- Email: [email protected]
621 GENETIC PREDISPOSITION AND ADHERENCE TO THE MEDITERRANEAN DIET IN CORONARY ARTERY DISEASE
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
FATP6 gene is associated with features of the metabolic syndrome and signs of myocardial alteration or heart failure. Methods: 755 male participants from the Caucasian Metabolic Intervention Cohort Kiel (MICK) were genotyped for the FATP6 −7T>A polymorphism (rs2526246) and phenotyped for features of the metabolic syndrome. Participants underwent a glucose tolerance test and the postprandial assessment of metabolic variables after a standardized mixed meal (1017 kcal, 51.6% fat, 29.6% carbohydrates, 11.9% protein). Left ventricular heart function was evaluated in 54 participants. Results: Homozygosity of allele A was associated with significantly lower systolic (P = 0.01) and diastolic blood (P = 0.01) pressure values compared to carriers of the wild type (TT+TA). Fasting (P = 0.01) and postprandial (P = 0.02) triglyceride concentrations were significantly lower in AA homozygotes after ingestion of a mixed meal when compared with wild-type carriers. Insulin concentrations in response to the mixed meal varied among FATP6 genotypes, with consistently lower concentrations in AA carriers. Left ventricular heart mass was significantly lower in 27 AA homozygotes in comparison to 27 TT homozygotes, matched for BMI (P = 0.04). Conclusion: FATP6 −7T>A polymorphism may protect from traits of the metabolic syndrome and cardiovascular disease. 621 GENETIC PREDISPOSITION AND ADHERENCE TO THE MEDITERRANEAN DIET IN CORONARY ARTERY DISEASE G. Vassileios Dedoussis1 , E.V. Theodoraki1 , T. Nikopensius2 , J. Suhorutˇsenko2 , M. Yannakoulia1 , M. Dimitriou1 , V. Peppes3 , G. Kolovou4 , N. Zakopoulos3 , A. Metspalu2 . 1 Harokopio University, Department of Nutrition and Dietetics, Athens, Greece, 2 Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia, 3 University of Athens, Medical School, 4 Onassis Cardiac Surgery, Athens, Greece Background and Aim: Coronary artery disease (CAD) results from the interplay between genetic predisposition and environmental factors. The aim of our study was to identify novel genetic variants associated CAD in the Greek population, to assess their additive effect by means of a genetic risk score (GRS) and to investigate the modifying effect of the Mediterranean diet. Patients and Methods: 297 tagSNPs in 41 candidate genes were genotyped in a sample of CAD patients (n = 305) and controls (n = 305). TagSNPs associated with disease were used to calculate the GRS. Adherence to the Mediterranean diet was evaluated through a food frequency questionnaire. Results: Twelve variants were associated with the presence of CAD, and were used to calculate the GRS. The likelihood of having CAD increased by 29.3%, for every 1-unit increase of the GRS (OR:1.293; 95% CI:1.152– 1.451; P = 1.5×10−5 ), and by 122.9% for subjects carrying 10 risk alleles (OR:2.229, 95% CI: 1.549–3.207, P = 1.2×10−5 ). For subjects with 10 risk alleles exhibiting low adherence to the Mediterranean diet, the likelihood of presenting with CAD was much higher comparing to those reporting high adherence to the Mediterranean diet (OR:3.329, 95% CI:1.747–6.334, P = 2.5×10−4 ). Conclusions: We identified 12 novel variants associated with CAD in our Greek population. The modest effects of single SNPs were propagated when the GRS was applied. Low adherence to the Mediterranean diet almost doubled the likelihood of CAD in subjects with high genetic predisposition, making adoption of this healthy dietary pattern a priority, especially in genetically predisposed individuals. 622 CHILHOOD-ONSET CHYLOMICRONEMIA WITH REDUCED PLASMA LPL ACTIVITY AND MASS: IDENTIFICATION OF A NOVEL GPIHBP1 MUTATION J. Magne1 , I. Coca-Prieto2 , O. Kroupa3 , P. Gonzalez-Santos2 , G. Olivecrona3 , E. Ehrenborg1 , P. Valdivielso2 . 1 Atherosclerosis Research Unit, Karolinska Institutet, Stockholm, Sweden, 2 Lipid Unit, Internal Medicine, Hospital Virgen de la Victoria and Department of Medicine & Dermatology, Malaga, Spain, 3 Department of Medical Biosciences/Physiological Chemistry, Umea˚ ˚ Sweden University, Umea, Deficiency in the catabolism of triglyceride-rich lipoproteins is the main cause of childhood-onset of chylomicronemia syndrome. Missense mutations in lipoprotein lipase (LPL) or in proteins influencing LPL activity or stability have demonstrated to be critical determinants of chylomicronemia syndrome. The main objective was to assess the primary deficiency in some cases of childhoodonset chylomicronemia syndrome. In this study, we report genetic analysis of LPL and GPIHBP1 in five cases of chylomicronemia syndrome with reduced LPL activity and mass. Among the selected five patients, one novel homozygous missense mutation (p.C68Y) in exon 3 of GPIHBP1 was identified. The other four patients were homozygous for the common LPL mutation p.G188E. This finding provides further evidence that GPIHBP1 is involved in the catabolism of triglycerides-rich lipoproteins and plays a role in the childhoodonset chylomicronemia.
131
623 DO THE DIFFERENT NUMBER OF CA REPEATS IN P1 PROMOTER OF IGF1 GENE MAY INFLUENCED PLASMA IGF1 LEVELS? P. Burchardt1 , A. Gozdzicka-Jozefiak2 , W. Nowak2 , T. Siminiak3 . 1 Division of Cardiology-Intensive Therapy, Poznan University of Medical Sciences, 2 University of Adam Mickiewicz, 3 Poznan University of Medical Sciences, Poznan, Poland Objectives and Methods: The IGF1 play an important role in vessels wall homeostasis. Few data have defined the influence of IGF1 gene molecular variants and its promoter P1 for IGF1 plasma levels changes and atherosclerosis. Blood samples were collected from 101 consecutive patients, undergoing routine angiography. Using PCR, analyses of sequences of the promoter P1 of IGF1 gene between −1115 to −784nt were performed. The products were analyzed using single strand conformation polymorphism technique (SSCP) and sequencing to evaluate promoter p1 polymorphism. The results of automated sequencing similar to control and SSCP results different from control indicated the necessarity of CA repeats estimation. It was done using “allelic ladder” technique. IGF1 plasma levels were measured by RIA technique. Results: SSCP in promoter P1 of IGF1 gene between −1115 to −784nt was found in 38 pts among total 101 studied pts. Several genotypes according to number of CA repeats were observed in 38 pts with SSCP. The genotypes were divided into two groups: variant carriers (subjects who were heterozygous for the 19-repeats genotype, heterozygous for the 21-repeats genotype, or noncarriers of these 2 alleles), non variant carriers (all subjects who were homozygous for the 19 genotype or homozygous for the 21 or the genotype 19/21 repeats). The higher IGF1 levels were reported in variant carriers (228±74 vs 182±48 ng/ml p = 0.026). We also divided patients into heterozygotes and homozygotes according to various number of GC repeats. We did not observe significant differences between groups according to: number of culprit lesions in coronary arteries or history of myocardial infarction as well as in IGF1 circulating levels. Conclusion: We established higher IGF1circulating levels in ‘variant’ carriers, but it wasn’t associated with advancing of CAD in our study. 624 THE TRP719ARG VARIANT OF KIF6 AND CARDIOVASCULAR OUTCOMES IN STATIN-TREATED, CORONARY STABLE PATIENTS OF THE TNT AND IDEAL PROSPECTIVE STUDIES B.J. Arsenault1 , S.M. Boekholdt1 , G.K. Hovingh1 , C.L. Hyde2 , D.A. DeMicco2 , A. Chatterjee2 , P. Barter3 , P. Deedwania4 , D.D. Waters5 , J.C. LaRosa6 , T.R. Pedersen7 , J.J.P. Kastelein1 , the Treating to New Targets (TNT) and the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) Investigators. 1 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2 Pfizer Inc., New York, NY, USA, 3 The Heart Research Institute, The University of Sydney, Sydney, NSW, Australia, 4 Division of Cardiology, VACCHCS UCSF School of Medicine, University of California at San Francisco, Fresno, 5 San Francisco General Hospital, San Francisco, CA, 6 State University of New York Downstate Medical Center, Brooklyn, NY, USA, 7 Cardiology Department, University of Oslo, Oslo, Norway Objective: To investigate whether carriers of the KIF6 Trp719Arg variant benefit more from high-dose statin therapy than noncarriers in two large randomized trials of stable coronary patients. Methods: We used Cox proportional hazard model adjusted for age, sex, and smoking to assess the reduction of major cardiovascular events (MCVE) by atorvastatin 80 mg/day over 10 mg/day in 4,599 patients of TNT study and by 80 mg/day atorvastatin over 20−40 mg/day simvastatin in 6,541 patients of IDEAL study. Non-Caucasian patients were excluded. Results: In both trials, the genotype distribution did not deviate from HardyWeinberg equilibrium (p = 0.50 in TNT; p = 0.59 in IDEAL). A total of 381 and 648 patients experienced a MCVE during follow-up in TNT and IDEAL, respectively. Only carriers of two copies of the Trp719Arg allele in TNT obtained a significant risk reduction (Table). The p-value for treatment by 3-level genotype was 0.063 for TNT and 0.699 in IDEAL; the p-value for treatment by Trp719Arg carrier status was 0.810 for TNT and 0.421 in IDEAL. MCVE risk and KIF6 Trp719Arg status Noncarriers of the Trp719Arg allele
Carriers of 1 or 2 Trp719Arg alleles
Carriers of 2 copies of the Trp719Arg allele
n
n
n
HR
95% CI
HR
95% CI
HR
95% CI
TNT 1883 0.81 0.59, 1.11 2716 0.85 0.66, 1.11 580 0.44 0.23, 0.84 IDEAL 2676 0.85 0.67, 1.10 3865 0.88 0.62, 1.07 834 0.91 0.58, 1.43
Conclusions: Carriers of the KIF6 Trp719Arg allele did not obtain greater cardiovascular benefits with high-dose statin therapy than noncarriers. Carriers of two copies of this variant had a significant risk reduction in TNT, but genotype did not affect treatment benefit in IDEAL.
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
FATP6 gene is associated with features of the metabolic syndrome and signs of myocardial alteration or heart failure. Methods: 755 male participants from the Caucasian Metabolic Intervention Cohort Kiel (MICK) were genotyped for the FATP6 −7T>A polymorphism (rs2526246) and phenotyped for features of the metabolic syndrome. Participants underwent a glucose tolerance test and the postprandial assessment of metabolic variables after a standardized mixed meal (1017 kcal, 51.6% fat, 29.6% carbohydrates, 11.9% protein). Left ventricular heart function was evaluated in 54 participants. Results: Homozygosity of allele A was associated with significantly lower systolic (P = 0.01) and diastolic blood (P = 0.01) pressure values compared to carriers of the wild type (TT+TA). Fasting (P = 0.01) and postprandial (P = 0.02) triglyceride concentrations were significantly lower in AA homozygotes after ingestion of a mixed meal when compared with wild-type carriers. Insulin concentrations in response to the mixed meal varied among FATP6 genotypes, with consistently lower concentrations in AA carriers. Left ventricular heart mass was significantly lower in 27 AA homozygotes in comparison to 27 TT homozygotes, matched for BMI (P = 0.04). Conclusion: FATP6 −7T>A polymorphism may protect from traits of the metabolic syndrome and cardiovascular disease. 621 GENETIC PREDISPOSITION AND ADHERENCE TO THE MEDITERRANEAN DIET IN CORONARY ARTERY DISEASE G. Vassileios Dedoussis1 , E.V. Theodoraki1 , T. Nikopensius2 , J. Suhorutˇsenko2 , M. Yannakoulia1 , M. Dimitriou1 , V. Peppes3 , G. Kolovou4 , N. Zakopoulos3 , A. Metspalu2 . 1 Harokopio University, Department of Nutrition and Dietetics, Athens, Greece, 2 Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia, 3 University of Athens, Medical School, 4 Onassis Cardiac Surgery, Athens, Greece Background and Aim: Coronary artery disease (CAD) results from the interplay between genetic predisposition and environmental factors. The aim of our study was to identify novel genetic variants associated CAD in the Greek population, to assess their additive effect by means of a genetic risk score (GRS) and to investigate the modifying effect of the Mediterranean diet. Patients and Methods: 297 tagSNPs in 41 candidate genes were genotyped in a sample of CAD patients (n = 305) and controls (n = 305). TagSNPs associated with disease were used to calculate the GRS. Adherence to the Mediterranean diet was evaluated through a food frequency questionnaire. Results: Twelve variants were associated with the presence of CAD, and were used to calculate the GRS. The likelihood of having CAD increased by 29.3%, for every 1-unit increase of the GRS (OR:1.293; 95% CI:1.152– 1.451; P = 1.5×10−5 ), and by 122.9% for subjects carrying 10 risk alleles (OR:2.229, 95% CI: 1.549–3.207, P = 1.2×10−5 ). For subjects with 10 risk alleles exhibiting low adherence to the Mediterranean diet, the likelihood of presenting with CAD was much higher comparing to those reporting high adherence to the Mediterranean diet (OR:3.329, 95% CI:1.747–6.334, P = 2.5×10−4 ). Conclusions: We identified 12 novel variants associated with CAD in our Greek population. The modest effects of single SNPs were propagated when the GRS was applied. Low adherence to the Mediterranean diet almost doubled the likelihood of CAD in subjects with high genetic predisposition, making adoption of this healthy dietary pattern a priority, especially in genetically predisposed individuals. 622 CHILHOOD-ONSET CHYLOMICRONEMIA WITH REDUCED PLASMA LPL ACTIVITY AND MASS: IDENTIFICATION OF A NOVEL GPIHBP1 MUTATION J. Magne1 , I. Coca-Prieto2 , O. Kroupa3 , P. Gonzalez-Santos2 , G. Olivecrona3 , E. Ehrenborg1 , P. Valdivielso2 . 1 Atherosclerosis Research Unit, Karolinska Institutet, Stockholm, Sweden, 2 Lipid Unit, Internal Medicine, Hospital Virgen de la Victoria and Department of Medicine & Dermatology, Malaga, Spain, 3 Department of Medical Biosciences/Physiological Chemistry, Umea˚ ˚ Sweden University, Umea, Deficiency in the catabolism of triglyceride-rich lipoproteins is the main cause of childhood-onset of chylomicronemia syndrome. Missense mutations in lipoprotein lipase (LPL) or in proteins influencing LPL activity or stability have demonstrated to be critical determinants of chylomicronemia syndrome. The main objective was to assess the primary deficiency in some cases of childhoodonset chylomicronemia syndrome. In this study, we report genetic analysis of LPL and GPIHBP1 in five cases of chylomicronemia syndrome with reduced LPL activity and mass. Among the selected five patients, one novel homozygous missense mutation (p.C68Y) in exon 3 of GPIHBP1 was identified. The other four patients were homozygous for the common LPL mutation p.G188E. This finding provides further evidence that GPIHBP1 is involved in the catabolism of triglycerides-rich lipoproteins and plays a role in the childhoodonset chylomicronemia.
131
623 DO THE DIFFERENT NUMBER OF CA REPEATS IN P1 PROMOTER OF IGF1 GENE MAY INFLUENCED PLASMA IGF1 LEVELS? P. Burchardt1 , A. Gozdzicka-Jozefiak2 , W. Nowak2 , T. Siminiak3 . 1 Division of Cardiology-Intensive Therapy, Poznan University of Medical Sciences, 2 University of Adam Mickiewicz, 3 Poznan University of Medical Sciences, Poznan, Poland Objectives and Methods: The IGF1 play an important role in vessels wall homeostasis. Few data have defined the influence of IGF1 gene molecular variants and its promoter P1 for IGF1 plasma levels changes and atherosclerosis. Blood samples were collected from 101 consecutive patients, undergoing routine angiography. Using PCR, analyses of sequences of the promoter P1 of IGF1 gene between −1115 to −784nt were performed. The products were analyzed using single strand conformation polymorphism technique (SSCP) and sequencing to evaluate promoter p1 polymorphism. The results of automated sequencing similar to control and SSCP results different from control indicated the necessarity of CA repeats estimation. It was done using “allelic ladder” technique. IGF1 plasma levels were measured by RIA technique. Results: SSCP in promoter P1 of IGF1 gene between −1115 to −784nt was found in 38 pts among total 101 studied pts. Several genotypes according to number of CA repeats were observed in 38 pts with SSCP. The genotypes were divided into two groups: variant carriers (subjects who were heterozygous for the 19-repeats genotype, heterozygous for the 21-repeats genotype, or noncarriers of these 2 alleles), non variant carriers (all subjects who were homozygous for the 19 genotype or homozygous for the 21 or the genotype 19/21 repeats). The higher IGF1 levels were reported in variant carriers (228±74 vs 182±48 ng/ml p = 0.026). We also divided patients into heterozygotes and homozygotes according to various number of GC repeats. We did not observe significant differences between groups according to: number of culprit lesions in coronary arteries or history of myocardial infarction as well as in IGF1 circulating levels. Conclusion: We established higher IGF1circulating levels in ‘variant’ carriers, but it wasn’t associated with advancing of CAD in our study. 624 THE TRP719ARG VARIANT OF KIF6 AND CARDIOVASCULAR OUTCOMES IN STATIN-TREATED, CORONARY STABLE PATIENTS OF THE TNT AND IDEAL PROSPECTIVE STUDIES B.J. Arsenault1 , S.M. Boekholdt1 , G.K. Hovingh1 , C.L. Hyde2 , D.A. DeMicco2 , A. Chatterjee2 , P. Barter3 , P. Deedwania4 , D.D. Waters5 , J.C. LaRosa6 , T.R. Pedersen7 , J.J.P. Kastelein1 , the Treating to New Targets (TNT) and the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) Investigators. 1 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2 Pfizer Inc., New York, NY, USA, 3 The Heart Research Institute, The University of Sydney, Sydney, NSW, Australia, 4 Division of Cardiology, VACCHCS UCSF School of Medicine, University of California at San Francisco, Fresno, 5 San Francisco General Hospital, San Francisco, CA, 6 State University of New York Downstate Medical Center, Brooklyn, NY, USA, 7 Cardiology Department, University of Oslo, Oslo, Norway Objective: To investigate whether carriers of the KIF6 Trp719Arg variant benefit more from high-dose statin therapy than noncarriers in two large randomized trials of stable coronary patients. Methods: We used Cox proportional hazard model adjusted for age, sex, and smoking to assess the reduction of major cardiovascular events (MCVE) by atorvastatin 80 mg/day over 10 mg/day in 4,599 patients of TNT study and by 80 mg/day atorvastatin over 20−40 mg/day simvastatin in 6,541 patients of IDEAL study. Non-Caucasian patients were excluded. Results: In both trials, the genotype distribution did not deviate from HardyWeinberg equilibrium (p = 0.50 in TNT; p = 0.59 in IDEAL). A total of 381 and 648 patients experienced a MCVE during follow-up in TNT and IDEAL, respectively. Only carriers of two copies of the Trp719Arg allele in TNT obtained a significant risk reduction (Table). The p-value for treatment by 3-level genotype was 0.063 for TNT and 0.699 in IDEAL; the p-value for treatment by Trp719Arg carrier status was 0.810 for TNT and 0.421 in IDEAL. MCVE risk and KIF6 Trp719Arg status Noncarriers of the Trp719Arg allele
Carriers of 1 or 2 Trp719Arg alleles
Carriers of 2 copies of the Trp719Arg allele
n
n
n
HR
95% CI
HR
95% CI
HR
95% CI
TNT 1883 0.81 0.59, 1.11 2716 0.85 0.66, 1.11 580 0.44 0.23, 0.84 IDEAL 2676 0.85 0.67, 1.10 3865 0.88 0.62, 1.07 834 0.91 0.58, 1.43
Conclusions: Carriers of the KIF6 Trp719Arg allele did not obtain greater cardiovascular benefits with high-dose statin therapy than noncarriers. Carriers of two copies of this variant had a significant risk reduction in TNT, but genotype did not affect treatment benefit in IDEAL.