👤 Stéphane Gobeil

RNA interference therapies targeting liver expression of the gene proprotein convertase subtilisin/kexin type 9 (PCSK9) lower LDL-cholesterol (LDL-C) and apolipoprotein B (apoB) levels. As opposed to monoclonal antibodies, which neutralise PCSK9 circulating protein, their effect on atherosclerotic cardiovascular disease (ASCVD) outcomes is unknown. We used genetic variants in the PCSK9 locus influencing PCSK9 function or gene expression in the liver to determine whether antibodies against PCSK9 and RNA interference therapies could have comparable effects on ASCVD. We performed genome-wide genotyping and RNA sequencing of 504 human liver sample and identified a genetic variant (rs472495) explaining 5.6% of liver PCSK9 gene expression to mimic lifelong RNA interference of PCSK9. We used the PCSK9 R46L variant, known to alter PCSK9 function, to model antibody-based PCSK9 inhibition. For each standard deviation decrease in apoB levels, both variants were similarly associated with coronary artery disease risk: (odds ratio [OR] = 0.40, 95% confidence interval [CI]: 0.31-0.51, P = 3.7e-13 for rs472495 which affects liver PCSK9 expression) and (OR = 0.48, 95% CI: 0.43-0.55, P = 1.3e-28 for R46L which affects protein levels). Comparable effects of these two genetic inhibition approaches were observed for aortic stenosis, heart failure, ischemic stroke, Type 2 diabetes and glycemic traits as well as non-alcoholic fatty liver disease and liver enzymes. For a given reduction in apoB levels, genetically predicted reductions in PCSK9 function (mimicking PCSK9 neutralizing antibodies) and liver PCSK9 gene expression levels (mimicking PCSK9 RNA interference) were comparably associated with a lower risk of coronary artery disease. These genetic data suggest that LDL-C/apoB reductions may provide cardiovascular benefits, regardless of how PCSK9 function is inhibited. Show less

Carriers of the E40K loss-of-function variant in Angiopoietin-like 4 (ANGPTL4), have lower plasma triglyceride levels as well as lower rates of coronary artery disease (CAD) and type 2 diabetes (T2D). These genetic data suggest ANGPTL4 inhibition as a potential therapeutic target for cardiometabolic diseases. However, it is unknown whether the association between E40K and human diseases is due to linkage disequilibrium confounding. The broader impact of genetic ANGPTL4 inhibition is also unknown, raising uncertainties about the safety and validity of this target. To assess the impact of ANGPLT4 inhibition, we evaluated whether E40K and other loss-of-function variants in ANGPTL4 influenced a wide range of health markers and diseases using 29 publicly available genome-wide association meta-analyses of cardiometabolic traits and diseases, as well as 1589 diseases assessed in electronic health records within FinnGen (n = 309,154). To determine whether these relationships were likely causal, and not driven by other correlated variants, we used the Bayesian fine mapping algorithm CoPheScan. The CoPheScan posterior probability of E40K being the causal variant for triglyceride levels was 99.99 %, validating the E40K to proxy lifelong lower activity of ANGPTL4. The E40K variant was associated with lower risk of CAD (odds ratio [OR] = 0.84, 95 % CI = 0.81 to 0.87, p=3.6e-21) and T2D (OR = 0.91, 95 % CI = 0.87 to 0.95, p=2.8e-05) in GWAS meta-analyses, with results replicated in FinnGen. These significant results were also replicated using other rare loss-of-function variants identified through whole exome sequencing in 488,278 participants of the UK Biobank. Using a Mendelian randomization study design, the E40K variant effect on cardiometabolic diseases was concordant with lipoprotein lipase enhancement (r = 0.82), but not hepatic lipase enhancement (r = -0.10), suggesting that ANGPTL4 effects on cardiometabolic diseases are potentially mainly mediated through lipoprotein lipase. After correction for multiple testing, the E40K variant did not significantly increase the risk of any of the 1589 diseases tested in FinnGen. ANGPTL4 inhibition may represent a potentially safe and effective target for cardiometabolic diseases prevention or treatment. Show less

RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation. Show less