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Last Posted: Mar 02, 2023
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Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.
Jacqueline S Dron et al. JAMA cardiology 2023 2

What is the prevalence of protein-truncating variants (PTVs) in the apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes and their association with low-density lipoprotein (LDL) cholesterol levels and coronary heart disease (CHD)? In this genetic association study including 19?073 US participants and 190?464 UK participants, a PTV was identified in 0.4% of individuals. Estimated untreated LDL cholesterol concentrations were 32% to 37% lower in PTV carriers vs noncarriers, and PTVs were associated with a 49% reduction in CHD risk.

Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study.
Fang Si et al. PLoS medicine 2023 1 (1) e1003988

Using genetic variants associated with LDL cholesterol, liver-derived gene expression, and plasma protein levels, the researchers applied drug target Mendelian randomization (MR) and colocalization to examine the association between lipid-lowering drug targets and the risk of overall, early-onset, and advanced prostate cancer. Additional MR analyses were conducted to explore putative mediators of drug effects. This study provided evidence of an association between genetically proxied PCSK9 inhibition and lower risk of overall and early-onset prostate cancer supported by both MR and colocalization approaches.

A pragmatic clinical trial of cascade testing for familial hypercholesterolemia.
Miller Alexandra A et al. Genetics in medicine : official journal of the American College of Medical Genetics 2022 9

We compared new cases detected per index case in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology. We enrolled 52 FH probands with a pathogenic variant (FHg+) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FHg–). New case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.

Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study.
Cupido Arjen J et al. JAMA cardiology 2022 8

In this cohort study, a 2?×?2 factorial Mendelian randomization study including 425?354 participants from the UK Biobank, an additive association of a genetically reduced combined concentration of CETP and PCSK9 was found for lipid levels and risk of coronary artery disease, while the association of CETP with age-related macular degeneration was not mitigated. Our findings suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid concentrations and clinical outcomes.

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