- Email: [email protected]
Gene therapy: Case study on the first lipoprotein lipase deficiency patient treated with Alipogene Tiparvovec in Germany
Abstracts / Atherosclerosis 252 (2016) e1ee196
Results: Statistically significant increase in the transcriptional activity of p50 gene (U-test of Mann-Whitney) was found in patients with early stages of coronary atherosclerosis in comparison with the control group (fig.1).
e83
0591 (awarded to AG), POSDRU/159/1.5/S/133391, and by the Romanian Academy.
EAS16-0879, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. DNA METHYLATION AND COPY NUMBER EVENTS IN ATHEROSCLEROTIC LESIONS M. Nazarenko 1, 2, A. Markov 1, 2, A. Sleptcov 1, 2, I. Lebedev 2, 3, N. Skryabin 2, 3, O. Barbarash 4, V. Puzyrev 1, 2. 1 Research Institute of Medical Genetics, Laboratory of Population Genetics, Tomsk, Russia; 2 Tomsk State University, Laboratory of Human Ontogenetics, Tomsk, Russia; 3 Research Institute of Medical Genetics, Laboratory of Cytogenetics, Tomsk, Russia; 4 Research Institute for Complex Issues of Cardiovascular Diseases, Department of Multifocal Atherosclerosis, Kemerovo, Russia
Ă
Conclusions: Increase in the gene expression of NF-kappaB - p50 in patients with early stages of atherosclerosis indicates its essential role in the initiation and development of atherosclerotic process. NF kappa B may be useful in non-invasive diagnostics of that group of patients.
EAS16-0726, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. ENDOTOXIN STRESS-INDUCED APOLIPOPROTEIN E GENE DOWNREGULATION IN MACROPHAGES IS REDUCED BY METFORMIN E.V. Fuior 1, S. Stavri 1, V.G. Trusca 1, I.F. Tudorache 1, M. Simionescu 1, D. Kardassis 2, A.V. Gafencu 1. 1 Institute of Cellular Biology and Pathology “N. Simionescu”, Genomics- Transcriptomics and Molecular Therapies, Bucharest, Romania; 2 University of Crete Medical School, Department of Basic Sciences, Heraklion, Greece Objectives: The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well-known. Here we evaluated the mechanisms involved in the repression of apoE gene expression in response to lipopolysaccharide (LPS) in macrophages and examined whether metformin, an oral anti-diabetic drug, could reduce apoE downregulation interfering with the LPS signalling pathways. Methods: ApoE expression was determined by Real-Time PCR using TaqMan probes. ApoE protein level and NF-kB intracellular distribution were detected by Western Blot. Transient transfections of RAW264.7 cells were performed with plasmids containing: apoE proximal promoter alone or together with the macrophage-specific enhancer (multienhancer 2; ME.2) and expression vectors for various kinases or transcription factors. DNA pull-down assays were performed with biotinylated fragments of apoE regulatory elements and antibodies to specific transcription factors. Results: We identified the kinases activating NF-kB responsible for apoE downregulation by LPS. LPS-induced NF-kB bound to apoE core promoter as well as to ME.2 induced a downregulatory effect. Metformin (1-3 mM) significantly reduced the LPS downregulation of apoE expression in macrophages as detected by RT-PCR and transient transfection. Metformin impaired NF-kB nuclear translocation, and thus, reduced the LPS-induced apoE downregulation. Conclusions: LPS represses apoE expression in macrophages via MEK kinases signalling pathways that activate NF-kB transcription factors acting on proximal and distal regulatory elements of apoE. Metformin inhibits NF-kB translocation and as a result attenuates LPS downregulatory effect, improving apoE levels in macrophages under inflammatory stress. Work supported by the Romanian National Authority for Scientific Research and Innovation, CNCS-UEFISCDI, project PN-II-ID-PCE-2011-3-
Objectives: We hypothesize that DNA methylation and copy number variations (CNVs) of arteries can contribute to regional vascular bed differences in susceptibility to atherosclerosis. Methods: The Illumina HumanMethylation27 BeadChip and Agilent SurePrint G3 Human CGH+SNP 2400K microarrays were used for DNA testing from right coronary arteries in the area of advanced atherosclerotic plaques (CAP) and atherosclerotic-resistant internal mammary arteries (IMA) of six patients with coronary artery disease. Results: A total 358 CpG sites showed significant differences in DNA methylation (FDR adjusted P<0.05), defined as a mean methylation difference of at least 20% between CAP and IMA samples. Forty differentially methylated genes have previously been linked to atherosclerosis in candidate-gene based association studies, but most of the loci were not previously connected to the disease. The most representative terms in KEGG included neuroactive ligand-receptor interaction (16 genes; FDR adjusted P¼0.02). We identified 90 high-confidence, identical CNVs that were present in matched arteries studied. Fifteen chromosomal regions contained CNVs that are candidates for genes previously associated with cardiovascular diseases and their risk factors. KEGG pathway analysis revealed enrichments in the olfactory transduction and metabolic pathways. There was not overlap between both DNA methylation and copy number changes in arteries. Conclusions: Although DNA methylation differences do not appear to be linked to the copy number changes in arteries of patients with coronary heart disease both mechanisms may be important in the disease. The study was supported by the Russian Science Foundation (14-15-00305).
EAS16-0147, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. GENE THERAPY: CASE STUDY ON THE FIRST LIPOPROTEIN LIPASE DEFICIENCY PATIENT TREATED WITH ALIPOGENE TIPARVOVEC IN GERMANY U. Kassner, T. Hollstein, M. Wühle-Demuth, I. Demuth, E. SteinhagenThiessen. Charit e University Berlin, Department of Lipid Disorders, Berlin, Germany Objectives: To report clinical results at 6 months of follow-up of the first patient treated with Alipogene Tiparvovec since EMA marketing authorization. Alipogene Tiparvovec is the first gene therapy approved in Europe, intended for treatment of patients with lipoprotein lipase deficiency (LPLD), suffering from acute and recurrent pancreatitis despite dietary restrictions. During clinical development, treatment has shown improvement of chylomicron (CM) metabolism and reduction of pancreatitis incidence up to 5.8 years of follow-up. Methods: A 43-year old female LPLD patient with compound heterozygous LPLD and a history of 40 pancreatitis episodes presented in our clinic. The patient suffered from severe hypertriglyceridemia with mean total triglyceride (TG) levels of 2931 mg/dl. She showed detectable levels of LPL mass (55,1 ng/ml) and consented to enrolment in the GENIALL Registry. In September 2015 the patient received 40 intramuscular injections of
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Abstracts / Atherosclerosis 252 (2016) e1ee196
Alipogene Tiparvovec (1x1012 genome copies/kg) in the upper legs under peridural anaesthesia. Immunosuppressive treatment started three days before Alipogene Tiparvovec application. Results: Procedure of administration occurred without complications. So far the patient has not experienced pancreatitis events; total TG levels dropped to 987 mg/dl. Conclusions: Alipogene Tiparvovec was well tolerated and the outcome was satisfactory for the first period of follow-up. Long term effects on TG and recurrence of pancreatitis are regularly monitored.
EAS16-0056, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. MAJOR ADIPOKINES AND ¡420C>G RESISTIN GENE POLYMORPHISHM AS PREDICTORS OF ACUTE ISCHEMIC STROKE SEVERITY AND INHOSPITAL OUTCOME S. Bouziana 1, K. Tziomalos 1, A. Goulas 2, T.A. Vyzantiadis 3, A. Panderi 2, A. Hatzitolios 1. 1 First Propedeutic Department of Internal Medicine, Medical School- Aristotle University of Thessaloniki- AHEPA Hospital, Thessaloniki, Greece; 2 First Laboratory of Pharmacology, Medical School- Aristotle University of Thessaloniki, Thessaloniki, Greece; 3 First Department of Microbiology, Medical School- Aristotle University of Thessaloniki, Thessaloniki, Greece Objectives: The role of adiponectin, leptin and resistin in the pathogenesis of ischemic stroke is controversial. We aimed to evaluate whether serum levels of these adipokines and the -420C>G polymorphism of the resistin gene promoter are associated with ischemic stroke severity and in-hospital outcome. Methods: 93 patients who were consecutively hospitalized for acute ischemic stroke were prospectively studied (39.8% males, age 79.7±6.3 years). Stroke severity was evaluated at admission with the National Institutes of Health Stroke Scale (NIHSS). In-hospital outcome was evaluated with the rate of functional dependence at discharge and with in-hospital mortality. Results: The G allele was more prevalent in patients with severe stroke (p<0.05). Independent predictors of severe stroke were high-sensitivity Creactive protein levels (relative risk (RR) 1.43, 95% confidence interval (CI) 1.08-1.91, p<0.05). Patients who were dependent at discharge had lower leptin levels than patients who were independent (p<0.05). Independent predictors of functional dependence were prior ischemic stroke (RR 7.55, 95% CI 1.69-33.58, p<0.01), triglyceride levels (RR 0.98, 95% CI 0.96-0.99, p<0.05) and NIHSS at admission (RR 1.47, 95% CI 1.17-1.84, p<0.001). The G allele was more prevalent in patients who died (p<0.05). Independent predictors of in-hospital mortality were systolic blood pressure (RR 1.09, 95% CI 1.01-1.19, p<0.05) and NIHSS at admission (RR 1.26, 95% CI 1.081.48, p<0.005). Conclusions: The G allele of the -420C>G polymorphism of the resistin gene promoter appears to be associated with more severe stroke and higher in-hospital mortality in patients with acute ischemic stroke. Higher leptin levels appear to be related with favorable functional outcome.
EAS16-0504, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. PPAR-ALPHA GENE HAPLOTYPES, ARSENIC EXPOSURE AND RISK OF CARDIOVASCULAR DISEASE F.I. Hsieh 1, S.H. Lin 1, C.F. Huang 2, H.Y. Chiou 1. 1 Taipei Medical University, School of Public Health, Taipei, Taiwan; 2 Saint Mary's Hospital Luodong, Department of Family Medicine, Yilan, Taiwan Objectives: Arsenic exposure increases the risk of CVD. PPAR-alpha involves in the process of atherosclerosis and plays an important role in regulating blood lipid changes. Atherosclerosis and dyslipidemia are important risk factors for CVD. Therefore, we aim to investigate the genetic effect of PPAR-alpha on the risk of cardiovascular disease under different arsenic exposure levels.
Methods: This is a case-cohort study with 421 CVD cases and 842 controls. All CVD cases were identified from self-report in a home-visit during 20112014. Controls were frequency matched with cases by age and sex under a ratio of 2. The information of demographic data and conventional CVD risk factors was from baseline collected in 1991. Hydride generation combined with flame atomic absorption spectrometry was used to determine the arsenic concentration from drinking water. Ten PPAR-alpha SNPs were genotyped by the method of MassARRAY® iPLEX Gold-SNP Genotyping. Multivariate logistic regression models were used to analyze the relationship between PPAR-alpha haplotypes, arsenic exposure and the risk of CVD. Results: A significantly protective effect was seen in study subjects carrying PPAR-alpha rs5766743G/rs5767700C haplotype (OR¼ 0.69; 95%CI: 0.53-0.90) after adjusted for conventional CVD risk factors as compared to those carrying non-GC haplotype. After stratified by arsenic exposure, this protective effect was only found in the stratum of arsenic exposure <50ppb, but not seen in the stratum S50ppb. No significant interaction was observed between arsenic exposure and PPAR-alpha GC haplotype on the risk of CVD. Conclusions: PPAR-alpha rs5766743G/rs5767700C haplotype significantly decreased the risk of CVD among study subjects with low arsenic exposure.
EAS16-0950, GENETICS, NUTRITION, BIOMARKERS: GUIDELINES AND MISCELLANEOUS. ACC/AHA GUIDELINES SUPERIOR TO ESC/EAS GUIDELINES FOR PRIMARY PREVENTION WITH STATINS: THE COPENHAGEN GENERAL POPULATION STUDY M.B. Mortensen 1, B.G. Nordestgaard 2, S. Afzal 2, E. Falk 1. 1 Aarhus University Hospital, Department of Cardiology, Aarhus, Denmark; 2 Herlev and Gentofte Hospital- Copenhagen University Hospital, Department of Clinical Biochemistry, Copenhagen, Denmark Objectives: We compared the 2013 American College of Cardiology/ American Heart Association (ACC/AHA) and the 2012 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on prevention of atherosclerotic cardiovascular disease (ASCVD) using different risk prediction models (US Pooled Cohort Equations (US-PCE for any ASCVD) and European Systematic COronary Risk Evaluation system (European-SCORE for fatal ASCVD)) and different statin eligibility criteria. Methods: We examined 44,889 individuals aged 40-75 recruited in 20032009 in the Copenhagen General Population Study, all free of ASCVD, diabetes and statin use at baseline. Results: We detected 2217 any ASCVD events and 199 fatal ASCVD events through 2014. The predicted-to-observed event ratio was 1.2 using US-PCE for any ASCVD and 5.0 using European-SCORE for fatal ASCVD. The US-PCE, but not the European-SCORE, was well-calibrated around decision thresholds for statin therapy. For a class I recommendation, 42% of individuals qualified for statins using the ACC/AHA guidelines versus 6% with the ESC/EAS guidelines. Using ACC/AHA- versus ESC/EAS-defined statin eligibility criteria led to a substantial gain in sensitivity (detection rate) with a smaller loss in specificity: for class I recommendations, the binary net reclassification index (to treat or not to treat) was +0.27 for any ASCVD and +0.40 for fatal ASCVD. Similar differences between the ACC/AHA and ESC/EAS guidelines were found for men and women separately, and for class IIa recommendations. Conclusions: The ACC/AHA guidelines were superior to the ESC/EAS guidelines for primary prevention of ASCVD, that is, for assigning statin therapy to those who would benefit the most.
EAS16-0071, GENETICS, NUTRITION, BIOMARKERS: GUIDELINES AND MISCELLANEOUS. PREDICTING THE IMPACT OF THE ORIGINAL AND GENERIC ROSUVASTATIN ON DIRECT MEDICAL COSTS FOR SECONDARY PREVENTION IN PATIENTS WITH CHRONIC ISCHEMIC HEART DISEASE A. Merezhanova 1, E. Tarlovskaya 1, B. Nechaeva 2, A. Semenkin 2, S. Malchikova 3. 1 Nizhnii Novgorod State Medical Academy, Internal
Results: Statistically significant increase in the transcriptional activity of p50 gene (U-test of Mann-Whitney) was found in patients with early stages of coronary atherosclerosis in comparison with the control group (fig.1).
e83
0591 (awarded to AG), POSDRU/159/1.5/S/133391, and by the Romanian Academy.
EAS16-0879, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. DNA METHYLATION AND COPY NUMBER EVENTS IN ATHEROSCLEROTIC LESIONS M. Nazarenko 1, 2, A. Markov 1, 2, A. Sleptcov 1, 2, I. Lebedev 2, 3, N. Skryabin 2, 3, O. Barbarash 4, V. Puzyrev 1, 2. 1 Research Institute of Medical Genetics, Laboratory of Population Genetics, Tomsk, Russia; 2 Tomsk State University, Laboratory of Human Ontogenetics, Tomsk, Russia; 3 Research Institute of Medical Genetics, Laboratory of Cytogenetics, Tomsk, Russia; 4 Research Institute for Complex Issues of Cardiovascular Diseases, Department of Multifocal Atherosclerosis, Kemerovo, Russia
Ă
Conclusions: Increase in the gene expression of NF-kappaB - p50 in patients with early stages of atherosclerosis indicates its essential role in the initiation and development of atherosclerotic process. NF kappa B may be useful in non-invasive diagnostics of that group of patients.
EAS16-0726, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. ENDOTOXIN STRESS-INDUCED APOLIPOPROTEIN E GENE DOWNREGULATION IN MACROPHAGES IS REDUCED BY METFORMIN E.V. Fuior 1, S. Stavri 1, V.G. Trusca 1, I.F. Tudorache 1, M. Simionescu 1, D. Kardassis 2, A.V. Gafencu 1. 1 Institute of Cellular Biology and Pathology “N. Simionescu”, Genomics- Transcriptomics and Molecular Therapies, Bucharest, Romania; 2 University of Crete Medical School, Department of Basic Sciences, Heraklion, Greece Objectives: The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well-known. Here we evaluated the mechanisms involved in the repression of apoE gene expression in response to lipopolysaccharide (LPS) in macrophages and examined whether metformin, an oral anti-diabetic drug, could reduce apoE downregulation interfering with the LPS signalling pathways. Methods: ApoE expression was determined by Real-Time PCR using TaqMan probes. ApoE protein level and NF-kB intracellular distribution were detected by Western Blot. Transient transfections of RAW264.7 cells were performed with plasmids containing: apoE proximal promoter alone or together with the macrophage-specific enhancer (multienhancer 2; ME.2) and expression vectors for various kinases or transcription factors. DNA pull-down assays were performed with biotinylated fragments of apoE regulatory elements and antibodies to specific transcription factors. Results: We identified the kinases activating NF-kB responsible for apoE downregulation by LPS. LPS-induced NF-kB bound to apoE core promoter as well as to ME.2 induced a downregulatory effect. Metformin (1-3 mM) significantly reduced the LPS downregulation of apoE expression in macrophages as detected by RT-PCR and transient transfection. Metformin impaired NF-kB nuclear translocation, and thus, reduced the LPS-induced apoE downregulation. Conclusions: LPS represses apoE expression in macrophages via MEK kinases signalling pathways that activate NF-kB transcription factors acting on proximal and distal regulatory elements of apoE. Metformin inhibits NF-kB translocation and as a result attenuates LPS downregulatory effect, improving apoE levels in macrophages under inflammatory stress. Work supported by the Romanian National Authority for Scientific Research and Innovation, CNCS-UEFISCDI, project PN-II-ID-PCE-2011-3-
Objectives: We hypothesize that DNA methylation and copy number variations (CNVs) of arteries can contribute to regional vascular bed differences in susceptibility to atherosclerosis. Methods: The Illumina HumanMethylation27 BeadChip and Agilent SurePrint G3 Human CGH+SNP 2400K microarrays were used for DNA testing from right coronary arteries in the area of advanced atherosclerotic plaques (CAP) and atherosclerotic-resistant internal mammary arteries (IMA) of six patients with coronary artery disease. Results: A total 358 CpG sites showed significant differences in DNA methylation (FDR adjusted P<0.05), defined as a mean methylation difference of at least 20% between CAP and IMA samples. Forty differentially methylated genes have previously been linked to atherosclerosis in candidate-gene based association studies, but most of the loci were not previously connected to the disease. The most representative terms in KEGG included neuroactive ligand-receptor interaction (16 genes; FDR adjusted P¼0.02). We identified 90 high-confidence, identical CNVs that were present in matched arteries studied. Fifteen chromosomal regions contained CNVs that are candidates for genes previously associated with cardiovascular diseases and their risk factors. KEGG pathway analysis revealed enrichments in the olfactory transduction and metabolic pathways. There was not overlap between both DNA methylation and copy number changes in arteries. Conclusions: Although DNA methylation differences do not appear to be linked to the copy number changes in arteries of patients with coronary heart disease both mechanisms may be important in the disease. The study was supported by the Russian Science Foundation (14-15-00305).
EAS16-0147, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. GENE THERAPY: CASE STUDY ON THE FIRST LIPOPROTEIN LIPASE DEFICIENCY PATIENT TREATED WITH ALIPOGENE TIPARVOVEC IN GERMANY U. Kassner, T. Hollstein, M. Wühle-Demuth, I. Demuth, E. SteinhagenThiessen. Charit e University Berlin, Department of Lipid Disorders, Berlin, Germany Objectives: To report clinical results at 6 months of follow-up of the first patient treated with Alipogene Tiparvovec since EMA marketing authorization. Alipogene Tiparvovec is the first gene therapy approved in Europe, intended for treatment of patients with lipoprotein lipase deficiency (LPLD), suffering from acute and recurrent pancreatitis despite dietary restrictions. During clinical development, treatment has shown improvement of chylomicron (CM) metabolism and reduction of pancreatitis incidence up to 5.8 years of follow-up. Methods: A 43-year old female LPLD patient with compound heterozygous LPLD and a history of 40 pancreatitis episodes presented in our clinic. The patient suffered from severe hypertriglyceridemia with mean total triglyceride (TG) levels of 2931 mg/dl. She showed detectable levels of LPL mass (55,1 ng/ml) and consented to enrolment in the GENIALL Registry. In September 2015 the patient received 40 intramuscular injections of
e84
Abstracts / Atherosclerosis 252 (2016) e1ee196
Alipogene Tiparvovec (1x1012 genome copies/kg) in the upper legs under peridural anaesthesia. Immunosuppressive treatment started three days before Alipogene Tiparvovec application. Results: Procedure of administration occurred without complications. So far the patient has not experienced pancreatitis events; total TG levels dropped to 987 mg/dl. Conclusions: Alipogene Tiparvovec was well tolerated and the outcome was satisfactory for the first period of follow-up. Long term effects on TG and recurrence of pancreatitis are regularly monitored.
EAS16-0056, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. MAJOR ADIPOKINES AND ¡420C>G RESISTIN GENE POLYMORPHISHM AS PREDICTORS OF ACUTE ISCHEMIC STROKE SEVERITY AND INHOSPITAL OUTCOME S. Bouziana 1, K. Tziomalos 1, A. Goulas 2, T.A. Vyzantiadis 3, A. Panderi 2, A. Hatzitolios 1. 1 First Propedeutic Department of Internal Medicine, Medical School- Aristotle University of Thessaloniki- AHEPA Hospital, Thessaloniki, Greece; 2 First Laboratory of Pharmacology, Medical School- Aristotle University of Thessaloniki, Thessaloniki, Greece; 3 First Department of Microbiology, Medical School- Aristotle University of Thessaloniki, Thessaloniki, Greece Objectives: The role of adiponectin, leptin and resistin in the pathogenesis of ischemic stroke is controversial. We aimed to evaluate whether serum levels of these adipokines and the -420C>G polymorphism of the resistin gene promoter are associated with ischemic stroke severity and in-hospital outcome. Methods: 93 patients who were consecutively hospitalized for acute ischemic stroke were prospectively studied (39.8% males, age 79.7±6.3 years). Stroke severity was evaluated at admission with the National Institutes of Health Stroke Scale (NIHSS). In-hospital outcome was evaluated with the rate of functional dependence at discharge and with in-hospital mortality. Results: The G allele was more prevalent in patients with severe stroke (p<0.05). Independent predictors of severe stroke were high-sensitivity Creactive protein levels (relative risk (RR) 1.43, 95% confidence interval (CI) 1.08-1.91, p<0.05). Patients who were dependent at discharge had lower leptin levels than patients who were independent (p<0.05). Independent predictors of functional dependence were prior ischemic stroke (RR 7.55, 95% CI 1.69-33.58, p<0.01), triglyceride levels (RR 0.98, 95% CI 0.96-0.99, p<0.05) and NIHSS at admission (RR 1.47, 95% CI 1.17-1.84, p<0.001). The G allele was more prevalent in patients who died (p<0.05). Independent predictors of in-hospital mortality were systolic blood pressure (RR 1.09, 95% CI 1.01-1.19, p<0.05) and NIHSS at admission (RR 1.26, 95% CI 1.081.48, p<0.005). Conclusions: The G allele of the -420C>G polymorphism of the resistin gene promoter appears to be associated with more severe stroke and higher in-hospital mortality in patients with acute ischemic stroke. Higher leptin levels appear to be related with favorable functional outcome.
EAS16-0504, GENETICS, NUTRITION, BIOMARKERS: GENETICS, GENE REGULATION. PPAR-ALPHA GENE HAPLOTYPES, ARSENIC EXPOSURE AND RISK OF CARDIOVASCULAR DISEASE F.I. Hsieh 1, S.H. Lin 1, C.F. Huang 2, H.Y. Chiou 1. 1 Taipei Medical University, School of Public Health, Taipei, Taiwan; 2 Saint Mary's Hospital Luodong, Department of Family Medicine, Yilan, Taiwan Objectives: Arsenic exposure increases the risk of CVD. PPAR-alpha involves in the process of atherosclerosis and plays an important role in regulating blood lipid changes. Atherosclerosis and dyslipidemia are important risk factors for CVD. Therefore, we aim to investigate the genetic effect of PPAR-alpha on the risk of cardiovascular disease under different arsenic exposure levels.
Methods: This is a case-cohort study with 421 CVD cases and 842 controls. All CVD cases were identified from self-report in a home-visit during 20112014. Controls were frequency matched with cases by age and sex under a ratio of 2. The information of demographic data and conventional CVD risk factors was from baseline collected in 1991. Hydride generation combined with flame atomic absorption spectrometry was used to determine the arsenic concentration from drinking water. Ten PPAR-alpha SNPs were genotyped by the method of MassARRAY® iPLEX Gold-SNP Genotyping. Multivariate logistic regression models were used to analyze the relationship between PPAR-alpha haplotypes, arsenic exposure and the risk of CVD. Results: A significantly protective effect was seen in study subjects carrying PPAR-alpha rs5766743G/rs5767700C haplotype (OR¼ 0.69; 95%CI: 0.53-0.90) after adjusted for conventional CVD risk factors as compared to those carrying non-GC haplotype. After stratified by arsenic exposure, this protective effect was only found in the stratum of arsenic exposure <50ppb, but not seen in the stratum S50ppb. No significant interaction was observed between arsenic exposure and PPAR-alpha GC haplotype on the risk of CVD. Conclusions: PPAR-alpha rs5766743G/rs5767700C haplotype significantly decreased the risk of CVD among study subjects with low arsenic exposure.
EAS16-0950, GENETICS, NUTRITION, BIOMARKERS: GUIDELINES AND MISCELLANEOUS. ACC/AHA GUIDELINES SUPERIOR TO ESC/EAS GUIDELINES FOR PRIMARY PREVENTION WITH STATINS: THE COPENHAGEN GENERAL POPULATION STUDY M.B. Mortensen 1, B.G. Nordestgaard 2, S. Afzal 2, E. Falk 1. 1 Aarhus University Hospital, Department of Cardiology, Aarhus, Denmark; 2 Herlev and Gentofte Hospital- Copenhagen University Hospital, Department of Clinical Biochemistry, Copenhagen, Denmark Objectives: We compared the 2013 American College of Cardiology/ American Heart Association (ACC/AHA) and the 2012 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on prevention of atherosclerotic cardiovascular disease (ASCVD) using different risk prediction models (US Pooled Cohort Equations (US-PCE for any ASCVD) and European Systematic COronary Risk Evaluation system (European-SCORE for fatal ASCVD)) and different statin eligibility criteria. Methods: We examined 44,889 individuals aged 40-75 recruited in 20032009 in the Copenhagen General Population Study, all free of ASCVD, diabetes and statin use at baseline. Results: We detected 2217 any ASCVD events and 199 fatal ASCVD events through 2014. The predicted-to-observed event ratio was 1.2 using US-PCE for any ASCVD and 5.0 using European-SCORE for fatal ASCVD. The US-PCE, but not the European-SCORE, was well-calibrated around decision thresholds for statin therapy. For a class I recommendation, 42% of individuals qualified for statins using the ACC/AHA guidelines versus 6% with the ESC/EAS guidelines. Using ACC/AHA- versus ESC/EAS-defined statin eligibility criteria led to a substantial gain in sensitivity (detection rate) with a smaller loss in specificity: for class I recommendations, the binary net reclassification index (to treat or not to treat) was +0.27 for any ASCVD and +0.40 for fatal ASCVD. Similar differences between the ACC/AHA and ESC/EAS guidelines were found for men and women separately, and for class IIa recommendations. Conclusions: The ACC/AHA guidelines were superior to the ESC/EAS guidelines for primary prevention of ASCVD, that is, for assigning statin therapy to those who would benefit the most.
EAS16-0071, GENETICS, NUTRITION, BIOMARKERS: GUIDELINES AND MISCELLANEOUS. PREDICTING THE IMPACT OF THE ORIGINAL AND GENERIC ROSUVASTATIN ON DIRECT MEDICAL COSTS FOR SECONDARY PREVENTION IN PATIENTS WITH CHRONIC ISCHEMIC HEART DISEASE A. Merezhanova 1, E. Tarlovskaya 1, B. Nechaeva 2, A. Semenkin 2, S. Malchikova 3. 1 Nizhnii Novgorod State Medical Academy, Internal