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MS534 GENOME-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR CORONARY ARTERY DISEASE ON CHROMOSOME 10p11.23
78th EAS Congress
Atherosclerosis Supplements 11, no. 2 (2010) 109–222
MS532 ASSOCIATION BETWEEN Lp(a) AND HDL CHOLESTEROL ON GENERAL POPULATION S. Pagoni1 , C. Charalampopoulos1 , D. Syrigos2 , E. Zoulias1 , C. Voulgari2 , B. Papalimneou2 , A. Mousouli1 , S. Paximadas2 . 1 Lipid Unit, General Hospital of Athens G. Gennimatas, 2 Lipid Unit, General Hospital of Athens ELPIS, Athens, Greece Introduction: Latter between risk factors for cardiovascular diseases included the increase of levels Lp(a) cholesterol. On the contrary, the elevated plasma levels of HDL cholesterol are a negative factor for coronary artery disease and stroke. Purpose: The aim of this study was to examine the possible role and association of Lp(a) on HDL on general population. Material and Methods: The study included 100 out patients, aged 35−81 years who examined in the Lipid Unit. Investigated the Lp(a) and HDL levels and correlated. All were whites and not taking any medication. All results were analyzed in the same laboratory. Statistical analysis was performed using a SPSS 11.0. Results: See the table. Table: Results for 100 out patients, with overall Lp(a) = 32.7±30.4 mg/dl (3.01– 164.7) and HDL = 45.6±6 (12–143) Lp(a), mg/dl
HDL
p-value
<10 <15 <20 <25 <30 <35
55.16 47.13 45.92 45.40 45.02 44.58
0.00 0.08 0.21 0.31 0.23 0.32
Conclusions: The study shows that when increased the Lp(a) levels, then decreased the HDL levels. MS533 THE CLINICAL IMPLICATIONS OF ADIPOCYTOKINE, SERUM RESISTEN IN DIABETICS WITH CORONARY ARTERY DISEASE W. Fatehy, A. Abd El Ghany, A. Abd El Kader, G. Kamal, M. Soliman. Menofyia, Sheben el Kom, Egypt Background: Diabetics with CAD have an unfavorable outcome even after PCI or CABG. So, investigations of novel atherogenesis markers such as serum resisten may have a potential role in early assessment of cardiovascular risk in such patients. Aim of the work: To assess serum resisten levels in diabetics with: stable CAD, ACS & healthy control. Subjects and Methods: The present study included forty patients with diabetes, twenty with CAD, group 1 (A with stable CAD and B with ACS), twenty without CAD, group 2 and twelve healthy as control, group 3. All subjects underwent: history taking and physical examinations ECG, Stress testing and or coronary angiography. Laboratory investigations: glycated HB, creatinine, lipid profile, HsCRP, Resisten. Results: Diabetics have significantly higher BMI, glycated HB, total cholesterol, TG, LDL, HsCRP & Resisten than healthy control. There was no significant deference between both diabetic groups as regards, BMI, lipogram, but group 1 have significantly higher HsCRP & Resisten. Diabetics with stable CAD have significantly higher age, glycated HB and significantly lower HsCRP& Resisten than those with ACS. Resisten was correlated with BMI, glycated HB, cholesterol, LDL, TG, HDL & HsCRP in diabetic patients. Conclusion: Diabetics with CAD have significantly higher serum resisten than diabetics without CAD & healty control. Also, diabetics with ACS have significantly higher serum resisten than diabetics with stable CAD. Serum resisten may serve as a biomarker of increased atherogenic risk in diabetic patients. MS534 GENOME-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR CORONARY ARTERY DISEASE ON CHROMOSOME 10p11.23 ¨ Lubeck, J. Erdmann. Medizinische Klinik II, Universitat ¨ Lubeck, ¨ Germany Recent GWAS identified 13 loci for CAD/MI. However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. We genotyped n = 1,157 MI cases and n = 1,748 controls from a populationbased study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage n = 462 SNPs showed association with MI at P < 1×10−3 in two-sided trend tests. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1,644 controls) and GerMIFS II (1,222 cases/1,298 controls). Nine SNPs, representing three regions, displayed consistent replication in this insilico analysis (P < 0.05 for each GWA sample): five SNPs at 9p21.3, a well-
217
known CAD/MI locus, two SNPs at 10p11.21 and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in KIAA1462 gene) in additional 5,790 cases and 5,302 controls confirmed the association (P = 9.54×10−4 ), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P = 3.52×10−11 [OR = 1.15 (1.11−1.20)]. Analysis of a GWA study followed by in-silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the etiology of these diseases. MS535 HOMOARGININE INDEPENDENTLY PREDICTS TOTAL AND CARDIOVASCULAR MORTALITY IN INDIVIDUALS WITH ANGIOGRAPHIC CORONARY ARTERY DISEASE W. Marz ¨ 1,2 , A. Meinitzer2 , S. Pilz3 , C. Drechsler4 , V. Krane4 , M. Kleber1 , 7 J. Fischer5 , B. Winkelmann6 , B. Bohm ¨ , E. Ritz8 , C. Wanner4 . 1 Synlab Medizinisches Versorgungszentrum Heidelberg GmbH, Eppelheim, Germany, 2 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, 3 Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Graz, Austria, 4 Department of Medicine, Division of Nephrology, University of Wurzburg, ¨ Wurzburg, ¨ 5 Mannheim Institute of Public Health, Medical Faculty Mannheim, Mannheim, 6 7 Division of Endocrinology and Diabetes, Ulm University, Ulm, Frankfurt Cardiology Centre, Frankfurt/Main, 8 Division of Nephrology, Ruperto Carola University Heidelberg, Heidelberg, Germany Introduction: Homoarginine is an amino acid derivate which increases nitric oxide levels and may prevent cardiovascular damage. We therefore evaluated whether homoarginine levels are associated with cardiovascular risk factors and mortality. Methods: We measured homoarginine levels in 3305 patients from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study, who had undergone coronary angiography at baseline (1997 to 2000). Results: Homoarginine levels declined with increasing age and were significantly higher in males compared to females. Impaired renal function, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and markers of endothelial dysfunction (ICAM-1 and VCAM-1) were significantly associated with homoarginine deficiency but we found no association with coronary artery disease, arterial hypertension and diabetes mellitus. During a median follow-up time of 7.7 years, 766 patients died including 482 deaths due to cardiovascular causes. Cox proportional hazard ratios (with 95% CI) for all-cause and cardiovascular mortality were 3.03 (2.44–3.77) and 4.13 (3.06–5.57), respectively, when comparing the first with the fourth homoarginine quartile. After adjustments for cardiovascular risk factors and indicators of malnutrition, these hazard ratios remained significant for all-cause mortality with 2.04 (1.56–2.65) and for cardiovascular mortality with 3.00 (2.11–4.28; p < 0.001 for all hazard ratios). Conclusions: Homoarginine deficiency is a significant and independent risk factor for all-cause and cardiovascular mortality in patients referred for coronary angiography. MS536 IMPORTANCE OF NON-HUMAN PRIMATES IN PRE-CLINICAL EVALUATION OF LXR AGONISTS H. McKinnon1 , S. Miller1 , N. Barnett1 , K. McGregor1 , D. Mallinson1 , H. Davidson-Smith1 , J. Bennett2 , H. Davis3 , D. Black1 . 1 Pharmacology, 2 Chemistry, Merck, Glasgow, UK , 3 Pharmacology, Merck, Kenilworth, NJ, USA LXR agonists provide an exciting opportunity for the treatment of metabolic diseases such as atherosclerosis. LXR has a central role in lipid metabolism to increase cholesterol efflux from macrophages via upregulation of ABCA1 and to increase circulating HDL, promoting the reverse cholesterol transport pathway. However, clinical development of LXR agonists has been hampered by their potential to adversely effect lipid balance, causing an increase in proatherogenic hepatic and plasma lipids. We have demonstrated that the lipid liability of an LXR agonist can be predicted from studies in cell systems. By measuring the expression of lipogenic genes and lipid accumulation, and comparing to the potency of the compound to upregulate ABCA1 mRNA expression, an apparent safety window can be identified. In order to establish how these in vitro effects translated in vivo, we tested a potent selective LXRab agonist in mice, rabbits and non-human primates (cynomolgus monkeys). Interestingly, when tested in mice and rabbits, the compound appeared to have a safety window between the desired potency on ABCA1 mRNA upregulation and the unwanted lipid side effects on triglyceride and LDL cholesterol. However, unlike this small animal data, in the cynomolgus monkey the compound did not show a safety window between these two effects; instead the in vitro cell data better predicted the in vivo responses. In summary, these data indicate that lipid liability can be assessed in robust cell systems in vitro, but caution should be taken in interpreting data from small laboratory animals.
Atherosclerosis Supplements 11, no. 2 (2010) 109–222
MS532 ASSOCIATION BETWEEN Lp(a) AND HDL CHOLESTEROL ON GENERAL POPULATION S. Pagoni1 , C. Charalampopoulos1 , D. Syrigos2 , E. Zoulias1 , C. Voulgari2 , B. Papalimneou2 , A. Mousouli1 , S. Paximadas2 . 1 Lipid Unit, General Hospital of Athens G. Gennimatas, 2 Lipid Unit, General Hospital of Athens ELPIS, Athens, Greece Introduction: Latter between risk factors for cardiovascular diseases included the increase of levels Lp(a) cholesterol. On the contrary, the elevated plasma levels of HDL cholesterol are a negative factor for coronary artery disease and stroke. Purpose: The aim of this study was to examine the possible role and association of Lp(a) on HDL on general population. Material and Methods: The study included 100 out patients, aged 35−81 years who examined in the Lipid Unit. Investigated the Lp(a) and HDL levels and correlated. All were whites and not taking any medication. All results were analyzed in the same laboratory. Statistical analysis was performed using a SPSS 11.0. Results: See the table. Table: Results for 100 out patients, with overall Lp(a) = 32.7±30.4 mg/dl (3.01– 164.7) and HDL = 45.6±6 (12–143) Lp(a), mg/dl
HDL
p-value
<10 <15 <20 <25 <30 <35
55.16 47.13 45.92 45.40 45.02 44.58
0.00 0.08 0.21 0.31 0.23 0.32
Conclusions: The study shows that when increased the Lp(a) levels, then decreased the HDL levels. MS533 THE CLINICAL IMPLICATIONS OF ADIPOCYTOKINE, SERUM RESISTEN IN DIABETICS WITH CORONARY ARTERY DISEASE W. Fatehy, A. Abd El Ghany, A. Abd El Kader, G. Kamal, M. Soliman. Menofyia, Sheben el Kom, Egypt Background: Diabetics with CAD have an unfavorable outcome even after PCI or CABG. So, investigations of novel atherogenesis markers such as serum resisten may have a potential role in early assessment of cardiovascular risk in such patients. Aim of the work: To assess serum resisten levels in diabetics with: stable CAD, ACS & healthy control. Subjects and Methods: The present study included forty patients with diabetes, twenty with CAD, group 1 (A with stable CAD and B with ACS), twenty without CAD, group 2 and twelve healthy as control, group 3. All subjects underwent: history taking and physical examinations ECG, Stress testing and or coronary angiography. Laboratory investigations: glycated HB, creatinine, lipid profile, HsCRP, Resisten. Results: Diabetics have significantly higher BMI, glycated HB, total cholesterol, TG, LDL, HsCRP & Resisten than healthy control. There was no significant deference between both diabetic groups as regards, BMI, lipogram, but group 1 have significantly higher HsCRP & Resisten. Diabetics with stable CAD have significantly higher age, glycated HB and significantly lower HsCRP& Resisten than those with ACS. Resisten was correlated with BMI, glycated HB, cholesterol, LDL, TG, HDL & HsCRP in diabetic patients. Conclusion: Diabetics with CAD have significantly higher serum resisten than diabetics without CAD & healty control. Also, diabetics with ACS have significantly higher serum resisten than diabetics with stable CAD. Serum resisten may serve as a biomarker of increased atherogenic risk in diabetic patients. MS534 GENOME-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR CORONARY ARTERY DISEASE ON CHROMOSOME 10p11.23 ¨ Lubeck, J. Erdmann. Medizinische Klinik II, Universitat ¨ Lubeck, ¨ Germany Recent GWAS identified 13 loci for CAD/MI. However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. We genotyped n = 1,157 MI cases and n = 1,748 controls from a populationbased study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage n = 462 SNPs showed association with MI at P < 1×10−3 in two-sided trend tests. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1,644 controls) and GerMIFS II (1,222 cases/1,298 controls). Nine SNPs, representing three regions, displayed consistent replication in this insilico analysis (P < 0.05 for each GWA sample): five SNPs at 9p21.3, a well-
217
known CAD/MI locus, two SNPs at 10p11.21 and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in KIAA1462 gene) in additional 5,790 cases and 5,302 controls confirmed the association (P = 9.54×10−4 ), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P = 3.52×10−11 [OR = 1.15 (1.11−1.20)]. Analysis of a GWA study followed by in-silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the etiology of these diseases. MS535 HOMOARGININE INDEPENDENTLY PREDICTS TOTAL AND CARDIOVASCULAR MORTALITY IN INDIVIDUALS WITH ANGIOGRAPHIC CORONARY ARTERY DISEASE W. Marz ¨ 1,2 , A. Meinitzer2 , S. Pilz3 , C. Drechsler4 , V. Krane4 , M. Kleber1 , 7 J. Fischer5 , B. Winkelmann6 , B. Bohm ¨ , E. Ritz8 , C. Wanner4 . 1 Synlab Medizinisches Versorgungszentrum Heidelberg GmbH, Eppelheim, Germany, 2 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, 3 Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Graz, Austria, 4 Department of Medicine, Division of Nephrology, University of Wurzburg, ¨ Wurzburg, ¨ 5 Mannheim Institute of Public Health, Medical Faculty Mannheim, Mannheim, 6 7 Division of Endocrinology and Diabetes, Ulm University, Ulm, Frankfurt Cardiology Centre, Frankfurt/Main, 8 Division of Nephrology, Ruperto Carola University Heidelberg, Heidelberg, Germany Introduction: Homoarginine is an amino acid derivate which increases nitric oxide levels and may prevent cardiovascular damage. We therefore evaluated whether homoarginine levels are associated with cardiovascular risk factors and mortality. Methods: We measured homoarginine levels in 3305 patients from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study, who had undergone coronary angiography at baseline (1997 to 2000). Results: Homoarginine levels declined with increasing age and were significantly higher in males compared to females. Impaired renal function, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and markers of endothelial dysfunction (ICAM-1 and VCAM-1) were significantly associated with homoarginine deficiency but we found no association with coronary artery disease, arterial hypertension and diabetes mellitus. During a median follow-up time of 7.7 years, 766 patients died including 482 deaths due to cardiovascular causes. Cox proportional hazard ratios (with 95% CI) for all-cause and cardiovascular mortality were 3.03 (2.44–3.77) and 4.13 (3.06–5.57), respectively, when comparing the first with the fourth homoarginine quartile. After adjustments for cardiovascular risk factors and indicators of malnutrition, these hazard ratios remained significant for all-cause mortality with 2.04 (1.56–2.65) and for cardiovascular mortality with 3.00 (2.11–4.28; p < 0.001 for all hazard ratios). Conclusions: Homoarginine deficiency is a significant and independent risk factor for all-cause and cardiovascular mortality in patients referred for coronary angiography. MS536 IMPORTANCE OF NON-HUMAN PRIMATES IN PRE-CLINICAL EVALUATION OF LXR AGONISTS H. McKinnon1 , S. Miller1 , N. Barnett1 , K. McGregor1 , D. Mallinson1 , H. Davidson-Smith1 , J. Bennett2 , H. Davis3 , D. Black1 . 1 Pharmacology, 2 Chemistry, Merck, Glasgow, UK , 3 Pharmacology, Merck, Kenilworth, NJ, USA LXR agonists provide an exciting opportunity for the treatment of metabolic diseases such as atherosclerosis. LXR has a central role in lipid metabolism to increase cholesterol efflux from macrophages via upregulation of ABCA1 and to increase circulating HDL, promoting the reverse cholesterol transport pathway. However, clinical development of LXR agonists has been hampered by their potential to adversely effect lipid balance, causing an increase in proatherogenic hepatic and plasma lipids. We have demonstrated that the lipid liability of an LXR agonist can be predicted from studies in cell systems. By measuring the expression of lipogenic genes and lipid accumulation, and comparing to the potency of the compound to upregulate ABCA1 mRNA expression, an apparent safety window can be identified. In order to establish how these in vitro effects translated in vivo, we tested a potent selective LXRab agonist in mice, rabbits and non-human primates (cynomolgus monkeys). Interestingly, when tested in mice and rabbits, the compound appeared to have a safety window between the desired potency on ABCA1 mRNA upregulation and the unwanted lipid side effects on triglyceride and LDL cholesterol. However, unlike this small animal data, in the cynomolgus monkey the compound did not show a safety window between these two effects; instead the in vitro cell data better predicted the in vivo responses. In summary, these data indicate that lipid liability can be assessed in robust cell systems in vitro, but caution should be taken in interpreting data from small laboratory animals.