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

Details

• Alternative Title:
  Circ Res
• Personal Author:
  Koenig, Sara N. ; Sucharski, Holly C. ; Jose, Elizabeth M. ; Dudley, Emma K. ; Madiai, Francesca ; Cavus, Omer ; Argall, Aaron D. ; Williams, Jordan L. ; Murphy, Nathaniel P. ; Keith, Caullin B. R. ; Refaey, Mona El ; Gumina, Richard J. ; Boudoulas, Konstantinos D. ; Milks, M. Wesley ; Sofowora, Gbemiga ; Smith, Sakima A. ; Hund, Thomas J. ; Wright, Nathan T. ; Bradley, Elisa A. ; Zareba, Karolina M. ; Wold, Loren E. ; Mazzaferri, Ernest L. ; Mohler, Peter J.
• Description:
  Rationale:
  
  Coronary artery disease (CAD) is a pervasive and critical healthcare problem. Elevated high density lipoprotein-associated cholesterol (HDL-C) is associated with improved atherosclerotic cardiovascular disease (ASCVD) outcomes on a population level, but clinical trials aimed at HDL-C elevation have not succeeded in improving ASCVD 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 two 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 (iPSC-HLCs) 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.
  
  
• Subjects:
  Adult Age Of Onset Animals Coronary Artery Disease Exome Sequencing Female Genetic Association Studies Genetic Predisposition To Disease Genetic Variation HEK293 Cells Hepatocytes Hep G2 Cells Heredity Heterozygote Humans Induced Pluripotent Stem Cells Male Mice Mice, Inbred C57BL Middle Aged Pedigree Phenotype Risk Assessment Risk Factors Scavenger Receptors, Class B Severity Of Illness Index

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• Keywords:
  Alzheimer's Disease Alzheimer's Disease Sequencing Project Animal Models Antiviral Agents Coronary Artery Disease Coronary Heart Disease Dyslipidemia Genetics Herpes Simplex High Density Lipoprotein Cholesterol Human Human Papillomavirus Lipids And Cholesterol Physiology SCARB1 Torque Teno Viruses Translational Studies Whole Exome Sequencing Whole Genome Sequencing

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• Source:
  Circ Res. 129(2):296-307
• Pubmed ID:
  33975440
• Pubmed Central ID:
  PMC8273129
• Document Type:
  Journal Article
• Funding:
  U01 OH012056/OH/NIOSH CDC HHSUnited States/ ; R01 HL127442/HL/NHLBI NIH HHSUnited States/ ; K08 HL135437/HL/NHLBI NIH HHSUnited States/ ; R00 HL146969/HL/NHLBI NIH HHSUnited States/ ; K08 HL148701/HL/NHLBI NIH HHSUnited States/ ; P30 CA016058/CA/NCI NIH HHSUnited States/ ; R01 HL135096/HL/NHLBI NIH HHSUnited States/ ; R01 MD011307/MD/NIMHD NIH HHSUnited States/ ; R01 HL114893/HL/NHLBI NIH HHSUnited States/ ; R01 HL134824/HL/NHLBI NIH HHSUnited States/ ; T32 GM139779/GM/NIGMS NIH HHSUnited States/ ; R35 HL135754/HL/NHLBI NIH HHSUnited States/ ; R01 AG057046/AG/NIA NIH HHSUnited States/ ; F30 HL137325/HL/NHLBI NIH HHSUnited States/ ; T32 GM136536/GM/NIGMS NIH HHSUnited States/ ; T32 HL098039/HL/NHLBI NIH HHSUnited States/ ; R01 HL139348/HL/NHLBI NIH HHSUnited States/ ; R13 HL154524/HL/NHLBI NIH HHSUnited States/ ; K99 HL146969/HL/NHLBI NIH HHSUnited States/
• Volume:
  129
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:86c8cd61d4b2bb85f4b5abf6bfee0ef4a9bfb9688a30531a5cb077d550b28b4ae5a04ab7e3aef135f6a87388531988788838a53a34fd258407ff8e2be6e465a3
• Download URL:
  https://stacks.cdc.gov/view/cdc/119175/cdc_119175_DS1.pdf
• File Type:
  [PDF - 2.06 MB ]