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The prevalence of familial hyperlipidaemia and hyper-lipoprotein(a) in mutation-negative familial hypercholesterolaemia and associations with cardiovascular events
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Abstracts / Atherosclerosis 252 (2016) e197ee235
of Chronic Disease Prevention, Turku, Finland; 3 Finnish Tax Administration, Helsinki, Finland; 4 Lund University, Department of Clinical Sciences, €, Sweden; 5 Helsinki University Central Hospital, Division of Malmo Endocrinology, Helsinki, Finland; 6 National Institute for Health and Welfare, Genomics and Biomarkers Unit, Helsinki, Finland; 7 Wihuri Research Institute, Helsinki, Finland Objectives: De novo lipogenesis (DNL), the synthesis of fatty acids from non-lipid precursors in adipose tissue and in the liver has been suggested to regulate metabolic homeostasis. High-fat diet efficiently inhibits the DNL pathway, but mice deficient in adipocyte lipid chaperones (fatty acidbinding proteins, FABPs, -4 and-5), are resistant to this feedback regulation. Sustained adipocyte DNL during high-fat diet leads to increased production and secretion of palmitoleate from adipocytes and finally incorporation of palmitoleate into circulating lipids. Palmitoleate in turn promotes insulin action in skeletal muscle and attenuates the development of hepatic steatosis, partially negating the detrimental effects of excess calorie intake. However, the role of FABPs, in the regulation of metabolic homeostasis remains largely unexplored in man. Methods: A low-expression variant of FABP4 (rs77878271) has been connected to improved lipid profile and reduced incidence of diabetes and cardiovascular events. Some of these metabolic advantages are enhanced or exclusively evident in obese carriers (BMI30), suggesting a mechanistic link between body weight and reduced FABP4 transcription. We hypothesized that this FABP4 haploinsufficiency could translate into sustained adipocyte DNL during obesity and in part explain the metabolic advantages in variant allele carriers. Results: Our results indicate that the FABP4 rs77878271 variant associates with increased proportion of palmitoleate and palmitoleate-to-palmitate ratio in total serum lipids, reduced circulating FABP4 protein levels, improved b-cell function, and reduced obesity-related type 2 diabetes risk (P¼0.001). Conclusions: Genetically reduced FABP4 expression may modulate adipocyte DNL and metabolic responses during obesity implicating a role for FABP4 in regulating obesity-related diabetes risk in man.
EAS16-0830, GENETIC, OMICS AND IN SILICO APPROACHES. THE PREVALENCE OF FAMILIAL HYPERLIPIDAEMIA AND HYPERLIPOPROTEIN(A) IN MUTATION-NEGATIVE FAMILIAL HYPERCHOLESTEROLAEMIA AND ASSOCIATIONS WITH CARDIOVASCULAR EVENTS K. Ellis 1, J. Pang 1, D. Chan 1, A. Hooper 2, D. Bell 1, J. Burnett 2, G. Watts 1. 1 The University of Western Australia, School of Medicine and Pharmacology-Royal Perth Hospital Unit, Perth, Australia; 2 Royal Perth Hospital, PathWest Laboratory Medicine WA, Perth, Australia Objectives: Familial hypercholesterolaemia (FH) is a highly atherogenic disorder of apolipoprotein B (apoB) metabolism. An FH-causing mutation is not identified in 40 to 60% of index cases presenting phenotypically with FH suggesting the existence of other inherited apoB hyperlipidaemias, such as familial combined hyperlipidaemia (FCHL) and hyper-lipoprotein(a), in these individuals. We investigated the prevalence of FCHL and hyper-Lp(a) in mutation-negative FH. Methods: A diagnostic nomogram for FCHL was applied to 282 FH mutation-negative index cases attending the Lipid Disorders Clinic at Royal Perth Hospital. Levels of plasma Lp(a) were measured by an immunoassay considered independent of apo(a) isoform size. Hyper-Lp(a) was defined as Lp(a) 0.5g/L based on previous associations with cardiovascular risk. Clinical characteristics between those with and without FCHL and hyperLp(a) were investigated using comparison of means and Chi-square analyses. Predictors of CVD events were assessed using binary logistic regression. Results: 51.9% of mutation-negative FH patients exhibited probable FCHL. These patients were older (P¼0.004), had a higher BMI (P¼0.004) and systolic (P¼0.002) and diastolic blood pressures (P¼0.001) compared with those without FCHL. Elevated Lp(a) was observed in 43.8% of index cases; there were no significant differences in clinical characteristics with Lp(a)
status. Elevated Lp(a) (P¼0.001; OR¼2.94; 95% CI¼1.52-2.66) but not FCHL was a predictor of CVD events, with this association independent of potential confounding factors. Elevated Lp(a) exacerbated CVD risk in patients with and without FCHL. Conclusions: FCHL and elevated Lp(a) are common in mutation-negative FH. Furthermore, elevated Lp(a) significantly increases CVD risk and should be considered in these patients.
EAS16-0320, GENETIC, OMICS AND IN SILICO APPROACHES. THE RS16900627 POLYMORPHISM OF THE RECEPTOR-INTERACTING PROTEIN 2 (RIP2) GENE IS ASSOCIATED WITH SUBCLINICAL ATHEROSCLEROSIS. THE GENETICS OF ATHEROSCLEROTIC DISEASE (GEA) MEXICAN STUDY nchez 2, J. Angeles-Martínez 1, E. G. Vargas-Alarcon 1, R. Posadas-Sa rez-Herna nez 1, J.M. Rodríguez-Pe rez 1, J.M. n 1, N. Pe Alvarez-Leo 1 2 3 G. Cardoso , T. Villarreal-Molina , C. PosadasFragoso , vez, Molecular Romero 2. 1 Instituto Nacional de Cardiología Ignacio Cha vez, Biology, Mexico, Mexico; 2 Instituto Nacional de Cardiología Ignacio Cha Endocrinology, Mexico, Mexico; 3 Cardiovascular Genomics Laboratory, mica, Mexico, Mexico Instituto de Medicina Geno Objectives: To evaluate the role of RIP2 gene polymorphisms as susceptibility markers for subclinical atherosclerosis (SA). Methods: Using an informatics analysis, four RIP2 gene polymorphisms with possible functional effect (rs2293808, rs43133, rs431264, and rs16900627) were selected. The polymorphisms were genotyped in 405 individuals with subclinical atherosclerosis (calcium score>1 assessed by computed tomography) and 1099 controls (calcium score¼0). Clinical, anthropometric and biochemical measurements were performed. The association between the RIP2 polymorphism with SA was evaluated using logistic regression analyses. Pairwise linkage disequilibrium (LD, D0 ) estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 4:1 Results: Under dominant and additive models adjusted by age, gender, body mass index, hypertension, diabetes mellitus, smoking habit, total cholesterol, cholesterol-HDL, cholesterol LDL and triglycerides, the rs16900627 polymorphism was associated with risk of developing SA (OR ¼ 1.59, 95%CI: 1.00-2.54, Pdom ¼ 0.048; OR ¼ 1.60, 95%CI: 1.05-2.54, Padd ¼ 0.028). The four polymorphisms were in high linkage disequilibrium forming 5 haplotypes (GAGA, GTAA, GAAG, AAAA, GAAA). The GAAG haplotype was associated with increased risk of developing SA (OR ¼ 1.47, 95%CI: 1.01-2.16, P ¼ 0.027). Conclusions: For the first time, our study shows that the RIP2 rs16900627 polymorphism is associated with risk of developing SA. The four RIP2 polymorphisms were in high linkage disequilibrium and one haplotype was significantly associated with risk of developing SA.
EAS16-0514, GENETIC, OMICS AND IN SILICO APPROACHES. RARE VARIANTS IN ABCG2 IDENTIFIED BY SEQUENCING MAY INFLUENCE THE LIPID RESPONSE TO ROSUVASTATIN TREATMENT M. Hu, J. Chan, B. Tomlinson. The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, Hong Kong, China Objectives: The efflux transporter ATP-binding cassette transporter G2 (ABCG2) plays an important role in the pharmacokinetics and the lipidlowering effect of rosuvastatin. In additional to common polymorphisms, rare variants in ABCG2 might also affect the lipid response to rosuvatatin. Methods: In 386 Chinese patients who received rosuvastatin 10 mg daily for at least 4 weeks, we sequenced the promoter and the 16 exons of ABCG2 in 80 patients with good or poor lipid response (n¼40 for each group). Results: The mean(±SD) LDL-C response to rosuvastatin in the good and poor responders were -66.7±3.6% and -31.6±7.4%, respectively. Poor responders were younger (54.3±11.6 years vs. 59.8±10.0, P<0.05) and there were more males in this group of patients (57.5% vs. 35.0%, P<0.05). We
Abstracts / Atherosclerosis 252 (2016) e197ee235
of Chronic Disease Prevention, Turku, Finland; 3 Finnish Tax Administration, Helsinki, Finland; 4 Lund University, Department of Clinical Sciences, €, Sweden; 5 Helsinki University Central Hospital, Division of Malmo Endocrinology, Helsinki, Finland; 6 National Institute for Health and Welfare, Genomics and Biomarkers Unit, Helsinki, Finland; 7 Wihuri Research Institute, Helsinki, Finland Objectives: De novo lipogenesis (DNL), the synthesis of fatty acids from non-lipid precursors in adipose tissue and in the liver has been suggested to regulate metabolic homeostasis. High-fat diet efficiently inhibits the DNL pathway, but mice deficient in adipocyte lipid chaperones (fatty acidbinding proteins, FABPs, -4 and-5), are resistant to this feedback regulation. Sustained adipocyte DNL during high-fat diet leads to increased production and secretion of palmitoleate from adipocytes and finally incorporation of palmitoleate into circulating lipids. Palmitoleate in turn promotes insulin action in skeletal muscle and attenuates the development of hepatic steatosis, partially negating the detrimental effects of excess calorie intake. However, the role of FABPs, in the regulation of metabolic homeostasis remains largely unexplored in man. Methods: A low-expression variant of FABP4 (rs77878271) has been connected to improved lipid profile and reduced incidence of diabetes and cardiovascular events. Some of these metabolic advantages are enhanced or exclusively evident in obese carriers (BMI30), suggesting a mechanistic link between body weight and reduced FABP4 transcription. We hypothesized that this FABP4 haploinsufficiency could translate into sustained adipocyte DNL during obesity and in part explain the metabolic advantages in variant allele carriers. Results: Our results indicate that the FABP4 rs77878271 variant associates with increased proportion of palmitoleate and palmitoleate-to-palmitate ratio in total serum lipids, reduced circulating FABP4 protein levels, improved b-cell function, and reduced obesity-related type 2 diabetes risk (P¼0.001). Conclusions: Genetically reduced FABP4 expression may modulate adipocyte DNL and metabolic responses during obesity implicating a role for FABP4 in regulating obesity-related diabetes risk in man.
EAS16-0830, GENETIC, OMICS AND IN SILICO APPROACHES. THE PREVALENCE OF FAMILIAL HYPERLIPIDAEMIA AND HYPERLIPOPROTEIN(A) IN MUTATION-NEGATIVE FAMILIAL HYPERCHOLESTEROLAEMIA AND ASSOCIATIONS WITH CARDIOVASCULAR EVENTS K. Ellis 1, J. Pang 1, D. Chan 1, A. Hooper 2, D. Bell 1, J. Burnett 2, G. Watts 1. 1 The University of Western Australia, School of Medicine and Pharmacology-Royal Perth Hospital Unit, Perth, Australia; 2 Royal Perth Hospital, PathWest Laboratory Medicine WA, Perth, Australia Objectives: Familial hypercholesterolaemia (FH) is a highly atherogenic disorder of apolipoprotein B (apoB) metabolism. An FH-causing mutation is not identified in 40 to 60% of index cases presenting phenotypically with FH suggesting the existence of other inherited apoB hyperlipidaemias, such as familial combined hyperlipidaemia (FCHL) and hyper-lipoprotein(a), in these individuals. We investigated the prevalence of FCHL and hyper-Lp(a) in mutation-negative FH. Methods: A diagnostic nomogram for FCHL was applied to 282 FH mutation-negative index cases attending the Lipid Disorders Clinic at Royal Perth Hospital. Levels of plasma Lp(a) were measured by an immunoassay considered independent of apo(a) isoform size. Hyper-Lp(a) was defined as Lp(a) 0.5g/L based on previous associations with cardiovascular risk. Clinical characteristics between those with and without FCHL and hyperLp(a) were investigated using comparison of means and Chi-square analyses. Predictors of CVD events were assessed using binary logistic regression. Results: 51.9% of mutation-negative FH patients exhibited probable FCHL. These patients were older (P¼0.004), had a higher BMI (P¼0.004) and systolic (P¼0.002) and diastolic blood pressures (P¼0.001) compared with those without FCHL. Elevated Lp(a) was observed in 43.8% of index cases; there were no significant differences in clinical characteristics with Lp(a)
status. Elevated Lp(a) (P¼0.001; OR¼2.94; 95% CI¼1.52-2.66) but not FCHL was a predictor of CVD events, with this association independent of potential confounding factors. Elevated Lp(a) exacerbated CVD risk in patients with and without FCHL. Conclusions: FCHL and elevated Lp(a) are common in mutation-negative FH. Furthermore, elevated Lp(a) significantly increases CVD risk and should be considered in these patients.
EAS16-0320, GENETIC, OMICS AND IN SILICO APPROACHES. THE RS16900627 POLYMORPHISM OF THE RECEPTOR-INTERACTING PROTEIN 2 (RIP2) GENE IS ASSOCIATED WITH SUBCLINICAL ATHEROSCLEROSIS. THE GENETICS OF ATHEROSCLEROTIC DISEASE (GEA) MEXICAN STUDY nchez 2, J. Angeles-Martínez 1, E. G. Vargas-Alarcon 1, R. Posadas-Sa rez-Herna nez 1, J.M. Rodríguez-Pe rez 1, J.M. n 1, N. Pe Alvarez-Leo 1 2 3 G. Cardoso , T. Villarreal-Molina , C. PosadasFragoso , vez, Molecular Romero 2. 1 Instituto Nacional de Cardiología Ignacio Cha vez, Biology, Mexico, Mexico; 2 Instituto Nacional de Cardiología Ignacio Cha Endocrinology, Mexico, Mexico; 3 Cardiovascular Genomics Laboratory, mica, Mexico, Mexico Instituto de Medicina Geno Objectives: To evaluate the role of RIP2 gene polymorphisms as susceptibility markers for subclinical atherosclerosis (SA). Methods: Using an informatics analysis, four RIP2 gene polymorphisms with possible functional effect (rs2293808, rs43133, rs431264, and rs16900627) were selected. The polymorphisms were genotyped in 405 individuals with subclinical atherosclerosis (calcium score>1 assessed by computed tomography) and 1099 controls (calcium score¼0). Clinical, anthropometric and biochemical measurements were performed. The association between the RIP2 polymorphism with SA was evaluated using logistic regression analyses. Pairwise linkage disequilibrium (LD, D0 ) estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 4:1 Results: Under dominant and additive models adjusted by age, gender, body mass index, hypertension, diabetes mellitus, smoking habit, total cholesterol, cholesterol-HDL, cholesterol LDL and triglycerides, the rs16900627 polymorphism was associated with risk of developing SA (OR ¼ 1.59, 95%CI: 1.00-2.54, Pdom ¼ 0.048; OR ¼ 1.60, 95%CI: 1.05-2.54, Padd ¼ 0.028). The four polymorphisms were in high linkage disequilibrium forming 5 haplotypes (GAGA, GTAA, GAAG, AAAA, GAAA). The GAAG haplotype was associated with increased risk of developing SA (OR ¼ 1.47, 95%CI: 1.01-2.16, P ¼ 0.027). Conclusions: For the first time, our study shows that the RIP2 rs16900627 polymorphism is associated with risk of developing SA. The four RIP2 polymorphisms were in high linkage disequilibrium and one haplotype was significantly associated with risk of developing SA.
EAS16-0514, GENETIC, OMICS AND IN SILICO APPROACHES. RARE VARIANTS IN ABCG2 IDENTIFIED BY SEQUENCING MAY INFLUENCE THE LIPID RESPONSE TO ROSUVASTATIN TREATMENT M. Hu, J. Chan, B. Tomlinson. The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, Hong Kong, China Objectives: The efflux transporter ATP-binding cassette transporter G2 (ABCG2) plays an important role in the pharmacokinetics and the lipidlowering effect of rosuvastatin. In additional to common polymorphisms, rare variants in ABCG2 might also affect the lipid response to rosuvatatin. Methods: In 386 Chinese patients who received rosuvastatin 10 mg daily for at least 4 weeks, we sequenced the promoter and the 16 exons of ABCG2 in 80 patients with good or poor lipid response (n¼40 for each group). Results: The mean(±SD) LDL-C response to rosuvastatin in the good and poor responders were -66.7±3.6% and -31.6±7.4%, respectively. Poor responders were younger (54.3±11.6 years vs. 59.8±10.0, P<0.05) and there were more males in this group of patients (57.5% vs. 35.0%, P<0.05). We