Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease

Details

• Personal Author:
  Argall AD ; Boudoulas KD ; Bradley EA ; Cavus O ; Dudley EK ; El Refaey M ; Gumina RJ ; Hund TJ ; Jose EM ; Keith CBR ; Koenig SN ; Madiai F ; Mazzaferri EL Jr. ; Milks MW ; Mohler PJ ; Murphy NP ; Smith SA ; Sofowora G ; Sucharski HC ; Williams JL ; Wold LE ; Wright NT ; Zareba KM
• Description:
  Rationale: Coronary artery disease (CAD) is a pervasive and critical health care problem. Elevated high-density lipoprotein-associated cholesterol (HDL-C) is associated with improved atherosclerotic cardiovascular disease outcomes on a population level, but clinical trials aimed at HDL-C elevation have not succeeded in improving atherosclerotic cardiovascular disease event risk. Nevertheless, human variants in the HDL receptor, encoded by SCARB1, are associated with dyslipidemia, suggesting that HDL metabolism, not HDL-C, is a suitable target for therapy. However, variants in SCARB1 have never been directly attributed to CAD by Mendelian inheritance. Objective: To determine if compound heterozygous variants in SCARB1 cause disease in 2 brothers with severe, early-onset CAD. Methods and Results: Using whole exome sequencing, we have identified rare, compound heterozygous variants in SCARB1 that segregate with severe, premature CAD, following patterns of Mendelian inheritance. Using induced pluripotent stem cell-derived hepatocyte-like cells from the proband, we discovered the maternal variant (c.754_755delinsC) to be the first identified SCARB1 null allele, characterized by the absence of RNA and protein expression. Further, we demonstrate that the variant on the paternal allele (c.956G>T [p.G319V]) results in decreased cholesterol uptake, decreased SR-BI:HDL binding, and increased affinity for SR-BI dimerization. Finally, we generated a p.G319V knock-in mouse model that displays nearly 100% homozygous lethality and elevated plasma cholesterol in heterozygous animals, confirming pathogenicity of this variant. Conclusions: In summary, our data provide the first molecular mechanism to show the Mendelian inheritance of CAD as a result of human SCARB1 variants. The rarity of these variants supports pathogenicity in this family. Furthermore, SR-BI p.G319V, which has previously been reported benign in the context of heterozygosity, was uniquely presented alongside a null allele, demonstrating the disease-contributing capability of loss-of-function SCARB1 variants within the population. [Description provided by NIOSH]
• Subjects:
  Cardiovascular Diseases Cardiovascular System Genetics Occupational Health Safety
• Keywords:
  Author Keywords: Cholesterol Cardiology Cardiovascular Health Circulatory System Coronary Disease Dyslipidemia Genes Genetic Factors Genetic Predisposition Genetics Heart Disease High-density Lipoprotein Human Physiology

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• ISSN:
  0009-7330
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 3 ; OSHA Region 5 ; Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  296-307
• Volume:
  129
• Issue:
  2
• NIOSHTIC Number:
  nn:20063237
• Citation:
  Circ Res 2021 Jul; 129(2):296-307
• Contact Point Address:
  Sara N. Koenig, PhD, 110 DHLRI, 473 W 12th Ave, Columbus, OH 43210, The Ohio State University College of Medicine
• Email:
  sara.koenig@osumc.edu
• Federal Fiscal Year:
  2021
• Performing Organization:
  Ohio State University
• Peer Reviewed:
  True
• Start Date:
  20200701
• Source Full Name:
  Circulation Research
• End Date:
  20210630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:c8db36c5dd31592e2681661a3e92c5f35404b8a61953f31993c7a077b621d7c2384ab4e55f8737137551c1bd678a9f7dc1f41285496f1fd6eb6243e8d6a50af5
• Download URL:
  https://stacks.cdc.gov/view/cdc/226333/cdc_226333_DS1.pdf
• File Type:
  [PDF - 5.76 MB ]