ArticleDiabetologia2015
The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis.
Article in Diabetologia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 2 of them syntheses that pooled it.
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Who cites it
25 citing papers in PubMed, 2 syntheses or guidelines pooled it, 60 citations in OpenAlex.
- What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis.Lipids in health and disease · 2017Pooled it
- Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.JAMA · 2016 · on this mapPooled it
- No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.European heart journal · 2016Trial
- Causal Association Between Cholesterol-Lowering Drugs and Diabetic Microvascular Complications: A Drug-Target Mendelian Randomization Study.Journal of diabetes research · 2025Article
- Association of lipid-lowering drugs with the risk of type 2 diabetes and its complications: a mendelian randomized study.Diabetology & metabolic syndrome · 2024Article
- Proprotein convertase subtilisin/kexin type 9 deficiency in extrahepatic tissues: emerging considerations.Frontiers in pharmacology · 2024Review
- Review
- E670G PCSK9 polymorphism in HeFH & CAD with diabetes: is the bridge to personalized therapy within reach?Frontiers in clinical diabetes and healthcare · 2023Article
- PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells.Lipids in health and disease · 2022Review
- New Treatment Targets and Innovative Lipid-Lowering Therapies in Very-High-Risk Patients with Cardiovascular Disease.Biomedicines · 2022Review
- Association between the rs615563 variant of PCSK9 gene and circulating lipids and Type 2 diabetes.BMC research notes · 2021Article
- How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol.European heart journal · 2021Review
- Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Levels and Cardiometabolic Risk Factors: A Population-Based Cohort Study.Frontiers in cardiovascular medicine · 2021Article
- Association of circulating proprotein convertase subtilisin/kexin type 9 levels and the risk of incident type 2 diabetes in subjects with prediabetes: a population-based cohort study.Cardiovascular diabetology · 2020 · on this mapObservational
- C679X loss-of-functionJournal of clinical & translational endocrinology · 2019Article
- A phenome-wide association study to discover pleiotropic effects ofNPJ genomic medicine · 2019Article
- Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.Drug safety · 2018Article
- Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials.Diabetic medicine : a journal of the British Diabetic Association · 2018Article
- PCSK9 and carbohydrate metabolism: A double-edged sword.World journal of diabetes · 2017Article
- Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisProprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study.
methodsPCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline.
resultsSignificant associations (p < 10(-6)) were found between p.R46L and lower total cholesterol (-0.394 mmol/l), LDL-cholesterol (-0.393 mmol/l) and apolipoprotein B concentrations (-0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA1c, HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. CONCLUSIONS/
interpretationThe PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in humans. These data are reassuring regarding the safety of PCSK9 inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.