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

Bonnefond, Amelie, Yengo, Loic, Le May, Cedric, Fumeron, Frederic, Marre, Michel, Balkau, Beverley, Charpentier, Guillaume, Franc, Sylvia, Froguel, Philippe and Cariou, Bertrand (2015) The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia, 58 9: 2051-2055. doi:10.1007/s00125-015-3659-8

Author Bonnefond, Amelie
Yengo, Loic
Le May, Cedric
Fumeron, Frederic
Marre, Michel
Balkau, Beverley
Charpentier, Guillaume
Franc, Sylvia
Froguel, Philippe
Cariou, Bertrand
Title The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis
Formatted title
The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis
Journal name Diabetologia   Check publisher's open access policy
ISSN 1432-0428
Publication date 2015-06-01
Year available 2015
Sub-type Article (original research)
DOI 10.1007/s00125-015-3659-8
Open Access Status Not yet assessed
Volume 58
Issue 9
Start page 2051
End page 2055
Total pages 5
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
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.

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.

Significant 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.

The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in humans. These data are reassuring regarding the safety of PCSK9 inhibitors.
Keyword Apolipoprotein B
Low-frequency genetic variant
Type 2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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