4.7 Article

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

期刊

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 67, 期 22, 页码 2578-2589

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2016.03.520

关键词

coronary artery disease; gene sequencing; genetics; low-density lipoprotein cholesterol

资金

  1. British Heart Foundation [RG/13/13/30194]
  2. U.K. Medical Research Council [MR/L003120/1]
  3. Wellcome Trust
  4. EU Framework 6-Bloodomics Integrated Project
  5. Pfizer
  6. Novartis
  7. Merck
  8. U.K. National Institute for Health Research Cambridge Biomedical Research Centre
  9. European Research Council [268834]
  10. European Commission Framework Programme 7 [HEALTH-F2-2012-279233]
  11. National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]
  12. National Institute on Minority Health and Health Disparities
  13. German Federal Ministry of Education and Research (BMBF)
  14. European Union [261123]
  15. Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes) [12CVD02]
  16. Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces
  17. National Institutes of Health through the American Recovery and Reinvestment Act [5RC2HL102419]
  18. NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268200800007C]
  19. Boston University [N01-HC-25195]
  20. Affymetrix, Inc. [N02-HL-6-4278]
  21. Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
  22. National Institute on Aging [R01AG023629]
  23. Programma di ricerca Regione-Universita Area 1-Strategic Programmes-Regione Emilia-Romagna
  24. American College of Cardiology/Merck Fellowship award
  25. Amarin Corporation
  26. National Heart, Lung, and Blood Institute award [K01HL125751]
  27. Deutsches Zentrum fur Herz-Kreislauf-Forschung rotation grant
  28. Zoll LifeCor
  29. Johnson Johnson
  30. Aegerion Pharmaceuticals
  31. Alnylam Pharmaceuticals
  32. Eli Lilly and Company
  33. Sanofi
  34. AstraZeneca
  35. Boehringer Ingelheim
  36. Bayer
  37. Daiichi-Sankyo
  38. GlaxoSmithKline
  39. Boston Scientific
  40. Bristol-Myers Squibb
  41. Menarini Group
  42. National Institutes of Health
  43. Massachusetts General Hospital
  44. Donovan Family Foundation
  45. Bayer Healthcare
  46. Regeneron Pharmaceuticals
  47. Leerink Partners
  48. Noble Insights
  49. Quest Diagnostics
  50. Genomics PLC
  51. [SFB 1123]
  52. [RFPS-2007-3-644382]
  53. [RC2 HL103010]
  54. [RC2 HL102923]
  55. [RC2 HL102924]
  56. [5U54HG003067]
  57. [R01 HL127564]
  58. [N01HC55222]
  59. [N01HC85079]
  60. [N01HC85080]
  61. [N01HC85081]
  62. [N01HC85082]
  63. [N01HC85083]
  64. [N01HC85086]
  65. [U01HL080295]
  66. [R01HL087652]
  67. [R01HL105756]
  68. [R01HL103612]
  69. [R01HL120393]
  70. MRC [MR/L003120/1] Funding Source: UKRI
  71. British Heart Foundation [RG/13/13/30194] Funding Source: researchfish
  72. Medical Research Council [MR/L003120/1] Funding Source: researchfish
  73. National Institute for Health Research [NF-SI-0513-10087] Funding Source: researchfish

向作者/读者索取更多资源

BACKGROUND Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol >= 190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. OBJECTIVES This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. METHODS Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) 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 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol >= 190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol >= 190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol >= 190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. CONCLUSIONS Among participants with LDL cholesterol >= 190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD. (C) 2016 by the American College of Cardiology Foundation.

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