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Genetics familial hypercholesterolemia

Federico Bigazzi, Francesco Sbrana, Daniele Berretti, Zenti Maria Grazia, Sabina Zambon, Antonia Fabris, Maurizio Fonda, Giovanni B Vigna, Giovanna D'Alessandri, Stefano Passalacqua, Beatrice Dal Pino, Mascia Pianelli, Roberta Luciani, Andrea Ripoli, Daniela Rafanelli, Enzo Manzato, Luigi Cattin, Tiziana Sampietro
BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease...
August 1, 2018: Transfusion and Apheresis Science
Amy C Sturm, Joshua W Knowles, Samuel S Gidding, Zahid S Ahmad, Catherine D Ahmed, Christie M Ballantyne, Seth J Baum, Mafalda Bourbon, Alain Carrié, Marina Cuchel, Sarah D de Ferranti, Joep C Defesche, Tomas Freiberger, Ray E Hershberger, G Kees Hovingh, Lala Karayan, Johannes Jacob Pieter Kastelein, Iris Kindt, Stacey R Lane, Sarah E Leigh, MacRae F Linton, Pedro Mata, William A Neal, Børge G Nordestgaard, Raul D Santos, Mariko Harada-Shiba, Eric J Sijbrands, Nathan O Stitziel, Shizuya Yamashita, Katherine A Wilemon, David H Ledbetter, Daniel J Rader
Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives...
August 7, 2018: Journal of the American College of Cardiology
Sophie Béliard, Jean-Pierre Rabès, Bertrand Cariou, Michel Farnier, Michel Krempf, Jean Ferrières, Nicolas Danchin, Eric Bruckert
INTRODUCTION: Heterozygous familial hypercholesterolemia (FH) is one of the most frequent genetic diseases with a prevalence of 1/250. It is characterized by a very high cholesterol level since birth and is often complicated by cardiovascular diseases (CV) in young patients. While early diagnosis and appropriate therapeutic management can avoid CV complications, HF is largely under-diagnosed and therefore under-treated. METHODS: To investigate the management of HF in France, we conducted a survey with 495 general practitioners (n=200) and specialists (n=295)...
July 27, 2018: La Presse Médicale
Maria Mytilinaiou, Ioannis Kyrou, Mike Khan, Dimitris K Grammatopoulos, Harpal S Randeva
Familial hypercholesterolemia (FH) is a common genetic cause of premature cardiovascular disease (CVD). The reported prevalence rates for both heterozygous FH (HeFH) and homozygous FH (HoFH) vary significantly, and this can be attributed, at least in part, to the variable diagnostic criteria used across different populations. Due to lack of consistent data, new global registries and unified guidelines are being formed, which are expected to advance current knowledge and improve the care of FH patients. This review presents a comprehensive overview of the pathophysiology, epidemiology, manifestations, and pharmacological treatment of FH, whilst summarizing the up-to-date relevant recommendations and guidelines...
2018: Frontiers in Pharmacology
Christian X Weichenberger, Johannes Rainer, Cristian Pattaro, Peter P Pramstaller, Francisco S Domingues
Motivation: Familial aggregation analysis is an important early step for characterizing the genetic determinants of phenotypes in epidemiological studies. To facilitate this analysis, a collection of methods to detect familial aggregation in large pedigrees has been made available recently. However, efficacy of these methods in real world scenarios remains largely unknown. Here, we assess the performance of five aggregation methods to identify individuals or groups of related individuals affected by a Mendelian trait within a large set of decoys...
July 13, 2018: Bioinformatics
J W Balder, P J Lansberg, M H Hof, A Wiegman, B A Hutten, J A Kuivenhoven
BACKGROUND: Atherosclerosis starts in childhood and its progression is influenced by lifelong low-density lipoprotein cholesterol (LDL-c) exposure, the so-called cholesterol burden. Early identification of children and adolescents with severely elevated LDL-c is thus of major clinical significance. This is especially true for children with familial hypercholesterolemia (FH), a frequent but undertreated genetic disorder. To identify children with possible FH, insight in the distribution of lipid levels in children is a prerequisite...
May 26, 2018: Journal of Clinical Lipidology
Hayato Tada, Akihiro Nomura, Masakazu Yamagishi, Masa-Aki Kawashiri
We present the first case of sitosterolemia caused by double heterozygous mutations in adenosine triphosphate-binding cassette subfamily G members 5 and 8 (ABCG5 and ABCG8) genes. A 1-year-old girl was admitted to Kanazawa University Hospital due to her hyper low-density lipoprotein (LDL)-cholesterolemia (453 mg/dL) as well as intertriginous xanthomas associated with breastfeeding. Initially, she was suspected as familial hypercholesterolemia (FH). However, her LDL cholesterol level significantly reduced after her weaning from breastfeeding...
June 20, 2018: Journal of Clinical Lipidology
Kristen Bede, Wai H Wilson Tang
PURPOSE OF REVIEW: Precision medicine is the concept of disease treatment and prevention using an individual's genomic profile in addition to personal and environmental factors. This review outlines examples of new biomarker strategies that enable the practice of precision cardiovascular medicine. RECENT FINDINGS: Although commonly attributed to identifying causative genetic variants, mono-genetic causes of cardiovascular diseases (CVD) are not common and largely focused on lipoprotein analyses...
July 9, 2018: Current Opinion in Cardiology
Jose Maria Bastida, Maria Luisa Giros, Rocio Benito, Kamila Janusz, Jesus Maria Hernandez-Rivas, Jose Ramon Gonzalez-Porras
Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis...
July 5, 2018: Current Medicinal Chemistry
Leire Pérez García
INTRODUCTION: Familial hypercholesterolaemia (FH) is the autosomal dominant genetic disorder most frequently associated with premature cardiovascular disease (CVD). MATERIAL AND METHODS: A retrospective, observational study was conducted to determine the clinical characteristics, analytical parameters and cardiovascular risk factors of 133 patients with a genetically confirmed diagnosis of FH on follow-up in the Lipid Clinic of Alava. RESULTS: CVD was observed in 8...
July 3, 2018: Clínica e Investigación en Arteriosclerosis
Chiharu Miyajima, Takayuki Iwaki, Kazuo Umemura, Victoria A Ploplis, Francis J Castellino
A murine genetic model of LDL-cholesterol- (LDL-C-) driven atherosclerosis, based on complete deficiencies of both the LDL-receptor ( Ldlr -/- ) and key catalytic component of an apolipoprotein B-edisome complex ( Apobec1 -/- ), which converts apoB-100 to apoB-48, has been extensively characterized. These gene deficiencies allow high levels of apoB-100 to be present and inefficiently cleared, thus leading to very high levels of LDL-C in mice on a normal diet. Many key features of atherosclerotic plaques observed in human familial hypercholesterolemia are found in these mice as they are allowed to age through 72 weeks...
2018: BioMed Research International
P Benedek, M Eriksson, K Duvefelt, A Freyschuss, M Frick, P Lundman, L Nylund, K Szummer
BACKGROUND: Familial hypercholesterolemia could be prevalent among patients with acute coronary syndrome. OBJECTIVE: To investigate both the frequency of causative mutations for familial hypercholesterolemia (FH) and the optimal selection of patients for genetic testing among patients with an acute coronary syndrome (ACS). METHODS: One hundred and sixteen patients with an ACS during 2009-2015 were identified through the SWEDEHEART registry...
July 5, 2018: Journal of Internal Medicine
Esther Mm Ooi, Katrina L Ellis, P Hugh R Barrett, GeraldF Watts, Joseph Hung, John P Beilby, Peter L Thompson, Paul Stobie, Brendan M McQuillan
BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque. METHODS: We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease)...
June 18, 2018: Atherosclerosis
Karen Forrest Keenan, Robert M Finnie, William G Simpson, Lorna McKee, John Dean, Zosia Miedzybrodzka
Familial hypercholesterolemia (FH) is a serious inherited disorder, which greatly increases individuals' risk of cardiovascular disease (CVD) in adult life. However, medical treatment and lifestyle adjustments can fully restore life expectancy. Whilst European guidance advises that where there is a known family mutation genetic testing is undertaken in early childhood, the majority of the at-risk population remain untested and undiagnosed. To date, only a small number of studies have explored parents' and children's experiences of testing and treatment for FH, and little is known about interactions between health professionals, parents, and children in clinic settings...
June 14, 2018: Journal of Community Genetics
Merel L Hartgers, Joost Besseling, Erik S Stroes, Janneke Wittekoek, Joost H W Rutten, Jacqueline de Graaf, Frank L J Visseren, Ben P M Imholz, Jeanine E Roeters van Lennep, Roeland Huijgen, John J P Kastelein, G Kees Hovingh
BACKGROUND: A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL). OBJECTIVE: We set out to model which proportion of patients reach targets using conventional and novel therapies. METHODS: We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2...
April 18, 2018: Journal of Clinical Lipidology
Kipp W Johnson, Joel T Dudley, Jason R Bobe
Familial hypercholesterolemia (FH) is a genetic disease associated with persistently elevated levels of low-density lipoprotein cholesterol (LDL-C), which ultimately leads to greatly increased rates of atherosclerosis and cardiovascular disease. Atherosclerosis progression can be clinically approximated through measurement of coronary artery calcification (CAC). CAC can be measured via electron beam computed tomography (EBCT), multi-slice computed tomography (MSCT), or contrast-enhanced CT coronary angiography (CTCA)...
April 9, 2018: Curēus
Ying-Yu Zhang, Zhen-Yan Fu, Jian Wei, Wei Qi, Gulinaer Baituola, Jie Luo, Ya-Jie Meng, Shu-Yuan Guo, Huiyong Yin, Shi-You Jiang, Yun-Feng Li, Hong-Hua Miao, Yong Liu, Yan Wang, Bo-Liang Li, Yi-Tong Ma, Bao-Liang Song
A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3 ) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane...
June 8, 2018: Science
Asier Benito-Vicente, Kepa B Uribe, Shifa Jebari, Unai Galicia-Garcia, Helena Ostolaza, Cesar Martin
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr). With a prevalence as high as 1/200 in some populations, genetic screening for pathogenic LDLr mutations is a cost-effective approach in families classified as 'definite' or 'probable' FH and can help to early diagnosis. However, with over 2000 LDLr variants identified, distinguishing pathogenic mutations from benign mutations is a long-standing challenge in the field...
June 5, 2018: International Journal of Molecular Sciences
Sébastien Thériault, Ricky Lali, Michael Chong, James L Velianou, Madhu K Natarajan, Guillaume Paré
BACKGROUND: Despite evidence of high heritability, monogenic disorders are identified in a minor fraction of individuals with early-onset coronary artery disease (EOCAD). We hypothesized that some individuals with EOCAD carry a high number of common genetic risk variants, with a combined effect similar to Mendelian forms of coronary artery disease, such as familial hypercholesterolemia. METHODS AND RESULTS: To confirm the polygenic contribution to EOCAD (age of ≤40 years for men and ≤45 years for women), we calculated in 111 418 British participants from the UK Biobank cohort a genetic risk score (GRS) based on the presence of 182 independent variants associated with coronary artery disease (GRS182)...
January 2018: Circulation. Genomic and precision medicine
Erhan Saracoglu, Salih Kılıç, Ertan Vuruşkan, Irfan Düzen, Yusuf Çekici, Zülfiye Kuzu, Arafat Yıldırım, Mehmet Küçükosmanoğlu, Mustafa Çetin
BACKGROUND AND AIMS: Few studies have shown the direct effect of familial hypercholesterolemia (FH) on myocardial systolic function. Studies focused on heterozygote FH patients but not homozygote ones, and they did not perform genetic analyses. We aimed to evaluate all types of patients with FH using the potentially more sensitive speckle tracking echocardiography (STE) technique to identify early left ventricular (LV) dysfunction. METHODS: Genetic analyses of patients with FH were conducted for LDL-receptor, PCSK9, and ApoB100...
June 5, 2018: Echocardiography
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