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MS214 ASSOCIATION BETWEEN LOW HDL-C AND FAMILY HISTORY OF PREMATURE CORONARY HEART DISEASE IN SPANISH STATIN-TREATED PATIENTS. THE DYSLIPIDEMIA INTERNATIONAL STUDY (DYSIS-SPAIN)
78th EAS Congress
Atherosclerosis Supplements 11, no. 2 (2010) 109–222
MS214 ASSOCIATION BETWEEN LOW HDL-C AND FAMILY HISTORY OF PREMATURE CORONARY HEART DISEASE IN SPANISH STATIN-TREATED PATIENTS. THE DYSLIPIDEMIA INTERNATIONAL STUDY (DYSIS-SPAIN) J. Millan1 , J.R. Gonzalez-Juanatey2 , C. Guijarro3 , E. Alegria4 , J.V. Lozano5 , ˜ Madrid, B. Gonzalez-Timon6 , G. Vitale6 . 1 Hospital Gregorio Maranon, 2 Hospital Clinico Univesitario de Santiago de Compostela, Santiago de Compostela, 3 Hospital de Alcorcon, Alcorcon, 4 Clinica Universitaria de Pamplona, Pamplona, 5 Primary Care Center La Serreria 2, Valencia, 6 Merck & Co., MSD, Madrid, Spain Introduction: Patients with a family history of coronary heart disease (CHD) have an additional risk factor of cardiovascular disease (CVD). Data suggest that low-HDL-C is also an important CV risk factor and statins have a limited action on it. In this analysis we assess the association between low-HDL-C and a family history of premature CHD (FamH-CHD) in DYSIS-Spanish patients. Methods: Analysis of 3710 Spanish patients of DYSIS (22063 participants in Europe and Canada) treated with statins. We used the ATP-III recommendations to classify patient’s risk and define the LDL-C goal and normality or not of the HDL-C and TG concentrations. Results: In 3710 patients, 19.9% had a FamH-CHD (56.7% men and 43.3% women). Of those, 60.4% did not achieve the LDL-C goal vs. 47.4% of patients without FamH-CHD (n = 2995; p < 0.0001). The prevalence of low HDL-C was higher in these patients, 35.5% vs. 28.3% (p < 0.001), compared to patients without FamH-CHD. The prevalence of CVD in patients with a FamH-CHD was 43.9% and it was more frequent than in those without family history, 33.5% (p < 0.001). Conclusions: In this analysis of Spanish statin-treated patients, FamH-CHD was associated with a higher CV risk and higher prevalence of low HDL-C. Most of the patients with FamH-CHD did not achieve the LDL-C goal. It may be of interest to manage the dyslipidemia as a multidimensional approach in order to reach LDL-C targets and to treat other lipid abnormalities that are frequent in these patients (low HDL-C and high TGs). MS215 IDENTIFICATION OF GENES ASSOCIATED WITH QT INTERVAL USING THE 50K CARDIO-METABOLIC SNP CHIP: RESULTS FROM THE WHITEHALL II STUDY S. Shah1 , F. Drenos2 , T. Shah3 , J. Palmen2 , R. Sofat3 , M. Kumari4 , J. Pallas5 , P. MacFarlane6 , J. Whittaker7 , P. Talmud2 , S. Humphries2 , A. Hingorani3,4 . 1 UCL Genetics Institute, 2 Division of Cardiovascular Genetics, Department of Medicine, 3 Centre for Clinical Pharmacology, 4 Department of Epidemiology and Public Health, 5 Wolfson Institute for Biomedical Research, UCL, London, 6 Division of Cardiovascular & Medical Sciences, Gardiner Institute, Glasgow, 7 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK Background: The QT interval on an electrocardiogram is a measure of the total time from ventricular depolarization to repolarization. QT interval, a heritable quantitative trait, and its prolongation by drugs, cardiac disease and electrolyte abnormalities are associated with the risk of developing ventricular arrhythmias and sudden cardiac death. Methods and Aims: Using a dense gene-centric SNP array (50,000 SNPs in 2100 genes implicated across a range of cardiovascular, metabolic and inflammatory traits) we analysed data from 5059 Caucasian individuals from a large prospective observational study of middle aged civil servants (Whitehall II) in which ECG QT interval was available from digitised ECG data. Results: We observed multiple associations at P < 1×10−4 of SNPs in NOS1AP, KCNH2 and PLN. NOS1AP codes for an adaptor protein known to be involved in myocardial repolarisation. KCNH2 codes for a potassium ion channel protein and mutations in the gene alters the activity of the channel leading to the abnormal heart rhythm characteristic of short QT syndrome. PLN encodes cardiac phosphlamban which has been linked to dilated cardiomyopathy and heart failure in mouse models. Additional novel loci identified will require replication in separate population studies and further analysis will be done to refine the genetic associations to identify independent signals of association. Conclusions: Common variants in the genes NOS1AP, KCNH2 and PLN influence QT interval in healthy men and women, confirming results from recent whole genome analyses. MS216 IL6 AND IL10 GENES ARE ASSOCIATED WITH UNFAVOURABLE OUTCOMES IN PATIENTS WITH ACUTE CORONARY SYNDROME K. Blagodatskikh1 , J. Agapkina1 , A. Nikitin1 , M. Evdokimova2 , V. Osmolovskaya2 , V. Nosikov1 , D. Zateyshchikov2 . 1 Molecular Biology, National Research Centre “GosNII Genetika’, 2 Russian President’s Educational Scientific Medical Centre, Moscow, Russia Objectives: It is obvious that individual genetic features play important role in the unfavourable outcomes (UO) after acute episodes of CAD. We suggested that the IL6 and IL10 genes which included in inflammation processes could
153
play an important role in the forming of genetic predisposition to development of UO. Methods: 1145 patients (717 male, 428 female), aged 61.6±0.35 years with acute coronary syndrome were studied. 933 patients had arterial hypertension, 367 – a previous ischemic stroke. Allele identification was performed using RFLP method. Results: We have found association of UO with G(−174)C polymorphism of IL6 gene and G(−1082)A of IL10 gene. In case of G(−174)C polymorphism of IL6 gene we have found that the carriers of GG genotype (c2=5.2, p = 0.023) have the lower survival time (2.10±0.08 years), whereas the carriers of CG and GG genotypes have the higher survival time (2.33±0.06 years). In case of G(−1082)A polymorphism of IL10 gene we have found that the carriers of AA and AG genotypes (c2=5.0, p = 0.026) have the lower survival time (2.10±0.07 years), whereas the carriers of GG genotype have the higher survival time (2.32±0.06 years). Conclusion: The result of our study are evidence that the carriers of GG genotype of G(−174)C polymorphism of IL6 gene and the carriers of AA and AG genotypes of G(−1082)A polymorphism of IL10 have the higher risk of UO in patients with acute coronary syndrome. Funding: A research grants from CJSC Taatta Bank and Russian Foundation for Basic Research. MS217 ASSOCIATION OF THE CHOLESTEROL ESTER TRANSFER PROTEIN GENE (CETP) WITH CORONARY ARTERY DISEASE A. Brovkin1 , E. Dankovtseva2 , A. Nikitin1 , L. Minushkina2 , D. Zateyshchikov2 , V. Nosikov1 . 1 National Research Centre ‘GosNII Genetika’, 2 Russian President’s Educational Scientific Medical Centre, Moscow, Russia Background and Aims: In the current investigation, we have studied an association with coronary artery disease (CAD) of candidate gene, which product is involved in regulation of lipid transport: cholesterol ester transfer protein (CETP). Patients and Methods: Two groups of Russian patients living in Moscow have been formed: group with acute unstable angina (n = 293) and control group (n = 132) in which all patients had no clinical CAD. Allele identification was performed using PCR, restriction endonuclease cleavage and PAAG separation. Results: We have not found any association with CAD of polymorphic markers TaqIB, C(−724)T and A(−629)C of CETP gene. But in case of polymorphic marker Ile405Val of CETP gene we have found that the carriers of Ile/Ile (OR = 0.44, p = 0.0006; CI = 0.27–0.73) have the lower risk of coronary artery disease, whereas the carriers of Ile/Val (OR = 2.67, p = 0.0006; CI = 1.61–4.42) have the higher risk of coronary artery disease. Conclusion: The result of our study is evidence that the carriers of Ile/Val genotype of Ile405Val polymorphism of CETP gene have the higher risk of coronary artery disease. MS218 ANTI-PHOSHOLIPID ANTIBODIES IN ACUTE CORONARY ATHEROTHROMBOSIS I. Burazor1 , A. Vojdani2 , M. Burazor1 . 1 Cardiology, University Clinical Center in Nis, Nis, Serbia, 2 Immnosciences Lab, Inc, Los Angeles, CA, USA The combined presents of anti-phospholipid antibodies and thrombosis is recognized as the antiphospholipid syndrome (APS). Also, atherosclerosis is a histologic process in which the immune system has important role. Based on this data and our experience we aimed to investigate the possible role of anti-phospholipid antibodies in acute coronary atherothrombosis. Methods and Results: The study included 312 participants; of whom 112 were patients with ACS (60.74±4.97 years of age, majority were males) and 200 were age and sex matched controls with no known coronary artery disease or other pro-coagulant state (lupus, deep vein thrombosis etc). Patients with previous infection, surgery, cancer, trauma or concomitant reumathological diseases were excluded from the study. Blood was sampled, frozen and sent on dry ice to Immunosciences Lab. Inc (USA) for analyzes. All traditional risk factors were noted. Several antibodies of antiphospholipid syndrome were determined: antiprothrombin (aPL), anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1. In addition, anti-coagulant protein C was determined. Our data showed significant prevalence of examined antibodies in patients with ACS. The levels of circulating antibodies were significantly higher in patients (p < 0.001). Protein C was 144.57±36% in patients and 101.30±23.11% ion controls, p < 0.001. There was a linear correlation between anti-phospoholipid antibodies themselves and between protein C and aCL (p < 0.01). Linear regression confirmed the involment of APS in acute coronary atherothombosis. In conclusion our data conifirmed that antiphospholipid antibodies are presents in acute coronary atherothrombosis. APS might represent a state which induce strong immune response in coronary arteries.
Atherosclerosis Supplements 11, no. 2 (2010) 109–222
MS214 ASSOCIATION BETWEEN LOW HDL-C AND FAMILY HISTORY OF PREMATURE CORONARY HEART DISEASE IN SPANISH STATIN-TREATED PATIENTS. THE DYSLIPIDEMIA INTERNATIONAL STUDY (DYSIS-SPAIN) J. Millan1 , J.R. Gonzalez-Juanatey2 , C. Guijarro3 , E. Alegria4 , J.V. Lozano5 , ˜ Madrid, B. Gonzalez-Timon6 , G. Vitale6 . 1 Hospital Gregorio Maranon, 2 Hospital Clinico Univesitario de Santiago de Compostela, Santiago de Compostela, 3 Hospital de Alcorcon, Alcorcon, 4 Clinica Universitaria de Pamplona, Pamplona, 5 Primary Care Center La Serreria 2, Valencia, 6 Merck & Co., MSD, Madrid, Spain Introduction: Patients with a family history of coronary heart disease (CHD) have an additional risk factor of cardiovascular disease (CVD). Data suggest that low-HDL-C is also an important CV risk factor and statins have a limited action on it. In this analysis we assess the association between low-HDL-C and a family history of premature CHD (FamH-CHD) in DYSIS-Spanish patients. Methods: Analysis of 3710 Spanish patients of DYSIS (22063 participants in Europe and Canada) treated with statins. We used the ATP-III recommendations to classify patient’s risk and define the LDL-C goal and normality or not of the HDL-C and TG concentrations. Results: In 3710 patients, 19.9% had a FamH-CHD (56.7% men and 43.3% women). Of those, 60.4% did not achieve the LDL-C goal vs. 47.4% of patients without FamH-CHD (n = 2995; p < 0.0001). The prevalence of low HDL-C was higher in these patients, 35.5% vs. 28.3% (p < 0.001), compared to patients without FamH-CHD. The prevalence of CVD in patients with a FamH-CHD was 43.9% and it was more frequent than in those without family history, 33.5% (p < 0.001). Conclusions: In this analysis of Spanish statin-treated patients, FamH-CHD was associated with a higher CV risk and higher prevalence of low HDL-C. Most of the patients with FamH-CHD did not achieve the LDL-C goal. It may be of interest to manage the dyslipidemia as a multidimensional approach in order to reach LDL-C targets and to treat other lipid abnormalities that are frequent in these patients (low HDL-C and high TGs). MS215 IDENTIFICATION OF GENES ASSOCIATED WITH QT INTERVAL USING THE 50K CARDIO-METABOLIC SNP CHIP: RESULTS FROM THE WHITEHALL II STUDY S. Shah1 , F. Drenos2 , T. Shah3 , J. Palmen2 , R. Sofat3 , M. Kumari4 , J. Pallas5 , P. MacFarlane6 , J. Whittaker7 , P. Talmud2 , S. Humphries2 , A. Hingorani3,4 . 1 UCL Genetics Institute, 2 Division of Cardiovascular Genetics, Department of Medicine, 3 Centre for Clinical Pharmacology, 4 Department of Epidemiology and Public Health, 5 Wolfson Institute for Biomedical Research, UCL, London, 6 Division of Cardiovascular & Medical Sciences, Gardiner Institute, Glasgow, 7 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK Background: The QT interval on an electrocardiogram is a measure of the total time from ventricular depolarization to repolarization. QT interval, a heritable quantitative trait, and its prolongation by drugs, cardiac disease and electrolyte abnormalities are associated with the risk of developing ventricular arrhythmias and sudden cardiac death. Methods and Aims: Using a dense gene-centric SNP array (50,000 SNPs in 2100 genes implicated across a range of cardiovascular, metabolic and inflammatory traits) we analysed data from 5059 Caucasian individuals from a large prospective observational study of middle aged civil servants (Whitehall II) in which ECG QT interval was available from digitised ECG data. Results: We observed multiple associations at P < 1×10−4 of SNPs in NOS1AP, KCNH2 and PLN. NOS1AP codes for an adaptor protein known to be involved in myocardial repolarisation. KCNH2 codes for a potassium ion channel protein and mutations in the gene alters the activity of the channel leading to the abnormal heart rhythm characteristic of short QT syndrome. PLN encodes cardiac phosphlamban which has been linked to dilated cardiomyopathy and heart failure in mouse models. Additional novel loci identified will require replication in separate population studies and further analysis will be done to refine the genetic associations to identify independent signals of association. Conclusions: Common variants in the genes NOS1AP, KCNH2 and PLN influence QT interval in healthy men and women, confirming results from recent whole genome analyses. MS216 IL6 AND IL10 GENES ARE ASSOCIATED WITH UNFAVOURABLE OUTCOMES IN PATIENTS WITH ACUTE CORONARY SYNDROME K. Blagodatskikh1 , J. Agapkina1 , A. Nikitin1 , M. Evdokimova2 , V. Osmolovskaya2 , V. Nosikov1 , D. Zateyshchikov2 . 1 Molecular Biology, National Research Centre “GosNII Genetika’, 2 Russian President’s Educational Scientific Medical Centre, Moscow, Russia Objectives: It is obvious that individual genetic features play important role in the unfavourable outcomes (UO) after acute episodes of CAD. We suggested that the IL6 and IL10 genes which included in inflammation processes could
153
play an important role in the forming of genetic predisposition to development of UO. Methods: 1145 patients (717 male, 428 female), aged 61.6±0.35 years with acute coronary syndrome were studied. 933 patients had arterial hypertension, 367 – a previous ischemic stroke. Allele identification was performed using RFLP method. Results: We have found association of UO with G(−174)C polymorphism of IL6 gene and G(−1082)A of IL10 gene. In case of G(−174)C polymorphism of IL6 gene we have found that the carriers of GG genotype (c2=5.2, p = 0.023) have the lower survival time (2.10±0.08 years), whereas the carriers of CG and GG genotypes have the higher survival time (2.33±0.06 years). In case of G(−1082)A polymorphism of IL10 gene we have found that the carriers of AA and AG genotypes (c2=5.0, p = 0.026) have the lower survival time (2.10±0.07 years), whereas the carriers of GG genotype have the higher survival time (2.32±0.06 years). Conclusion: The result of our study are evidence that the carriers of GG genotype of G(−174)C polymorphism of IL6 gene and the carriers of AA and AG genotypes of G(−1082)A polymorphism of IL10 have the higher risk of UO in patients with acute coronary syndrome. Funding: A research grants from CJSC Taatta Bank and Russian Foundation for Basic Research. MS217 ASSOCIATION OF THE CHOLESTEROL ESTER TRANSFER PROTEIN GENE (CETP) WITH CORONARY ARTERY DISEASE A. Brovkin1 , E. Dankovtseva2 , A. Nikitin1 , L. Minushkina2 , D. Zateyshchikov2 , V. Nosikov1 . 1 National Research Centre ‘GosNII Genetika’, 2 Russian President’s Educational Scientific Medical Centre, Moscow, Russia Background and Aims: In the current investigation, we have studied an association with coronary artery disease (CAD) of candidate gene, which product is involved in regulation of lipid transport: cholesterol ester transfer protein (CETP). Patients and Methods: Two groups of Russian patients living in Moscow have been formed: group with acute unstable angina (n = 293) and control group (n = 132) in which all patients had no clinical CAD. Allele identification was performed using PCR, restriction endonuclease cleavage and PAAG separation. Results: We have not found any association with CAD of polymorphic markers TaqIB, C(−724)T and A(−629)C of CETP gene. But in case of polymorphic marker Ile405Val of CETP gene we have found that the carriers of Ile/Ile (OR = 0.44, p = 0.0006; CI = 0.27–0.73) have the lower risk of coronary artery disease, whereas the carriers of Ile/Val (OR = 2.67, p = 0.0006; CI = 1.61–4.42) have the higher risk of coronary artery disease. Conclusion: The result of our study is evidence that the carriers of Ile/Val genotype of Ile405Val polymorphism of CETP gene have the higher risk of coronary artery disease. MS218 ANTI-PHOSHOLIPID ANTIBODIES IN ACUTE CORONARY ATHEROTHROMBOSIS I. Burazor1 , A. Vojdani2 , M. Burazor1 . 1 Cardiology, University Clinical Center in Nis, Nis, Serbia, 2 Immnosciences Lab, Inc, Los Angeles, CA, USA The combined presents of anti-phospholipid antibodies and thrombosis is recognized as the antiphospholipid syndrome (APS). Also, atherosclerosis is a histologic process in which the immune system has important role. Based on this data and our experience we aimed to investigate the possible role of anti-phospholipid antibodies in acute coronary atherothrombosis. Methods and Results: The study included 312 participants; of whom 112 were patients with ACS (60.74±4.97 years of age, majority were males) and 200 were age and sex matched controls with no known coronary artery disease or other pro-coagulant state (lupus, deep vein thrombosis etc). Patients with previous infection, surgery, cancer, trauma or concomitant reumathological diseases were excluded from the study. Blood was sampled, frozen and sent on dry ice to Immunosciences Lab. Inc (USA) for analyzes. All traditional risk factors were noted. Several antibodies of antiphospholipid syndrome were determined: antiprothrombin (aPL), anti-cardiolipin (aCL) and anti-beta 2 glycoprotein 1. In addition, anti-coagulant protein C was determined. Our data showed significant prevalence of examined antibodies in patients with ACS. The levels of circulating antibodies were significantly higher in patients (p < 0.001). Protein C was 144.57±36% in patients and 101.30±23.11% ion controls, p < 0.001. There was a linear correlation between anti-phospoholipid antibodies themselves and between protein C and aCL (p < 0.01). Linear regression confirmed the involment of APS in acute coronary atherothombosis. In conclusion our data conifirmed that antiphospholipid antibodies are presents in acute coronary atherothrombosis. APS might represent a state which induce strong immune response in coronary arteries.