Familial Hypercholesterolemia: Genes and Beyond

Review

Familial Hypercholesterolemia: Genes and Beyond

Bruce A. Warden¹, Sergio Fazio², Michael D. Shapiro³

Kenneth R Feingold¹, Bradley Anawalt², Marc R Blackman³, Alison Boyce⁴, George Chrousos⁵, Emiliano Corpas⁶, Wouter W de Herder⁷, Ketan Dhatariya⁸, Kathleen Dungan⁹, Johannes Hofland¹⁰, Sanjay Kalra¹¹, Gregory Kaltsas¹², Nitin Kapoor¹³, Christian Koch¹⁴, Peter Kopp¹⁵, Márta Korbonits¹⁶, Christopher S Kovacs¹⁷, Wendy Kuohung¹⁸, Blandine Laferrère¹⁹, Miles Levy²⁰, Elizabeth A McGee²¹, Robert McLachlan²², Radhika Muzumdar²³, Jonathan Purnell²⁴, Rakesh Sahay²⁵, Amy S Shah²⁶, Frederick Singer²⁷, Mark A Sperling²⁸, Constantine A Stratakis²⁹, Dace L Trence³⁰, Don P Wilson³¹

, editors.

In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

2024 Sep 23.

Affiliations

¹ Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239.
² Chair, Scientific Council – Cardiometabolic Area - Global Development, Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591.
³ Fred M. Parrish Professor of Cardiology and Molecular Medicine, Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Book Affiliations

¹ Professor of Medicine Emeritus, University of California, San Francisco, CA
² Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
³ Sr. Physician Scientist, Washington DC VA Medical Center; Professor of Medicine & Rehabilitation Medicine, Georgetown University; Clinical Professor of Medicine, Biochemistry and Molecular Medicine, George Washington University; and Professor of Medicine (Part-time), Johns Hopkins University
⁴ Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
⁵ Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
⁶ M.D. Ph.D in Gerontology. Honorary Professor of Medicine, Universidad de Alcalá, Madrid. Consultant in Endocrinology, Hospital HLA Guadalajara (Spain).
⁷ Professor of Endocrine Oncology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
⁸ Consultant in Diabetes, Endocrinology and General Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.
⁹ Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
¹⁰ Consultant Endocrinologist, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
¹¹ Consultant Endocrinologist, Department of Endocrinology, Bharti Hospital, Karnal, India
¹² Professor of General Medicine-Endocrinology, 1st Department of Propaedeutic Medicine, National and Kapodistrian University of Athens, Athens, Greece
¹³ Professor of Endocrinology, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College & Hospital, Vellore, Tamil Nadu, India, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Australia.
¹⁴ Professor, The University of Tennessee Health Science Center, Memphis, Tennessee
¹⁵ Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
¹⁶ Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
¹⁷ University Research Professor and Professor of Medicine (Endocrinology and Metabolism), Obstetrics & Gynecology, and BioMedical Sciences, at Memorial University of Newfoundland in St. John’s, Newfoundland, Canada.
¹⁸ Director of the Division of Reproductive Endocrinology at Boston Medical Center and an Associate Professor of Obstetrics and Gynecology at the Boston University School of Medicine
¹⁹ Professor of Medicine, New York Nutrition Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Consultant endocrinologist at University Hospitals of Leicester and Honorary Associate Professor at Leicester University
²¹ Professor of Obstetrics and Gynecology at the University of Vermont and Director of the Division of Reproductive Endocrinology and Infertility. Burlington, Vermont
²² Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
²³ Allan L. Drash Endowed Chair, Chief, Division of Endocrinology and Diabetes, UPMC Children’s Hospital of Pittsburgh, Professor of Pediatrics and Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
²⁴ Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
²⁵ Professor and Head of Department of Endocrinology, Osmania Medical College and Osmania General Hospital, Hyderabad, India.
²⁶ Professor of Pediatrics, The University of Cincinnati, Department of Pediatrics and Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, OH, USA
²⁷ Director of the Endocrine/Bone Disease Program, Saint Johns Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
²⁸ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY. Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh.
²⁹ CSO, ELPEN, Inc. & Director, Research Institute, Athens, Greece & Senior Investigator, Human Genetics & Precision Medicine, FORTH (ITE), Heraklion, Greece. Emeritus Scientific Director & Senior Investigator, NICHD, NIH, Bethesda, MD, USA
³⁰ Professor of Medicine, Emeritus, University of Washington, Seattle, WA
³¹ Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX

PMID: 26844336
Bookshelf ID: NBK343488

Free Books & Documents

Review

Familial Hypercholesterolemia: Genes and Beyond

Bruce A. Warden et al.

Free Books & Documents

In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

2024 Sep 23.

Authors

Bruce A. Warden¹, Sergio Fazio², Michael D. Shapiro³

Book Editors

Affiliations

¹ Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239.
² Chair, Scientific Council – Cardiometabolic Area - Global Development, Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591.
³ Fred M. Parrish Professor of Cardiology and Molecular Medicine, Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Book Affiliations

¹ Professor of Medicine Emeritus, University of California, San Francisco, CA
² Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
³ Sr. Physician Scientist, Washington DC VA Medical Center; Professor of Medicine & Rehabilitation Medicine, Georgetown University; Clinical Professor of Medicine, Biochemistry and Molecular Medicine, George Washington University; and Professor of Medicine (Part-time), Johns Hopkins University
⁴ Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
⁵ Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
⁶ M.D. Ph.D in Gerontology. Honorary Professor of Medicine, Universidad de Alcalá, Madrid. Consultant in Endocrinology, Hospital HLA Guadalajara (Spain).
⁷ Professor of Endocrine Oncology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
⁸ Consultant in Diabetes, Endocrinology and General Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.
⁹ Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
¹⁰ Consultant Endocrinologist, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
¹¹ Consultant Endocrinologist, Department of Endocrinology, Bharti Hospital, Karnal, India
¹² Professor of General Medicine-Endocrinology, 1st Department of Propaedeutic Medicine, National and Kapodistrian University of Athens, Athens, Greece
¹³ Professor of Endocrinology, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College & Hospital, Vellore, Tamil Nadu, India, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Australia.
¹⁴ Professor, The University of Tennessee Health Science Center, Memphis, Tennessee
¹⁵ Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
¹⁶ Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
¹⁷ University Research Professor and Professor of Medicine (Endocrinology and Metabolism), Obstetrics & Gynecology, and BioMedical Sciences, at Memorial University of Newfoundland in St. John’s, Newfoundland, Canada.
¹⁸ Director of the Division of Reproductive Endocrinology at Boston Medical Center and an Associate Professor of Obstetrics and Gynecology at the Boston University School of Medicine
¹⁹ Professor of Medicine, New York Nutrition Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Consultant endocrinologist at University Hospitals of Leicester and Honorary Associate Professor at Leicester University
²¹ Professor of Obstetrics and Gynecology at the University of Vermont and Director of the Division of Reproductive Endocrinology and Infertility. Burlington, Vermont
²² Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
²³ Allan L. Drash Endowed Chair, Chief, Division of Endocrinology and Diabetes, UPMC Children’s Hospital of Pittsburgh, Professor of Pediatrics and Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
²⁴ Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
²⁵ Professor and Head of Department of Endocrinology, Osmania Medical College and Osmania General Hospital, Hyderabad, India.
²⁶ Professor of Pediatrics, The University of Cincinnati, Department of Pediatrics and Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, OH, USA
²⁷ Director of the Endocrine/Bone Disease Program, Saint Johns Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
²⁸ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY. Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh.
²⁹ CSO, ELPEN, Inc. & Director, Research Institute, Athens, Greece & Senior Investigator, Human Genetics & Precision Medicine, FORTH (ITE), Heraklion, Greece. Emeritus Scientific Director & Senior Investigator, NICHD, NIH, Bethesda, MD, USA
³⁰ Professor of Medicine, Emeritus, University of Washington, Seattle, WA
³¹ Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX

PMID: 26844336
Bookshelf ID: NBK343488

Excerpt

Genetic disorders resulting in familial hypercholesterolemia (FH) include autosomal dominant hypercholesterolemia (ADH), polygenic hypercholesterolemia, as well as other rare conditions such as autosomal recessive hypercholesterolemia (ARH). All of these disorders cause elevations in low-density lipoprotein (LDL)-cholesterol (LDL-C) and, as a result, greatly increase the risk of cardiovascular disease (CVD). Genetic loci involved in ADH include the LDLR, which codes for the LDL receptor (LDLR), APOB, which codes for apolipoprotein B-100 (apoB-100), the major protein component of LDL, PCSK9, which codes for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), the low abundance circulatory protein that terminates the lifecycle of the LDLR, and apolipoprotein E (APOE), which is an important constituent of triglyceride rich lipoproteins. Importantly, a large percentage of people with the severe hypercholesterolemic phenotype do not possess a readily identifiable gene defect and many likely have polygenic hypercholesterolemia. Thus, identification of a specific genetic pathologic variant is not a necessary condition for the diagnosis of a genetic hypercholesterolemia. Several formal diagnostic criteria exist for FH and include lipid levels, family history, personal history, physical exam findings, and genetic testing. As all individuals with severe hypercholesterolemia are at high risk for CVD, treatment is centered on dietary and lifestyle modifications and early institution of lipid-lowering pharmacotherapy. Treatment should initially be statin-based, but most patients require adjunctive medications such as ezetimibe and PCSK9 blocking monoclonal antibodies. Three large cardiovascular outcome trials have shown a reduction in atherosclerotic CVD when ezetimibe or PCSK9 blocking monoclonal antibodies were added to a background of statin therapy and consequently have assisted in shaping international guidelines and consensus recommendations. Novel therapeutics recently developed, include: inclisiran – a small interfering ribonucleic acid (siRNA)-based gene-silencing technology that inhibits PCSK9 production, bempedoic acid – an inhibitor of adenosine triphosphate (ATP)-citrate lyase with a large cardiovascular outcome trial demonstrating a reduction in CVD in patients with statin intolerance and is now FDA approved for a wide range of patients including heterozygous FH and patients with prior CVD (secondary prevention) or those at high-risk for CVD (primary prevention) and elevated LDL-C, and evinacumab – a fully human monoclonal antibody inhibiting angiopoietin-like 3 (ANGPTL3) (FDA approved for homozygous FH only). Patients with extreme and unresponsive elevations in LDL-C will require more aggressive therapies such as lipoprotein apheresis and agents for the treatment of severe hypercholesterolemia such as microsomal triglyceride transfer protein (MTP) inhibitors and evinacumab. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

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References

1. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science (New York, NY). 1986;232(4746):34-47. - PubMed
1. Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nature reviews Cardiology. 2019;16(1):9-20. - PubMed
1. Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC, Hovingh GK. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circulation research. 2014;115(6):552-555. - PubMed
1. Kanuri B, Fong V, Haller A, Hui DY, Patel SB. Mice lacking global Stap1 expression do not manifest hypercholesterolemia. BMC Med Genet. 2020;21(1):234. - PMC - PubMed
1. Mohebi R, Chen Q, Hegele RA, Rosenson RS. Failure of cosegregation between a rare STAP1 missense variant and hypercholesterolemia. J Clin Lipidol. 2020;14(5):636-638. - PubMed

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[1] Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science (New York, NY). 1986;232(4746):34-47. - PubMed

[2] Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science (New York, NY). 1986;232(4746):34-47. - PubMed

[3] Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nature reviews Cardiology. 2019;16(1):9-20. - PubMed

[4] Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nature reviews Cardiology. 2019;16(1):9-20. - PubMed

[5] Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC, Hovingh GK. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circulation research. 2014;115(6):552-555. - PubMed

[6] Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC, Hovingh GK. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circulation research. 2014;115(6):552-555. - PubMed

[7] Kanuri B, Fong V, Haller A, Hui DY, Patel SB. Mice lacking global Stap1 expression do not manifest hypercholesterolemia. BMC Med Genet. 2020;21(1):234. - PMC - PubMed

[8] Kanuri B, Fong V, Haller A, Hui DY, Patel SB. Mice lacking global Stap1 expression do not manifest hypercholesterolemia. BMC Med Genet. 2020;21(1):234. - PMC - PubMed

[9] Mohebi R, Chen Q, Hegele RA, Rosenson RS. Failure of cosegregation between a rare STAP1 missense variant and hypercholesterolemia. J Clin Lipidol. 2020;14(5):636-638. - PubMed

[10] Mohebi R, Chen Q, Hegele RA, Rosenson RS. Failure of cosegregation between a rare STAP1 missense variant and hypercholesterolemia. J Clin Lipidol. 2020;14(5):636-638. - PubMed

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Familial Hypercholesterolemia: Genes and Beyond

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Familial Hypercholesterolemia: Genes and Beyond

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