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Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia
33
Workshom I
Inflammation IWI 1
- Related Aspects
EVALUATION OF SERUM NEOPTERIN LEVELS IN PATIENTS WITH CHRONIC CORONARY ARTERY DISEASE AND HYPERLIPIDAEMIA BEFORE AND AFTER LIPID LOWERING TREATMENT
P. Kiriakou,
T. Papadopoulos, M. Salame, S. Dhar, H. Steele, R. Ecob, I. Haq, D. Oakley. Northern General Hospital, UK
The aim of this study was to establish whether treatment of elevated lipids in patients with Hyperlipidaemia and coronary artery disease (CAD) has any consistent and significant effect on serum levels of neopterin. Neopterin and dihydroneopterin can be used as clinical markers of monocyte macrophage activation. (Ref 1). Macrophage activation is thought to play an important role in the pathogenesis of acute coronary syndromes (Ref 2, 3, 4) and in the progression of atherosclerotic lesions. (Ref 5) Plasma levels of neopterin were determined in 12 patients with chronic coronary artery disease and Hyperlipidaemia unresponsive to a tow fat diet. The control sample was taken at presentation and then three more samples were taken, one after 6 weeks on diet and another two at three months and six months after starting treatment with pravastatin. We called the control sample, sample 1, the six weeks sample, sample 2 and the three months and six months, sample 3 and sample 4 respectively. Only in 2 out of 12 patients the level of neopterin was above normal in the control sample and in all the other patients the level of neopterin was within normal limits in all samples. Using the paired t-test we compared the control sample with each one of the other samples independently. There was no significant difference between the control sample and sample 2 (t = .-23 p = 0.58), but there was a significant difference between the control sample and samples 2 and 3 respectively, (t = 0.84, p = 0.008, t = 0.49, p = 0.019). By comparing the means of samples 1 and 2 and samples 1 and 3, it seems that neopterin levels tend to decrease after starting treatment with pravastatin. Although the number of patients was small and most of the patients had normal neopterin levels throughout, these results may indicate that treatment of Hyperlipidaemia in patients with Coronary artery disease may lead to reduction of serum neopterin and hence influence macrophage activation. References [1] Dihydroneopterin inhibits low density lipoprotein oxidation in vitro. Evidence that this macrophage secreted pteridine is an anti-oxidant. Gieseg SP et al. H. Free Radical Research 23 (2): 123-36 1995 Aug [2] Macrophages, smooth muscle cells and tissue factor in unstable angina. lmplications for cell mediated tbrombogenicity in acute coronary syndromes. Moreno PR et al. Clinical Chemistry 40 (2): 338-7, 1996 Dee 15 [3] Increased urinary neopterin in acute myocardial infarction. Melichar B et al. Clinical Chemistry 40 (2): 338-9, 1994 Feb [4] Increased neopterin in patients with chronic and acute coronary syndromes. Schumacher M et al. JACC 30 (3): 703-7, 1997 Sep. [5] Increased concentrations of neopterin in carotid atherosclerosis. Weiss G et al. Atherosclerosis 106 (2): 263-71, 1994 April Iw1.21
PARAOXONASE GENE POLYMORPHISMS ARE ASSOCIATED WITH CAROTID ARTERIAL WALL THICKNESS IN SUBJECTS WITH FAMILIAL HYPERCHOLESTEROLEMIA
M. Roest, J.J. Kastelein, F.R. Leus, H.A.M. Voorbij. UMC-Utrecht, AX Clinical Chemistry, HPG03-647 PO-Box 85500, 3508 GA Utrecht, The Netherlands Human serum paraoxonase (PON-1) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON-1 inhibits oxidative modification of LDL and may therefore protect against atherosclerosis. PON-l-activity and plasma PON-l-levels are highly dependent of a L55M and a Rl92Q-polymorphism in the coding region of the PON-l-gene. Previously we have reported findings that FH-patients who were homozygous for both polymorphisms (LLQQ) expressed increased carotid atherosclerosis. Three, recently discovered polymorphisms (C-107T,
A-824G and G-907C) in the promotor region of PON-1 are associated with increased plasma PON-1 levels. We have studied the contribution of those five functional polymorphisms of PON-1 to arylesterase (PON-1) activity and to carotid atherosclerosis in 187 familial hypercholesterolemia (FH) patients. Carotid atherosclerosis was estimated with intima-media wall thickness (IMT) which was measured with high resolution B-mode ultrasound. The -107T polymorphism in the promotor region of the PON-1 gene was associated with 28% increased arylesterase activity (P < 0.001) and with 10.1% increased IMT (P = 0.02). Subjects who were homozygous for the L55, the Q192 and the -107T polymorphism had a 22.2% increased IMT (P = 0.02) and a 25% increased arylesterase activity when compared to other genotypes. In conclusion, functional polymorphisms in the PON-l-gene and in the promotor region of PON-1 was associated with increased PON-l-activity and with increased carotid atherosclerosis in subjects with FH. Those findings support the hypothesis that PON-1 is involved in atherosclerosis. Iw1.31
PARAOXONASE
(PONl)
& CORONARY
HEART
DISEASE
(CHD)
B. Mackness, PN. Durrington, W. Turkie, G.K. Davies, M.I. Mackness. University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester, UK The purpose of this investigation was to determine the relative importance of the PONl genetic polymorphisms compared to PONl quality (activity and concentration) in CHD PONl activity with paraoxon as substrate, concentration by ELISA and the PONl-55 and -192 polymorphisms by PCR and restriction digestion plus serum lipid and lipoprotein concentrations were determined in 427 subjects with angiographically proven CHD and 282 healthy controls. Subjects with CHD had higher serum triglycerides and lower total cholesterol and apo Al then controls (all P < 0.05). However, there were no differences in HDL-C or apo-B between the populations. Serum PONl activity in the CHD was half of that found in controls (122.8 (3.3-802.8) vs 214.6 (26.3-620.8) U\L, P < 0.001) and the PONl concentration was also significantly lower (71.6 (11.4489.3) vs 89.1 (16.8-527.4) pg\ml, P < 0.001) in the CHD population. Both were reduced independently of PONl genotype and there were no differences in the PONl-55 and -192 gene distributions between the 2 populations and no effect of the polymorphisms on serum lipids or lipoproteins. These results indicate that quality and PONl which may protect LDL by hydrolysing lipid-peroxides is decreased in both activity and concentration in CHD and that derangement of the quality of the enzyme is more important than genotype. jw1.41
ASSOCIATION BETWEEN THE PPARA L162V POLYMORPHISM AND PLASMA LIPID LEVELS. INTERACTIONS WITH THE APOE, APOC3 AND LOCI: THE FRAMINGHAM OFFSPRING STUDY
LPL
E.S. Tai, D. Corella, F!W.E Wilson, L.A. Cupples, E.J. Schaefer, J.M. Ordovas. Human Nut&ion Research Center on Ageing at Tufts University, 711 Washington Street, Boston, MA 02111. USA Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. Recently, polymorphisms at the PPARA locus have been shown to influence lipid levels. We have studied the Ll62V polymorphism in 2786 subjects (1367 mean and 1419 women) participating in a large prospective study: The Framingham Offspring study. Frequency of the V162 allele was 0.069. Male carriers of the V 162 allele had higher total cholesterol and LDL cholesterol as compared to non-carriers (211 mg/dl vs 204 mgdl, p = 0.023 and 140 mg/dl vs 134 mg/dl, p = 0.03 respectively). A similar trend was observed in women but this did not achieve statistical significance. No association was observed between this polymorphism and BMI. Gene-Gene interactions were examined with other candidate genes, namely the APOE, APOC3 and LPL. Our data reveals that the hypercholesterolemic effect of the PPARA V162 allele was greatest in carriers of the ~2 allele at the APOE locus and
72nd EAS Congress
Workshom I
Inflammation IWI 1
- Related Aspects
EVALUATION OF SERUM NEOPTERIN LEVELS IN PATIENTS WITH CHRONIC CORONARY ARTERY DISEASE AND HYPERLIPIDAEMIA BEFORE AND AFTER LIPID LOWERING TREATMENT
P. Kiriakou,
T. Papadopoulos, M. Salame, S. Dhar, H. Steele, R. Ecob, I. Haq, D. Oakley. Northern General Hospital, UK
The aim of this study was to establish whether treatment of elevated lipids in patients with Hyperlipidaemia and coronary artery disease (CAD) has any consistent and significant effect on serum levels of neopterin. Neopterin and dihydroneopterin can be used as clinical markers of monocyte macrophage activation. (Ref 1). Macrophage activation is thought to play an important role in the pathogenesis of acute coronary syndromes (Ref 2, 3, 4) and in the progression of atherosclerotic lesions. (Ref 5) Plasma levels of neopterin were determined in 12 patients with chronic coronary artery disease and Hyperlipidaemia unresponsive to a tow fat diet. The control sample was taken at presentation and then three more samples were taken, one after 6 weeks on diet and another two at three months and six months after starting treatment with pravastatin. We called the control sample, sample 1, the six weeks sample, sample 2 and the three months and six months, sample 3 and sample 4 respectively. Only in 2 out of 12 patients the level of neopterin was above normal in the control sample and in all the other patients the level of neopterin was within normal limits in all samples. Using the paired t-test we compared the control sample with each one of the other samples independently. There was no significant difference between the control sample and sample 2 (t = .-23 p = 0.58), but there was a significant difference between the control sample and samples 2 and 3 respectively, (t = 0.84, p = 0.008, t = 0.49, p = 0.019). By comparing the means of samples 1 and 2 and samples 1 and 3, it seems that neopterin levels tend to decrease after starting treatment with pravastatin. Although the number of patients was small and most of the patients had normal neopterin levels throughout, these results may indicate that treatment of Hyperlipidaemia in patients with Coronary artery disease may lead to reduction of serum neopterin and hence influence macrophage activation. References [1] Dihydroneopterin inhibits low density lipoprotein oxidation in vitro. Evidence that this macrophage secreted pteridine is an anti-oxidant. Gieseg SP et al. H. Free Radical Research 23 (2): 123-36 1995 Aug [2] Macrophages, smooth muscle cells and tissue factor in unstable angina. lmplications for cell mediated tbrombogenicity in acute coronary syndromes. Moreno PR et al. Clinical Chemistry 40 (2): 338-7, 1996 Dee 15 [3] Increased urinary neopterin in acute myocardial infarction. Melichar B et al. Clinical Chemistry 40 (2): 338-9, 1994 Feb [4] Increased neopterin in patients with chronic and acute coronary syndromes. Schumacher M et al. JACC 30 (3): 703-7, 1997 Sep. [5] Increased concentrations of neopterin in carotid atherosclerosis. Weiss G et al. Atherosclerosis 106 (2): 263-71, 1994 April Iw1.21
PARAOXONASE GENE POLYMORPHISMS ARE ASSOCIATED WITH CAROTID ARTERIAL WALL THICKNESS IN SUBJECTS WITH FAMILIAL HYPERCHOLESTEROLEMIA
M. Roest, J.J. Kastelein, F.R. Leus, H.A.M. Voorbij. UMC-Utrecht, AX Clinical Chemistry, HPG03-647 PO-Box 85500, 3508 GA Utrecht, The Netherlands Human serum paraoxonase (PON-1) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON-1 inhibits oxidative modification of LDL and may therefore protect against atherosclerosis. PON-l-activity and plasma PON-l-levels are highly dependent of a L55M and a Rl92Q-polymorphism in the coding region of the PON-l-gene. Previously we have reported findings that FH-patients who were homozygous for both polymorphisms (LLQQ) expressed increased carotid atherosclerosis. Three, recently discovered polymorphisms (C-107T,
A-824G and G-907C) in the promotor region of PON-1 are associated with increased plasma PON-1 levels. We have studied the contribution of those five functional polymorphisms of PON-1 to arylesterase (PON-1) activity and to carotid atherosclerosis in 187 familial hypercholesterolemia (FH) patients. Carotid atherosclerosis was estimated with intima-media wall thickness (IMT) which was measured with high resolution B-mode ultrasound. The -107T polymorphism in the promotor region of the PON-1 gene was associated with 28% increased arylesterase activity (P < 0.001) and with 10.1% increased IMT (P = 0.02). Subjects who were homozygous for the L55, the Q192 and the -107T polymorphism had a 22.2% increased IMT (P = 0.02) and a 25% increased arylesterase activity when compared to other genotypes. In conclusion, functional polymorphisms in the PON-l-gene and in the promotor region of PON-1 was associated with increased PON-l-activity and with increased carotid atherosclerosis in subjects with FH. Those findings support the hypothesis that PON-1 is involved in atherosclerosis. Iw1.31
PARAOXONASE
(PONl)
& CORONARY
HEART
DISEASE
(CHD)
B. Mackness, PN. Durrington, W. Turkie, G.K. Davies, M.I. Mackness. University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester, UK The purpose of this investigation was to determine the relative importance of the PONl genetic polymorphisms compared to PONl quality (activity and concentration) in CHD PONl activity with paraoxon as substrate, concentration by ELISA and the PONl-55 and -192 polymorphisms by PCR and restriction digestion plus serum lipid and lipoprotein concentrations were determined in 427 subjects with angiographically proven CHD and 282 healthy controls. Subjects with CHD had higher serum triglycerides and lower total cholesterol and apo Al then controls (all P < 0.05). However, there were no differences in HDL-C or apo-B between the populations. Serum PONl activity in the CHD was half of that found in controls (122.8 (3.3-802.8) vs 214.6 (26.3-620.8) U\L, P < 0.001) and the PONl concentration was also significantly lower (71.6 (11.4489.3) vs 89.1 (16.8-527.4) pg\ml, P < 0.001) in the CHD population. Both were reduced independently of PONl genotype and there were no differences in the PONl-55 and -192 gene distributions between the 2 populations and no effect of the polymorphisms on serum lipids or lipoproteins. These results indicate that quality and PONl which may protect LDL by hydrolysing lipid-peroxides is decreased in both activity and concentration in CHD and that derangement of the quality of the enzyme is more important than genotype. jw1.41
ASSOCIATION BETWEEN THE PPARA L162V POLYMORPHISM AND PLASMA LIPID LEVELS. INTERACTIONS WITH THE APOE, APOC3 AND LOCI: THE FRAMINGHAM OFFSPRING STUDY
LPL
E.S. Tai, D. Corella, F!W.E Wilson, L.A. Cupples, E.J. Schaefer, J.M. Ordovas. Human Nut&ion Research Center on Ageing at Tufts University, 711 Washington Street, Boston, MA 02111. USA Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. Recently, polymorphisms at the PPARA locus have been shown to influence lipid levels. We have studied the Ll62V polymorphism in 2786 subjects (1367 mean and 1419 women) participating in a large prospective study: The Framingham Offspring study. Frequency of the V162 allele was 0.069. Male carriers of the V 162 allele had higher total cholesterol and LDL cholesterol as compared to non-carriers (211 mg/dl vs 204 mgdl, p = 0.023 and 140 mg/dl vs 134 mg/dl, p = 0.03 respectively). A similar trend was observed in women but this did not achieve statistical significance. No association was observed between this polymorphism and BMI. Gene-Gene interactions were examined with other candidate genes, namely the APOE, APOC3 and LPL. Our data reveals that the hypercholesterolemic effect of the PPARA V162 allele was greatest in carriers of the ~2 allele at the APOE locus and
72nd EAS Congress