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Cascade genetic screening for familial hypercholesterolemia in West Siberia
Abstracts / Atherosclerosis 252 (2016) e1ee196
protocols for FH management. Only 30% had a network of lipid clinics. More than half of the countries provided genetic (53%) and paediatric services (66%) to FH patients. Formal LDL apheresis service was only available in 7 countries (45%). All 15 countries or regions had cardiovascular imaging facilities available for FH patients. Australia, United Kingdom and Japan are the three countries providing all six services and facilities to FH patients. In contrast, the care of FH in Vietnam and the Philippines is suboptimal with less than three services and facilities available in their countries. Conclusions: This survey has identified important gaps in services and facilities for FH management. Further focus on implementation of national management guidelines, lipid clinic network and apheresis facilities are required, particularly in less developed countries.
EAS16-0680, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. SWITCH TO ROSUVASTATIN VERSUS ADDITION OF EZETIMIBE IN PATIENTS RECEIVING ATORVASTATIN: EFFECT ON URINE 8ISOPROSTANE LEVELS E. Klouras 1, C. Tellis 2, F. Barkas 1, E. Liberopoulos 1, M. Elisaf 1, A. Tselepis 2. 1 School of Medicine - University of Ioannina, Department of Internal Medicine, Ioannina, Greece; 2 Department of Chemistry- University of Ioannina, Atherothrombosis Research Centre / Laboratory of Biochemistry, Ioannina, Greece Objectives: Oxidative stress is an essential part of atherosclerosis, while statin treatment exhibit significant antioxidant activity. Urine 8-isoprostane, a non-enzymatic product of phospholipids’ oxidation, is a reliable marker of oxidative stress. The aim of the present study is to assess the effect of switch to rosuvastatin or addition of ezetimibe on urine 8-isoprostane levels of dyslipidemic patients receiving atorvastatin. Methods: Study’s population consisted of dyslipidemic patients taking atorvastatin (10 or 20 mg daily for at least three months) and not attaining the LDL-cholesterol targets according to European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) guidelines (n¼28). Thirteen subjects were assigned to rosuvastatin (20 or 40 mg daily, respectively) and 15 to ezetimibe (10 mg daily) on top of atorvastatin. After three months of treatment, we assessed the change of urine 8-isoprostane levels (expressed as urine 8-isoprostane/urine creatine ratio), quantificated with enzyme immunoassay (Cayman Chemical’s ACE EIA Kits), in the two groups. Results: In the group switching from atorvastatin to higher dose of rosuvastatin, urine 8-isoprostane levels reduced significantly by 43.5% (from 14.15 ± 9.47 ng/mmol to 8.00 ± 3.08 ng/mmol, p¼0.03). On the other hand, a non-significant change of urine 8-isoprostane levels was found after the addition of ezetimibe (from 14.16 ± 12.3 ng/mmol to 9.02 ± 5.99 ng/mmol, NS). Conclusions: Switching to higher dose of rosuvastatin significantly reduces urine 8-isoprostane levels in dyslipidemic subjects receiving atorvastatin, an effect which is not observed after a three month addition of ezetimibe to atorvastatin.
EAS16-0415, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. CASCADE GENETIC SCREENING FOR FAMILIAL HYPERCHOLESTEROLEMIA IN WEST SIBERIA E. Shakhtshneider 1, K. Makarenkova 2, D. Ivanoshchuk 1, P. Orlov 1, Y. Ragino 3, M. Voevoda 1. 1 Institute of Internal and Preventive Medicine, Laboratory of medical genetics, Novosibirsk, Russia; 2 Institute of Internal and Preventive Medicine, Clinical department, Novosibirsk, Russia; 3 Institute of Internal and Preventive Medicine, Laboratory of bichemistry, Novosibirsk, Russia Objectives: Familial hypercholesterolemia (FH) is one of the most common congenital metabolic disorders. Aim of study is examine of patients with FH using the principle of a cascade genetic screening in West Siberia.
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Methods: The study was performed in patients with a clinical diagnosis of definite FH (The Simon Broom Register Group and Dutch Lipid Clinic Network Criteria). 32 patients with total cholesterol level > 7 mmol/l were examined in clinical department in 2015 year. Definite FH according clinical criteria was identified in 12 patients, 47±14 age. It was 10 unrelated patients and 2 patients from one family (mother and son). The plasma lipid levels were determined by standard enzymatic assays. The LDLR gene was analyzed by targeted high-throughput sequencing (NimbleGen SeqCap Target Enrichment; GS Junior, Roche). Results: Mean TC level was 8±1,8 mmol/l in patients with FH. 50% of patients used statins. 42% of patients with FH had xanthomas. We found rs5930 and rs121908038 of LDLR that were associated with the FH in previous studies. Missense mutation Cys340Phe (rs755757866) has been identified as damaging (PolyPhen2, Score of 1.000). All of non-synonymous SNP were presented in heterozygous state. All patients had synonymous SNPs in LDLR and a lot of SNPs in introns of LDLR. Conclusions: In 10 of 12 patients with FH (83.3%) were identified changes in structure LDLR, which may lead to a change in the function of the LDL receptor. This study confirmed genetic heterogeneity of the spectrum of structural modifications of LDLR in FH patients. The study supported by RHF, N14-06-00867.
EAS16-0129, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. LIPID CLINIC EXPERIENCE OF GENOTYPING FOR FAMILIAL HYPERCHOLESTEROLAEMIA K. Shipman, R. Cramb. University Hospitals Birmingham NHS Foundation Trust, Department of Clinical Chemistry, Birmingham, United Kingdom Objectives: In the West Midlands commissioners have refused to fund widespread genotyping of possible familial hypercholesterolaemia (FH) cases therefore clinics have performed testing only when the data may help management of the case and their family. It is hoped that a cascade screening service will soon start in the region so clinic data were assessed to see if standard criteria would be suitable to select cases for screening. Methods: Six months of data from a large secondary care lipid clinic were examined, via laboratory systems and electronic notes. Results: Not all data were available but in total 21 patients were tested: 6 were heterozygous (5 LDLR and 1 ApoB), two were homozygous for LDLR mutations and one was compound heterozygous for LDLR and ApoB mutations (43% positive rate). Three patients were part of cascade screening; 2 were positive. Of the genotype negative 11 (92%) had documented family history of high lipids and all had a family history of premature cardiovascular disease except for 2, and 3 who had nothing on family history documented. The average total cholesterol was higher in the gene positive (11.5 mmol/L) versus the gene negative (8.0 mmol/L) but some numbers were estimated based on letters stating pre-treatment values. Only 1 had tendon xanthomata, the homozygous LDLR patient. Conclusions: Despite very selective testing, with only 3 of the 21 being for cascade screening, the mutation positive rate was only 43%. Higher cholesterol is more likely to be associated with a positive mutation in this cohort.
EAS16-0144, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. CAROTID PLAQUES AND INTIMA-MEDIA THICKNESS-ARE THE SAME RISK FACTORS IN MEN AND WOMEN WITH FAMILIAL HYPERCHOLESTEROLEMIA? M. Walus-Miarka 1, B. Idzior-Walus 1, D. Czarnecka 2, M. KlochBadełek 2, W. Wojciechowska 2, M. Kapusta 3. 1 Jagiellonian University Medical College, Metabolic Diseases, Krakow, Poland; 2 Jagiellonian University Medical College, I Department of Cardiology, Krakow, Poland; 3 Jagiellonian University Medical College, Biochemistry, Krakow, Poland Objectives: Familial hypercholesterolemia (FH) is strongly associated with premature coronary heart disease. It is autosomal dominant disorder and
protocols for FH management. Only 30% had a network of lipid clinics. More than half of the countries provided genetic (53%) and paediatric services (66%) to FH patients. Formal LDL apheresis service was only available in 7 countries (45%). All 15 countries or regions had cardiovascular imaging facilities available for FH patients. Australia, United Kingdom and Japan are the three countries providing all six services and facilities to FH patients. In contrast, the care of FH in Vietnam and the Philippines is suboptimal with less than three services and facilities available in their countries. Conclusions: This survey has identified important gaps in services and facilities for FH management. Further focus on implementation of national management guidelines, lipid clinic network and apheresis facilities are required, particularly in less developed countries.
EAS16-0680, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. SWITCH TO ROSUVASTATIN VERSUS ADDITION OF EZETIMIBE IN PATIENTS RECEIVING ATORVASTATIN: EFFECT ON URINE 8ISOPROSTANE LEVELS E. Klouras 1, C. Tellis 2, F. Barkas 1, E. Liberopoulos 1, M. Elisaf 1, A. Tselepis 2. 1 School of Medicine - University of Ioannina, Department of Internal Medicine, Ioannina, Greece; 2 Department of Chemistry- University of Ioannina, Atherothrombosis Research Centre / Laboratory of Biochemistry, Ioannina, Greece Objectives: Oxidative stress is an essential part of atherosclerosis, while statin treatment exhibit significant antioxidant activity. Urine 8-isoprostane, a non-enzymatic product of phospholipids’ oxidation, is a reliable marker of oxidative stress. The aim of the present study is to assess the effect of switch to rosuvastatin or addition of ezetimibe on urine 8-isoprostane levels of dyslipidemic patients receiving atorvastatin. Methods: Study’s population consisted of dyslipidemic patients taking atorvastatin (10 or 20 mg daily for at least three months) and not attaining the LDL-cholesterol targets according to European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) guidelines (n¼28). Thirteen subjects were assigned to rosuvastatin (20 or 40 mg daily, respectively) and 15 to ezetimibe (10 mg daily) on top of atorvastatin. After three months of treatment, we assessed the change of urine 8-isoprostane levels (expressed as urine 8-isoprostane/urine creatine ratio), quantificated with enzyme immunoassay (Cayman Chemical’s ACE EIA Kits), in the two groups. Results: In the group switching from atorvastatin to higher dose of rosuvastatin, urine 8-isoprostane levels reduced significantly by 43.5% (from 14.15 ± 9.47 ng/mmol to 8.00 ± 3.08 ng/mmol, p¼0.03). On the other hand, a non-significant change of urine 8-isoprostane levels was found after the addition of ezetimibe (from 14.16 ± 12.3 ng/mmol to 9.02 ± 5.99 ng/mmol, NS). Conclusions: Switching to higher dose of rosuvastatin significantly reduces urine 8-isoprostane levels in dyslipidemic subjects receiving atorvastatin, an effect which is not observed after a three month addition of ezetimibe to atorvastatin.
EAS16-0415, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. CASCADE GENETIC SCREENING FOR FAMILIAL HYPERCHOLESTEROLEMIA IN WEST SIBERIA E. Shakhtshneider 1, K. Makarenkova 2, D. Ivanoshchuk 1, P. Orlov 1, Y. Ragino 3, M. Voevoda 1. 1 Institute of Internal and Preventive Medicine, Laboratory of medical genetics, Novosibirsk, Russia; 2 Institute of Internal and Preventive Medicine, Clinical department, Novosibirsk, Russia; 3 Institute of Internal and Preventive Medicine, Laboratory of bichemistry, Novosibirsk, Russia Objectives: Familial hypercholesterolemia (FH) is one of the most common congenital metabolic disorders. Aim of study is examine of patients with FH using the principle of a cascade genetic screening in West Siberia.
e29
Methods: The study was performed in patients with a clinical diagnosis of definite FH (The Simon Broom Register Group and Dutch Lipid Clinic Network Criteria). 32 patients with total cholesterol level > 7 mmol/l were examined in clinical department in 2015 year. Definite FH according clinical criteria was identified in 12 patients, 47±14 age. It was 10 unrelated patients and 2 patients from one family (mother and son). The plasma lipid levels were determined by standard enzymatic assays. The LDLR gene was analyzed by targeted high-throughput sequencing (NimbleGen SeqCap Target Enrichment; GS Junior, Roche). Results: Mean TC level was 8±1,8 mmol/l in patients with FH. 50% of patients used statins. 42% of patients with FH had xanthomas. We found rs5930 and rs121908038 of LDLR that were associated with the FH in previous studies. Missense mutation Cys340Phe (rs755757866) has been identified as damaging (PolyPhen2, Score of 1.000). All of non-synonymous SNP were presented in heterozygous state. All patients had synonymous SNPs in LDLR and a lot of SNPs in introns of LDLR. Conclusions: In 10 of 12 patients with FH (83.3%) were identified changes in structure LDLR, which may lead to a change in the function of the LDL receptor. This study confirmed genetic heterogeneity of the spectrum of structural modifications of LDLR in FH patients. The study supported by RHF, N14-06-00867.
EAS16-0129, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. LIPID CLINIC EXPERIENCE OF GENOTYPING FOR FAMILIAL HYPERCHOLESTEROLAEMIA K. Shipman, R. Cramb. University Hospitals Birmingham NHS Foundation Trust, Department of Clinical Chemistry, Birmingham, United Kingdom Objectives: In the West Midlands commissioners have refused to fund widespread genotyping of possible familial hypercholesterolaemia (FH) cases therefore clinics have performed testing only when the data may help management of the case and their family. It is hoped that a cascade screening service will soon start in the region so clinic data were assessed to see if standard criteria would be suitable to select cases for screening. Methods: Six months of data from a large secondary care lipid clinic were examined, via laboratory systems and electronic notes. Results: Not all data were available but in total 21 patients were tested: 6 were heterozygous (5 LDLR and 1 ApoB), two were homozygous for LDLR mutations and one was compound heterozygous for LDLR and ApoB mutations (43% positive rate). Three patients were part of cascade screening; 2 were positive. Of the genotype negative 11 (92%) had documented family history of high lipids and all had a family history of premature cardiovascular disease except for 2, and 3 who had nothing on family history documented. The average total cholesterol was higher in the gene positive (11.5 mmol/L) versus the gene negative (8.0 mmol/L) but some numbers were estimated based on letters stating pre-treatment values. Only 1 had tendon xanthomata, the homozygous LDLR patient. Conclusions: Despite very selective testing, with only 3 of the 21 being for cascade screening, the mutation positive rate was only 43%. Higher cholesterol is more likely to be associated with a positive mutation in this cohort.
EAS16-0144, DYSLIPIDEMIAS: DYSLIPIDEMIAS, SCREENING AND TREATMENT. CAROTID PLAQUES AND INTIMA-MEDIA THICKNESS-ARE THE SAME RISK FACTORS IN MEN AND WOMEN WITH FAMILIAL HYPERCHOLESTEROLEMIA? M. Walus-Miarka 1, B. Idzior-Walus 1, D. Czarnecka 2, M. KlochBadełek 2, W. Wojciechowska 2, M. Kapusta 3. 1 Jagiellonian University Medical College, Metabolic Diseases, Krakow, Poland; 2 Jagiellonian University Medical College, I Department of Cardiology, Krakow, Poland; 3 Jagiellonian University Medical College, Biochemistry, Krakow, Poland Objectives: Familial hypercholesterolemia (FH) is strongly associated with premature coronary heart disease. It is autosomal dominant disorder and