Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease
| Autor: | Thomas J. Hund, Konstantinos Dean Boudoulas, Aaron D. Argall, Omer Cavus, Sara N. Koenig, Gbemiga G. Sofowora, M Wesley Milks, Mona El Refaey, Loren E. Wold, Sakima A. Smith, Elizabeth M. Jose, Holly C. Sucharski, Jordan L. Williams, Peter J. Mohler, Nathan T. Wright, Francesca Madiai, Emma K. Dudley, Karolina M. Zareba, Nathaniel P. Murphy, Elisa A. Bradley, Richard J. Gumina, Ernest L. Mazzaferri, Caullin B. R. Keith |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Proband Heterozygote Heredity Physiology Induced Pluripotent Stem Cells Population Coronary Artery Disease Biology Compound heterozygosity Risk Assessment Severity of Illness Index Article symbols.namesake Risk Factors Exome Sequencing Animals Humans Genetic Predisposition to Disease Age of Onset Allele education Genetic Association Studies Exome sequencing Genetics education.field_of_study Genetic Variation Hep G2 Cells Middle Aged Scavenger Receptors Class B Null allele SCARB1 Pedigree Mice Inbred C57BL HEK293 Cells Phenotype Hepatocytes Mendelian inheritance symbols Female Cardiology and Cardiovascular Medicine |
| Zdroj: | Circ Res |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.120.318793 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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