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HT03-IS-001 Application of genetic testing in cascade genetic screening for familial hypercholesterolemia
How to Sessions HT3 Familial hypercholesterolaemia: clinical versus molecular diagnosis
178
increases the level of HDL-C is associated with a reduced incidence of coronary events. This was clearly apparent in the Helsinki Heart Study and the VA-HIT Study, both of which used a fibrate as the active agent. A reduction in coronary events associated with an elevation of HDL-C was also observed with a statin in the 4S trial. The benefit of increasing the HDL-C in both the fibrate and statin trials was independent of decreases in LDL-C or plasma triglyceride, although in the 4S trial most of the reduction in events could be explained by the decrease in LDL-C. In a more recent study the infusion of reconstituted HDL over a period of only 5 weeks resulted in a significant reduction in atheroma burden in humans with coronary artery disease. In the fibrate studies the extent of reduction in coronary events is disproportionately large in people with features of the metabolic syndrome such as overweight, elevated baseline levels of plasma triglyceride and low baseline HDL-C. In such people, treatment with fibrates resulted in a 40%-80% reduction in CHD events. It may be concluded that high coronary risk people whose HDL-C concentration is low will benefit by having their HDL-C increased to at least 40 mg/dl (1.0 mmol/L) by any means, whether by lifestyle measures (weight loss, regular exercise, stopping smoking) or drugs (fibrates, nicotinic acid, statins). In high risk people with features of the metabolic syndrome, however, the evidence favours therapy with a fibrate which, in such people, has clear benefits beyond effects on plasma lipid and lipopretein concentrations.
HT3 FAMILIAL H Y P E R C H O L E S T E R O L A E M I A : C L I N I C A L VERSUS M O L E C U L A R DIAGNOSIS [ HT03-1S-001 ] A P P L I C A T I O N OF GENETIC TESTING IN CASCADE GENETIC SCREENING F O R FAMILIAL H Y P E R C H O L E S T E R O L E M I A 1
1
T.P. Leren~ T.E. Manshaus, K.E. Berge. Medical Genetic Laboratory,
Department of Medical Genetics, Rikshospitale~ Oslo, Norway
Objective: A total
of 130 different mutations in the low density lipoprotein (LDL) receptor gene have been found to cause familial hypercholesterolemia among Norwegian patients. As of December 2004 3240 patients from 1243 unrelated families have been provided with a molecular genetic diagnosis. The most effective way of diagnosing FH patients is to screen close relatives of already diagnosed patients. This is referred to as cascade genetic screening. In this setting DNA testing in families where the underlying mutation in the LDL receptor gene has been identified, has a sensitivity and specificity close to 1.0. The objective of this study is to evaluate the feasibility of cascade genetic screening based upon genetic testing as part of ordinary health care in Norway. Methods: During the last four years a systematic cascade genetic screening program has been established in Norway. A total of 1660 relatives of 345 index patients have undergone genetic testing for the mutation that has been identified as the cause of FH in the family. A follow-up study of lipid measurements was conducted in affected relatives 6 months after the genetic testing to determine whether lif-style changes or changes in lipid lowering drug therapy, had been made subsequent to genetic testing. Remits: 48% of those tested were affected and 52% were unaffected. Only 42% of those affected were on lipid lowering drugs and only 6% had a value for total serum cholesterol bellow 5.0 mmol/1 at the time of genetic testing. Of those not under treatment aged 18 and above at the time of genetic testing, reductions in total serum cholesterol and LDL cholesterol of 21% (p<0.0001) and 30% (p<0.0001), respectively, were achieved 6 months after genetic testing. Conclnsions: We conclude that genetic testing as part of a cascade genetic screening program is a highly efficient tool to diagnose FH. Moreover, a molecular genetic diagnosis provided as part of a cascade genetic screening program, results in efficient therapeutic measures that significantly will reduce the risk of future coronary heart disease.
HT03-1S-O02 ] FAMILIAL H Y P E R C H O L E S T E R O L E M I A IN CHILDREN J.C. Dcfesche, J. Rodenburg, S. de Jongh, J.J.P. Kastelein, A. Wiegman.
Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, Amsterdam, the Netherlands. Background: Elevated LDL-cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial Hypercholesterelemia (FH) represents the paradigm of this relation.
Objective: To assess the value of LDL-C and carotid intima-media thickness (IMT) as predictors for CVD later in life. Methods: A total of 1034 consecutive children from FH kindreds were investigated with regard to fipoprotein levels, CVD risk factors and family history. 201 children with heterozygous FH and 80 unaffected sibfings, both in the age ranges of 8 to 18 years, were examined with B-mode ultrasound by measuring carotid wall IMT. Results: LDL-C levels over 3.50 mmol/l had a 0.98 post-test probability of predicting the presence of an LDL- receptor gene mutation. Children with FH in the highest LDL-C tertile (>6.23 retool/l) had a 1.7-times higher incidence of having a parent with FH suffering from premature CVD (P=0.001). In addition, such a parent was found 1.8 times more often among children with FH who had HDL-C below 1.00 mmol/l (P=0.004). Children with FH whose hpoprotein(a) was >300 mg/L had a 1.45-times higher incidence of having a parent with FH suffering from premature CVD (P=0.05). Mean combined carotid IMT of FH children was significantly greater than that of unaffected sibfings (0-494 mm [SD 0.051] vs. 0.472 [SD 0.049], P=0.002). A significant deviation in intima-media thickness was noted from age 12 years in children with FH. Conclusions: LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk. This risk is also reflected in the 5 times more rapid increase of carotid arterial wall intima-media thickness (IMT) during childhood years, compared to unaffected siblings. This faster progression led to a significant deviation in terms of IMT from the age of 12 years and onwards. Conversely, lipid lowering by statin therapy was accompanied by carotid IMT regression in children with FI-I, which suggested that initiation of LDL-C lowering medication in childhood can reduce or possibly inhibit the faster progression of athemsclerosis. I HT03-1S-003 1 DIAGNOSIS AND T R E A T M E N T OF FAMILIAL H Y P E R C H O L E S T E R O L E M I A IN C E N T R A L - E A S T E R N EUROPEAN C O U N T R I E S K. Raglovh 1, J. Gagparovic 1, T. Freiberger 2 . For Slovak and Czech MED PED group; 1Institute of Preventive and Clinical Medicine, Bratislava, Slovakia; 2 Center for Cardiovascular Surgery and Transplantation, Brno, Czech Republic Background: The clinical phenotype of familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature coronary heart disease. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified PCSK9 gene. Mutations in the APOB gene cause a metabolic disorder designated familial defective apoB-100 (FDB) which phenotype is often clinically indistinguishable from FH. It has been reported that the frequencies of FDB (mutations R3500Q) in hypercholesterolemic patients differ across Europe with the highest frequencies found in central Europe. Early diagnosis and treatment of FH patients has been a major objective of the international MED PED project. With respect to the national health care systems, different strategies of national MED PED projects have been implemented in Central - Eastern European (CEE) countries. In Slovakia since 2005, a three level medical system of screening, diagnosis and family DNA register of FH has been established and guaranteed by health insurance. Objective: For the current report we have compared prevalence of FDB among patients with clinical diagnosis of FH in Slovakia (SK), Czech Republic (CZ), Hungary (H,) Poland (P), Bulgaria (B) and Russia. Results: No FDB subject has been found among Russian FH patients. Frequencies of FDB among the unrelated hypercholesterolemic patients are presented in the table. Country FH/FDBnumber (%) Population/FDBnumber (%) CZ 1319/145 (11%) 409215 (0.12%)* SK 362/35 (9.7%) 2130/2 (0.09%)** H 73•4 (5.4%) No data P 525/13 (3.7%) No data B 13014 (3.1%) No data Legend: newborns, random population ofquadragenarians. There were no statistically significant differences in frequencies of FDB among FH patients and random population between CZ and SK. Frequencies of FDB were significantly higher in CZ and SK than in P
75th EAS Congress, 23-26 April 2005, Prague, Czech Republic
178
increases the level of HDL-C is associated with a reduced incidence of coronary events. This was clearly apparent in the Helsinki Heart Study and the VA-HIT Study, both of which used a fibrate as the active agent. A reduction in coronary events associated with an elevation of HDL-C was also observed with a statin in the 4S trial. The benefit of increasing the HDL-C in both the fibrate and statin trials was independent of decreases in LDL-C or plasma triglyceride, although in the 4S trial most of the reduction in events could be explained by the decrease in LDL-C. In a more recent study the infusion of reconstituted HDL over a period of only 5 weeks resulted in a significant reduction in atheroma burden in humans with coronary artery disease. In the fibrate studies the extent of reduction in coronary events is disproportionately large in people with features of the metabolic syndrome such as overweight, elevated baseline levels of plasma triglyceride and low baseline HDL-C. In such people, treatment with fibrates resulted in a 40%-80% reduction in CHD events. It may be concluded that high coronary risk people whose HDL-C concentration is low will benefit by having their HDL-C increased to at least 40 mg/dl (1.0 mmol/L) by any means, whether by lifestyle measures (weight loss, regular exercise, stopping smoking) or drugs (fibrates, nicotinic acid, statins). In high risk people with features of the metabolic syndrome, however, the evidence favours therapy with a fibrate which, in such people, has clear benefits beyond effects on plasma lipid and lipopretein concentrations.
HT3 FAMILIAL H Y P E R C H O L E S T E R O L A E M I A : C L I N I C A L VERSUS M O L E C U L A R DIAGNOSIS [ HT03-1S-001 ] A P P L I C A T I O N OF GENETIC TESTING IN CASCADE GENETIC SCREENING F O R FAMILIAL H Y P E R C H O L E S T E R O L E M I A 1
1
T.P. Leren~ T.E. Manshaus, K.E. Berge. Medical Genetic Laboratory,
Department of Medical Genetics, Rikshospitale~ Oslo, Norway
Objective: A total
of 130 different mutations in the low density lipoprotein (LDL) receptor gene have been found to cause familial hypercholesterolemia among Norwegian patients. As of December 2004 3240 patients from 1243 unrelated families have been provided with a molecular genetic diagnosis. The most effective way of diagnosing FH patients is to screen close relatives of already diagnosed patients. This is referred to as cascade genetic screening. In this setting DNA testing in families where the underlying mutation in the LDL receptor gene has been identified, has a sensitivity and specificity close to 1.0. The objective of this study is to evaluate the feasibility of cascade genetic screening based upon genetic testing as part of ordinary health care in Norway. Methods: During the last four years a systematic cascade genetic screening program has been established in Norway. A total of 1660 relatives of 345 index patients have undergone genetic testing for the mutation that has been identified as the cause of FH in the family. A follow-up study of lipid measurements was conducted in affected relatives 6 months after the genetic testing to determine whether lif-style changes or changes in lipid lowering drug therapy, had been made subsequent to genetic testing. Remits: 48% of those tested were affected and 52% were unaffected. Only 42% of those affected were on lipid lowering drugs and only 6% had a value for total serum cholesterol bellow 5.0 mmol/1 at the time of genetic testing. Of those not under treatment aged 18 and above at the time of genetic testing, reductions in total serum cholesterol and LDL cholesterol of 21% (p<0.0001) and 30% (p<0.0001), respectively, were achieved 6 months after genetic testing. Conclnsions: We conclude that genetic testing as part of a cascade genetic screening program is a highly efficient tool to diagnose FH. Moreover, a molecular genetic diagnosis provided as part of a cascade genetic screening program, results in efficient therapeutic measures that significantly will reduce the risk of future coronary heart disease.
HT03-1S-O02 ] FAMILIAL H Y P E R C H O L E S T E R O L E M I A IN CHILDREN J.C. Dcfesche, J. Rodenburg, S. de Jongh, J.J.P. Kastelein, A. Wiegman.
Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, Amsterdam, the Netherlands. Background: Elevated LDL-cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial Hypercholesterelemia (FH) represents the paradigm of this relation.
Objective: To assess the value of LDL-C and carotid intima-media thickness (IMT) as predictors for CVD later in life. Methods: A total of 1034 consecutive children from FH kindreds were investigated with regard to fipoprotein levels, CVD risk factors and family history. 201 children with heterozygous FH and 80 unaffected sibfings, both in the age ranges of 8 to 18 years, were examined with B-mode ultrasound by measuring carotid wall IMT. Results: LDL-C levels over 3.50 mmol/l had a 0.98 post-test probability of predicting the presence of an LDL- receptor gene mutation. Children with FH in the highest LDL-C tertile (>6.23 retool/l) had a 1.7-times higher incidence of having a parent with FH suffering from premature CVD (P=0.001). In addition, such a parent was found 1.8 times more often among children with FH who had HDL-C below 1.00 mmol/l (P=0.004). Children with FH whose hpoprotein(a) was >300 mg/L had a 1.45-times higher incidence of having a parent with FH suffering from premature CVD (P=0.05). Mean combined carotid IMT of FH children was significantly greater than that of unaffected sibfings (0-494 mm [SD 0.051] vs. 0.472 [SD 0.049], P=0.002). A significant deviation in intima-media thickness was noted from age 12 years in children with FH. Conclusions: LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk. This risk is also reflected in the 5 times more rapid increase of carotid arterial wall intima-media thickness (IMT) during childhood years, compared to unaffected siblings. This faster progression led to a significant deviation in terms of IMT from the age of 12 years and onwards. Conversely, lipid lowering by statin therapy was accompanied by carotid IMT regression in children with FI-I, which suggested that initiation of LDL-C lowering medication in childhood can reduce or possibly inhibit the faster progression of athemsclerosis. I HT03-1S-003 1 DIAGNOSIS AND T R E A T M E N T OF FAMILIAL H Y P E R C H O L E S T E R O L E M I A IN C E N T R A L - E A S T E R N EUROPEAN C O U N T R I E S K. Raglovh 1, J. Gagparovic 1, T. Freiberger 2 . For Slovak and Czech MED PED group; 1Institute of Preventive and Clinical Medicine, Bratislava, Slovakia; 2 Center for Cardiovascular Surgery and Transplantation, Brno, Czech Republic Background: The clinical phenotype of familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature coronary heart disease. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified PCSK9 gene. Mutations in the APOB gene cause a metabolic disorder designated familial defective apoB-100 (FDB) which phenotype is often clinically indistinguishable from FH. It has been reported that the frequencies of FDB (mutations R3500Q) in hypercholesterolemic patients differ across Europe with the highest frequencies found in central Europe. Early diagnosis and treatment of FH patients has been a major objective of the international MED PED project. With respect to the national health care systems, different strategies of national MED PED projects have been implemented in Central - Eastern European (CEE) countries. In Slovakia since 2005, a three level medical system of screening, diagnosis and family DNA register of FH has been established and guaranteed by health insurance. Objective: For the current report we have compared prevalence of FDB among patients with clinical diagnosis of FH in Slovakia (SK), Czech Republic (CZ), Hungary (H,) Poland (P), Bulgaria (B) and Russia. Results: No FDB subject has been found among Russian FH patients. Frequencies of FDB among the unrelated hypercholesterolemic patients are presented in the table. Country FH/FDBnumber (%) Population/FDBnumber (%) CZ 1319/145 (11%) 409215 (0.12%)* SK 362/35 (9.7%) 2130/2 (0.09%)** H 73•4 (5.4%) No data P 525/13 (3.7%) No data B 13014 (3.1%) No data Legend: newborns, random population ofquadragenarians. There were no statistically significant differences in frequencies of FDB among FH patients and random population between CZ and SK. Frequencies of FDB were significantly higher in CZ and SK than in P
75th EAS Congress, 23-26 April 2005, Prague, Czech Republic