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.