Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia

Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia · SciRah

^aCenter for Human Genetic Research, Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
^bProgram in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
^cSamsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
^dDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
^eHuman Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas
^fDepartment of Biostatistics, University of Washington, Seattle, Washington
^gDepartment of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
^hCardiovascular Health Research Unit, University of Washington, Seattle, Washington
ⁱDivision of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
^jDeutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany, and Munich Heart Alliance, München, Germany
^kDepartment of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy, and Humanitas Clinical and Research Center, Rozzano, Milan, Italy
^lDepartments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington
^mDepartments of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
ⁿPublic Health and Primary Care, University of Cambridge, Cambridge, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge and National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
^oUniversity of Ottawa Heart Institute, Ottawa, Canada
^pDivision of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
^qDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
^rJackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi

Abstract

Background About 7% of US adults have severe hypercholesterolemia (untreated LDL cholesterol ≥190 mg/dl). Such high LDL levels may be due to familial hypercholesterolemia (FH), a condition caused by a single mutation in any of three genes. Lifelong elevations in LDL cholesterol in FH mutation carriers may confer CAD risk beyond that captured by a single LDL cholesterol measurement. Objectives Assess the prevalence of a FH mutation among those with severe hypercholesterolemia and determine whether CAD risk varies according to mutation status beyond the observed LDL cholesterol. Methods Three genes causative for FH (LDLR, APOB, PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD cases, 8,577 CAD-free controls) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. Results Among 8,577 CAD-free control participants, 430 had LDL cholesterol ≥190 mg/dl; of these, only eight (1.9%) carried a FH mutation. Similarly, among 11,908 participants from 5 prospective cohorts, 956 had LDL cholesterol ≥190 mg/dl and of these, only 16 (1.7%) carried a FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers when compared with non-carriers. When compared to a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had six-fold higher risk for CAD (OR 6.0; 95%CI 5.2–6.9) whereas those with LDL cholesterol ≥190 mg/dl as well as a FH mutation demonstrated twenty-two fold increased risk (OR 22.3; 95%CI 10.7–53.2). Conclusions Among individuals with LDL cholesterol ≥190 mg/dl, gene sequencing identified a FH mutation in <2%. However, for any given observed LDL cholesterol, FH mutation carriers are at substantially increased risk for CAD.

TL;DRAmong individuals with LDL cholesterol ≥190 mg/dl, gene sequencing identified a FH mutation in <2%. (Semantic Scholar)

Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia

Abstract

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