOLESTEROLEMIA IN RUSSIAN POPULATION
M.I. Voevoda, E.V. Shakhtshneider, I.V. Kulikov, V.N. Maksimov, I.V. Pilipenko, I.P. Tereshchenko, Yu.I. Ragino, A.G. Romashchenko, Yu.P. Nikitin. Institute of Internal Medicine SB RAMS, Novosibirsk, Russia Background and aims: The present study was aimed at the identification of the spectrum of mutations in low-density lipoproteins receptor (LDLR) gene in a population sample of Russian patients with hypercholesterolemia. Methods: The patients included in the analyses were selected based on total cholesterol level from population sample surveyed in frame of HAPIEE project (∼9000 participants, aged 45-69). Totally 10 men and 10 women aged 45-49 with highest total cholesterol level in this age group were included in the analyses. The plasma lipid levels were determined by standard enzymatic assays. All patients were of Caucasian origin. For each patient all exons of LDLR gene were sequenced. Results: Seven different heretofore undeclared mutations in exon 9 (R410G; M412V) and exon 12 (Y/Y576; N/N591; L605V; L605R; A612G) and twelve previously described mutations in exon 2 (C/C27), exon 5 (C261F; E240X), exon 6 (E288K), exon 8 (A391T), exon 9 (E418G; L432R; D433E), exon 11 (G/G549; E558K; L/L568), exon 12 (G592E) in twenty unrelated patients were identified; thirteen of the detected mutations being missence mutations and one, a nonsense mutation. Only 1 of these mutations was previously described in clinically selected Russian patients with familial hypercholesterolemia. Conclusions: Population sample of Russian patients with hypercholesterolemia significantly differs from clinically selected patients with familial hypercholesterolemia by the spectrum of mutations in LDLR gene. This work was supported by Program of Grants of Federal Agency of Science of Russia B-02.442.11.7515, 2006.
THE DIFFERENTIAL EFFECT OF SOD ALA16VAL POLYMORPHISM ON OXIDIZED LDL-C LEVELS IN YOUNGER AND OLDER ADULTS
G.V. Dedoussis 1 , S. Kanoni 1 , D.B. Panagiotakos 1 , E. Louizou 1 , E. Grigoriou 1 , C. Chrysohoou 2 , C. Pitsavos 2 , C. Stefanadis 2 . 1 Department of Dietetics and Nutrition, Harokopio University; 2 First Cardiology Clinic, School of Medicine, University of Athens, Ippocration Hospital Background and aims: Superoxide dismutase (SOD) is part of a fundamental system, developed to prevent oxidative damage, with potential impact on the atherosclerotic and the ageing process. We sought to examine the effect of superoxide dismutase (SOD) Ala16Val polymorphism on the levels of ox-LDL-C in two Greek cohorts of middle-aged and elderly participants. Methods: We obtained sociodemographic, genotype and biochemical data from 495 middle-aged (n=127 females: 43.2±13 years, n=268 males: 43.3±14 years) Caucasian Greek subjects and 88 elderly (n=44 females: 81.7±5 years; n=44 males: 81.4±4 years). Results: Multiple linear regression analysis, stratified by gender and adjusted for age, smoking habits and body mass index as covariates, showed higher ox-LDL-C levels for the middle aged men with the Val/Val genotype, compared to the other allele (Ala/Ala and Ala/Val) carriers (65.9±25.7 vs. 55.7±20.5 mg/dl; standardized β coefficient=0.192, P=0.012). On the contrary, elderly women with the Ala/Ala or Ala/Val genotype occurred with higher ox-LDL-C levels compared to the Val/Val genotype (77.3±16.1 vs. 66.4±15.8 mg/dl; standardized β coefficient=0.324, P=0.044). Additionally, middle aged men with the Val/Val genotype had higher HDL-C levels compared to the Ala allele carriers, while elderly men and women with the Ala/Ala or Ala/Val genotype presented higher triglycerides levels compared to Val/Val (women: 165.0±77.2 vs. 108.5±24.7 mg/dl, P=0.001; men: 143.2±65.7 vs. 101.9±36.8 mg/dl, P=0.015). Conclusions: The results suggest that SOD Ala16Val polymorphism is an age-dependent modulator of ox-LDL-C levels in middle-aged men and elderly women. PO24-345
PCSK9, FROM GENE AND VARIANTS TO PROTEIN AND PHENOTYPE
M. Abifadel 1,2 , L. Bernier 3 , J. Bonneau 1 , A. Marques 1 , M. Marduel 1 , M. Devillers 1 , D. Erlich 1 , J.-P. Rabes 1,4 , M. Varret 1 , J. Davignon 3 , C. Boileau 1,4 . 1 INSERM U781, hospital Necker, 149-161 rue de Sevres, 75743 Paris cedex 15; 2 Faculty of Pharmacy, University Saint-Joseph, Beirut, Lebanon; 3 Institut de Recherche Clinique, Montreal, Canada; 4 Laboratoire de Biochimie, Genetique Moleculaire, CHU Ambroise Pare Autosomal Dominant Hypercholesterolemia (ADH) is a very frequent human inherited disorder. Until 2003, mutations in the LDLR and the APOB genes had been clearly implicated in the disease. We were the first to identify the PCSK9 gene (Proprotein Convertase Subtilisin Kexin 9) as the third gene involved in ADH by positional cloning in French non LDLR/non APOB families. Several hypercholesterolemic mutations of PCSK9 have been reported: p.S127R, p.F216L, p.D374Y. Two non sense variations p.Y142X and p.C679X were associated with a reduction of LDL-cholesterol levels and of CHD. The p.R46L variation (frequency of 3.2% in white Americans) is associated with a reduction of LDL-cholesterol of 15% and 47% of CHD. We studied the frequency of 2 variations in 600 Caucasian subjects (400 hypercholesterolemic and 200 normolipemic). p.R46L was found only in the control population with a frequency of 2%. p.A443T was found in a woman with mild hypercholesterolemia. This variation was not found in 340 Caucasian controls and it turns out to be a rare polymorphism in whites, more frequent in blacks, associated with lower plasma levels of LDL-C but which has been found in both low and high LDL-C subjects in the Dallas Heart Study. Finally, a third variation, found in two Canadian families, segregates with a lipid alteration previously unknown to be associated with variations in the PCSK9 gene. PCSK9 is an attractive therapeutic target for LDL-C lowering but further investigations of natural variants are required to understand its precise role in cholesterol homeostasis and to identify its inhibitors.
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
POSTER SESSIONS
Background and aim: Gene Ontology (GO) is the established standard for the functional annotation of gene products (www.geneontology.org/). GO provides a systematic language, or ontology, for the description of attributes of genes and gene products in three key domains shared by all organisms: molecular function, biological process and cellular component. Funded by the British Heart Foundation and in association with the EBI, our aim is to provide a unique public resource for the cardiovascular community, both in the UK and internationally, by providing comprehensive functional annotation for genes implicated in heart development and cardiovascular processes and disease. Methods: Manual annotation will be undertaken. This requires time and care but yields a far more detailed and accurate set of GO annotations for particular genes than any other annotation approach. These annotations will be made in accordance with GOC annotation standards and will be contributed to the GOC open source database via existing pipelines. Results: This project is in its infancy but over the next 5 years we will create a comprehensive list of genes associated with cardiovascular processes by drawing on the knowledge and expertise available in the cardiovascular community and the international advisory panel. At the end of the five year initiative the manual annotation of 1500 well-known genes relevant to the cardiovascular system will be completed. Conclusions: The functional annotation of genes associated with the cardiovascular system will enable the accumulated knowledge of heart disease and cardiovascular processes to be effectively utilised by high-throughput technologies, such as microarray.
PO24-344
101