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Characterization of two low density lipoprotein receptor (LDLR) gene mutations in Tunisian familial hypercholesterolemia
208
Skoumas
LDL levels S-times more than HDL predicts an adverse cardiovascular event, in patients with familial hypercholesterolemia. No associations were found between the outcome and the other investigated clinical and biochemical factors.
HYPERTRIGLYCERIDEMIA: 16591 PRIMARY
PREVENTION
A SECONDARY (ATP III)
TARGET
FOR
H. Slater E. Parafioriti, A. Tortora, S. Ilutovich. Ramos Mejia Hospital, -> Buenos Aires, Argentina Introduction:
ACTIVITY ON LIPOPROTEIN I657 THE EFFECT OF PHYSICAL LEVELS: THE ATTICA EPIDEMIOLOGICAL STUDY .I. Skoumas, C. Pitsavos, C. Chrysohoou, D. Panagiotakos, M. Toutouza, I. Papaioannou, A. Zeimbekis, C. Stefanadis, F! Toutouzas. Department Cardiology, School ofMedicine, Uniuersify ofAthens, Greece
of
Background:
The aim of this study is to evaluate the impact of physical activity on lipoproteins and fibrinogen levels on cardiovascular disease free subjects. Methods: The ATTICA study is a prospective population - based cohort designed to enrol 3073 men and women from the greater area of Athens. In this work we analysed data from 654 men (18-87 years old) and 826 women (18-89 years old). The levels of weekly physical activity classified by frequency (times per week) and duration (in y’s). Physically active were those who reported engaging in non-occupational physical activity >l/week. Fast serum concentrations of total cholesterol, triglycerides, HDL, apoA1, apoB, and Lp(a) were measured. Results: 846 (57%) subjects reported sedentary life while 220 (15%) reported rare exercise (l-2/ week) and 308 (21%) that regular exercise (>3 times/ week). An inverse association was found between body mass index and exercise status (27&5 vs. 26&4 vs. 25.5&4 Kg/m2, respectively, p
Our present knowledge of risk factors for atherosclerosis, compels us to focus our attention not only on LDL-C levels (historical goal) but also on triglyceride (TG) levels. Guidelines proposed by the NCEP Adult Treatment Panel (ATP III) emphasize that, besides reaching appropriate LDL-C levels, normal TG levels must also be achieved. And treatment targets have been changed accordingly. Objective: Quantify the achievement of the secondary targets of therapy (TG at 200 mg %) in primary prevention patients under diet and simvastatin. Material and Methods: Study design: retrospective. Primary prevention patients data base (1996&2001) from the Lipids & Atherosclerosis Working Group was revised. A selection was made of patients who, after 8 weeks on step 1 diet, still had LDL-C >160 mg % or >130 mg % (patients with either low or high CHD risk, respectively) and TG >200 mg %. Patients who had achieved the LDL-C goal (ATP II) after 12 weeks of treatment with diet and simvastatin (10 mg) were included in the analysis. Patients with diabetes were excluded. For each subgroup, the number of patients who had or had not achieved the recommended TG levels was assessed, as well as their pre- and post-treatment TG levels. Statistical analysis was performed using Students t-test for paired samples. PiO.05 was considered significant. Results: From a total of 590 primary prevention follow-up patients, 179 patients who had achieved ATP II LDL-C goals, after 8 weeks on step 1 diet, followed by 12 weeks on diet + simvastatin 10 mg/day, were selected. TG levels were significantly reduced in all patients: first visit: mean 273.51 mg % (SD 131.10) and week 12 (S12): 185.26 mg % (SD 84.27) P=O.OOl. TG level was reduced to less than 200 mg % in 132 patients (73.74%). In this group of patients, the initial TG level was 247.67 mg % (SD 86.43) and 155.3 1 mg % (SD 25.96) at week 12; P=O.OOl. Forty-seven patients (26.26%) remained with TG levels over 200 mg %; in this group of patients, initial TG levels were 346.46 mg % (SD 144.97) at first visit and 268.42mg% (SD 126.30) at week 12: P=O.O04. Conclusions: The treatment with diet and simvastatin to reach LDL-C target goal levels, can also achieve desirable TG levels in a high proportion of patients. There is, however, a number of patients (usually those with TG levels over the global TG sample mean at first visit), with persistent high TG levels after receiving this treatment. Some controversy exists in the literature as to the course of action to be followed in this group of patients.
I658 THE BENEFITS ACTIVITY MARKERS, OF MALES
J. Skoumas,
FROM LEISURE TIME PHYSICAL ON ANTHROPOGENIC AND INFLAMMATORY IN A POPULATION-BASED RANDOM SAMPLE AND FEMALES: THE ATTICA STUDY
C. Pitsavos, C. Chrysohoou, D. Panagiotakos, M. Toutouza, I. Papaioannou, A. Zeimbekis, C. Stefanadis, F! Toutouzas. Department Cardiology, School ofMedicine, Uniuersify ofAthens, Greece
Aims:
CHARACTERIZATION 16601
OF TWO LOW DENSITY LIPOPROTEIN RECEPTOR (LDLR) GENE MUTATIONS TUNISIAN FAMILIAL HYPERCHOLESTEROLEMIA
of
The aim of this study is to evaluate the effect of leisure time physical activity on fibrinogen and C-reactive protein (CRP) levels, in a random sample of cardiovascular disease-free subjects. Methods: In this work we analysed data from 654 men (18-87 years old) and 826 women (18-89 years old). Physically active were those who reported non-occupational physical activity >l/week (light, moderate, vigorous). The rest were considered physically inactive. Fast plasma fibrinogen concentration and levels of C-reactive protein (CRP) were measured by nephelometry. These data were examined cross-sectionally after taking into account the effect of several socio-demographic and other related variables. Results: Five hundred and thirty (36%) subjects reported physically active. The analysis showed that physical exercise, compared to sedentary life, is associated with a significant reduction of C-reactive protein (1.99 3.8 vs. 2.42 3.6 mg/dl, piO.05) and fibrinogen levels (30758 vs. 32783 mg/dl, PiO.05). The observed inverse association between CRP, fibrinogen levels and physical activity becomes stronger by the years and the duration of exercise. In particular, 5 years of systematic physical activity (>3 times/week) is associated with a reduction by 10% of CRP levels, in males (piO.05) and by 17% (piO.Ol), in females, while it was associated with a 15% reduction of fibrinogen levels, in males (p
IN
M.N. Slimane', S. Lestavel’, V. Clavey’, F! Benlian3, F. Maatouk4, M.H. Ben Farhat4, M. Hammami’ ‘Biochemistry Faculty ofMedicine, Monastir, Tunisia: ‘Pasteur Institute lJ545, Lille University: ‘Department ofBiology, St. Antoine Hospital, Paris, France: 4Department of Cardiology, Monastir Hospital, Monastir, Tunisia The aim of our study was to define mutations causing Familial Hypercholesterolemia (FH) in Tunisia. To gain information on this issue, DNA sequencing and functional studies of the LDLR activity on primary cell culture of skin fibroblasts was used for this purpose. We report two missense mutations in the LDLR gene in two unrelated FH families. One is a novel mutation (FH-Kairouan): a cysteine to serine substitution at codon 127 (TGT-TCT) in exon 4A. This mutation, which creates a recognition site for MnlI, was detected in 3 homozygotes and 6 heterozygotes from the same family. The second mutation (FH-Tozeur) is an aspartic to asparagine substitution at codon 245 (GAT-AAT) in exon 5 involving a CpG dinucleotide,previously reported in FH patient originating from Europe. In homozygotes, both mutations were associated with a severe clinical expression and abolished LDLR activity in cultured skin fibroblasts. Adults heterozygotes carriers of either of the two mutations, had significantly increased plasma LDL cholesterol but a moderate clinical expression. These mutations enrich the spectrum of FH mutations found in Tunisia with should be useful to perform more accurate studies on genotype/phenotype correlation.
73rd EAS Congress
Skoumas
LDL levels S-times more than HDL predicts an adverse cardiovascular event, in patients with familial hypercholesterolemia. No associations were found between the outcome and the other investigated clinical and biochemical factors.
HYPERTRIGLYCERIDEMIA: 16591 PRIMARY
PREVENTION
A SECONDARY (ATP III)
TARGET
FOR
H. Slater E. Parafioriti, A. Tortora, S. Ilutovich. Ramos Mejia Hospital, -> Buenos Aires, Argentina Introduction:
ACTIVITY ON LIPOPROTEIN I657 THE EFFECT OF PHYSICAL LEVELS: THE ATTICA EPIDEMIOLOGICAL STUDY .I. Skoumas, C. Pitsavos, C. Chrysohoou, D. Panagiotakos, M. Toutouza, I. Papaioannou, A. Zeimbekis, C. Stefanadis, F! Toutouzas. Department Cardiology, School ofMedicine, Uniuersify ofAthens, Greece
of
Background:
The aim of this study is to evaluate the impact of physical activity on lipoproteins and fibrinogen levels on cardiovascular disease free subjects. Methods: The ATTICA study is a prospective population - based cohort designed to enrol 3073 men and women from the greater area of Athens. In this work we analysed data from 654 men (18-87 years old) and 826 women (18-89 years old). The levels of weekly physical activity classified by frequency (times per week) and duration (in y’s). Physically active were those who reported engaging in non-occupational physical activity >l/week. Fast serum concentrations of total cholesterol, triglycerides, HDL, apoA1, apoB, and Lp(a) were measured. Results: 846 (57%) subjects reported sedentary life while 220 (15%) reported rare exercise (l-2/ week) and 308 (21%) that regular exercise (>3 times/ week). An inverse association was found between body mass index and exercise status (27&5 vs. 26&4 vs. 25.5&4 Kg/m2, respectively, p
Our present knowledge of risk factors for atherosclerosis, compels us to focus our attention not only on LDL-C levels (historical goal) but also on triglyceride (TG) levels. Guidelines proposed by the NCEP Adult Treatment Panel (ATP III) emphasize that, besides reaching appropriate LDL-C levels, normal TG levels must also be achieved. And treatment targets have been changed accordingly. Objective: Quantify the achievement of the secondary targets of therapy (TG at 200 mg %) in primary prevention patients under diet and simvastatin. Material and Methods: Study design: retrospective. Primary prevention patients data base (1996&2001) from the Lipids & Atherosclerosis Working Group was revised. A selection was made of patients who, after 8 weeks on step 1 diet, still had LDL-C >160 mg % or >130 mg % (patients with either low or high CHD risk, respectively) and TG >200 mg %. Patients who had achieved the LDL-C goal (ATP II) after 12 weeks of treatment with diet and simvastatin (10 mg) were included in the analysis. Patients with diabetes were excluded. For each subgroup, the number of patients who had or had not achieved the recommended TG levels was assessed, as well as their pre- and post-treatment TG levels. Statistical analysis was performed using Students t-test for paired samples. PiO.05 was considered significant. Results: From a total of 590 primary prevention follow-up patients, 179 patients who had achieved ATP II LDL-C goals, after 8 weeks on step 1 diet, followed by 12 weeks on diet + simvastatin 10 mg/day, were selected. TG levels were significantly reduced in all patients: first visit: mean 273.51 mg % (SD 131.10) and week 12 (S12): 185.26 mg % (SD 84.27) P=O.OOl. TG level was reduced to less than 200 mg % in 132 patients (73.74%). In this group of patients, the initial TG level was 247.67 mg % (SD 86.43) and 155.3 1 mg % (SD 25.96) at week 12; P=O.OOl. Forty-seven patients (26.26%) remained with TG levels over 200 mg %; in this group of patients, initial TG levels were 346.46 mg % (SD 144.97) at first visit and 268.42mg% (SD 126.30) at week 12: P=O.O04. Conclusions: The treatment with diet and simvastatin to reach LDL-C target goal levels, can also achieve desirable TG levels in a high proportion of patients. There is, however, a number of patients (usually those with TG levels over the global TG sample mean at first visit), with persistent high TG levels after receiving this treatment. Some controversy exists in the literature as to the course of action to be followed in this group of patients.
I658 THE BENEFITS ACTIVITY MARKERS, OF MALES
J. Skoumas,
FROM LEISURE TIME PHYSICAL ON ANTHROPOGENIC AND INFLAMMATORY IN A POPULATION-BASED RANDOM SAMPLE AND FEMALES: THE ATTICA STUDY
C. Pitsavos, C. Chrysohoou, D. Panagiotakos, M. Toutouza, I. Papaioannou, A. Zeimbekis, C. Stefanadis, F! Toutouzas. Department Cardiology, School ofMedicine, Uniuersify ofAthens, Greece
Aims:
CHARACTERIZATION 16601
OF TWO LOW DENSITY LIPOPROTEIN RECEPTOR (LDLR) GENE MUTATIONS TUNISIAN FAMILIAL HYPERCHOLESTEROLEMIA
of
The aim of this study is to evaluate the effect of leisure time physical activity on fibrinogen and C-reactive protein (CRP) levels, in a random sample of cardiovascular disease-free subjects. Methods: In this work we analysed data from 654 men (18-87 years old) and 826 women (18-89 years old). Physically active were those who reported non-occupational physical activity >l/week (light, moderate, vigorous). The rest were considered physically inactive. Fast plasma fibrinogen concentration and levels of C-reactive protein (CRP) were measured by nephelometry. These data were examined cross-sectionally after taking into account the effect of several socio-demographic and other related variables. Results: Five hundred and thirty (36%) subjects reported physically active. The analysis showed that physical exercise, compared to sedentary life, is associated with a significant reduction of C-reactive protein (1.99 3.8 vs. 2.42 3.6 mg/dl, piO.05) and fibrinogen levels (30758 vs. 32783 mg/dl, PiO.05). The observed inverse association between CRP, fibrinogen levels and physical activity becomes stronger by the years and the duration of exercise. In particular, 5 years of systematic physical activity (>3 times/week) is associated with a reduction by 10% of CRP levels, in males (piO.05) and by 17% (piO.Ol), in females, while it was associated with a 15% reduction of fibrinogen levels, in males (p
IN
M.N. Slimane', S. Lestavel’, V. Clavey’, F! Benlian3, F. Maatouk4, M.H. Ben Farhat4, M. Hammami’ ‘Biochemistry Faculty ofMedicine, Monastir, Tunisia: ‘Pasteur Institute lJ545, Lille University: ‘Department ofBiology, St. Antoine Hospital, Paris, France: 4Department of Cardiology, Monastir Hospital, Monastir, Tunisia The aim of our study was to define mutations causing Familial Hypercholesterolemia (FH) in Tunisia. To gain information on this issue, DNA sequencing and functional studies of the LDLR activity on primary cell culture of skin fibroblasts was used for this purpose. We report two missense mutations in the LDLR gene in two unrelated FH families. One is a novel mutation (FH-Kairouan): a cysteine to serine substitution at codon 127 (TGT-TCT) in exon 4A. This mutation, which creates a recognition site for MnlI, was detected in 3 homozygotes and 6 heterozygotes from the same family. The second mutation (FH-Tozeur) is an aspartic to asparagine substitution at codon 245 (GAT-AAT) in exon 5 involving a CpG dinucleotide,previously reported in FH patient originating from Europe. In homozygotes, both mutations were associated with a severe clinical expression and abolished LDLR activity in cultured skin fibroblasts. Adults heterozygotes carriers of either of the two mutations, had significantly increased plasma LDL cholesterol but a moderate clinical expression. These mutations enrich the spectrum of FH mutations found in Tunisia with should be useful to perform more accurate studies on genotype/phenotype correlation.
73rd EAS Congress