The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

Aims/hypothesis Proprotein 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 homeo...

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Bibliographic Details
Published in:Diabetologia 2015-09, Vol.58 (9), p.2051-2055
Main Authors: Bonnefond, Amélie, Yengo, Loïc, Le May, Cédric, Fumeron, Fréderic, Marre, Michel, Balkau, Beverley, Charpentier, Guillaume, Franc, Sylvia, Froguel, Philippe, Cariou, Bertrand
Format: Article
Language:English
Subjects:
Adult
Age Factors
Apolipoproteins
Blood Glucose - metabolism
Body Mass Index
Cholesterol
Cholesterol - blood
Cholesterol - metabolism
Diabetes
Diabetes Mellitus, Type 2 - blood
Endocrinology
Epidemiology
Female
France
Gene Expression Regulation
Genetic Variation
Genotype
Glucose
Homeostasis
Human Physiology
Humans
Insulin resistance
Internal Medicine
Life Sciences
Longitudinal Studies
Low density lipoprotein
Male
Medicine
Medicine & Public Health
Metabolic Diseases
Middle Aged
Proprotein Convertase 9
Proprotein Convertases - antagonists & inhibitors
Proprotein Convertases - blood
Proprotein Convertases - genetics
Prospective Studies
Regression Analysis
Risk Factors
Serine Endopeptidases - blood
Serine Endopeptidases - genetics
Sex Factors
Short Communication
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Summary:Aims/hypothesis Proprotein 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. Methods PCSK9 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. Results Significant associations ( p  
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-015-3659-8