Work

Novel protein-truncating variant in the APOB gene may protect from coronary artery disease and adverse cardiovascular events

Year: 2022

Type: article

Abstract: Background and aims: Genetic testing is still rarely used for the diagnosis of dyslipidemia, even though Familial Hypercholesterolemia (FH) is considered the most common genetic cause of coronary artery disease (CAD). To perform a pilot-analysis of targeted Next Generation Sequencing (NGS) of FH related genes in patients selected within a cohort of subjects with or without angiographically-demonstrated CAD. Methods: NGS of LDLR, APOB, PCSK9, HMGCR, and APOE genes was performed in 24 subjects not taking lipid-lowering drugs, presenting very high (≥190 mg/dL, n=18) or very low (≤60 mg/dL, n=6) LDL-cholesterol plasma levels. Results: Within the group with hypercholesterolemia, 6 subjects (33.3%) had 7 rare variants predicted to be potentially pathogenic. Five variants were in LDLR gene: 2 nonsense, c.274C>T(rs774467219) and c.126C>A (rs751317621), 2 missense, c.662A>G(rs373822756) and c.1735G>T(rs875989929), and 1 in a splice region, c.2312-3C>A(rs875989942). Two APOB missense variants, c.5741A>G(rs1801699) and c.3337G>C(rs12713844) were found. All subjects carrying LDLR variants had CAD. Among subjects with low LDL-cholesterol we found a novel rare mutation in APOB gene, c.6943G>T, determining a truncating variant with premature stop codon after the ApoB-48, thus allowing chylomicron synthesis but reducing VLDL secretion and then LDL levels. The heterozygous carrier of APOB c.6943G>T, despite a very high-risk profile encompassing all the traditional risk factors except for dyslipidemia, had normal coronary arteries by angiography and did not report any major adverse cardiovascular event during a 20-years follow-up. Conclusions: Our data support the use of targeted NGS in well-characterized clinical settings. APOB genetic variants reducing ApoB production may improve cardiovascular outcomes.

Source: Atherosclerosis Plus

DOI: 10.1016/j.athplu.2022.06.001