title: The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis.
abstract: OBJECTIVE
  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 < 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
  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.
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Loïc
authors.initials: L
authors.lastname: Yengo
authors.forename: Cédric
authors.initials: C
authors.lastname: Le May
authors.forename: Fréderic
authors.initials: F
authors.lastname: Fumeron
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: Sylvia
authors.initials: S
authors.lastname: Franc
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
mesh_terms: D000328:Adult; D000367:Age Factors; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D005602:France; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics*; D011446:Prospective Studies; D012044:Regression Analysis; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics*; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases