title: Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels.
abstract: BACKGROUND
  We previously reported that the low-frequency, loss-of-function variant p.R270H in FFAR4 encoding the lipid sensor GPR120 was associated with obesity. Gpr120-deficient mice develop obesity and both impaired fasting glucose and glucose intolerance under a high-fat diet. We aimed to assess the contribution of p.R270H to type 2 diabetes (T2D) risk and the variation of glucose-related traits.
  
  
  METHODS
  We genotyped p.R270H in 8996 non-diabetic individuals (among whom 4523 had an oral glucose tolerance test (OGTT)) and in a T2D case-control study including 4725 cases and 4339 controls. The regression models were adjusted for age, sex and body mass index (BMI).
  
  
  RESULTS
  We found a significant association between p.R270H and increased fasting glucose levels (β=0.092±0.05 mmol/L; p=4.13×10(-4)). Furthermore, p.R270H nominally contributed to decreased homeostasis model of pancreatic β-cell function (HOMA-B; β=-0.090±0.06; p=6.01×10(-3)). Despite a high statistical power, we did not find any significant association between p.R270H and T2D risk or the variation of fasting insulin levels, the homeostasis model of insulin resistance or OGTT-derived indices.
  
  
  CONCLUSIONS
  These results suggest that the low-frequency p.R270H variant which inhibits GPR120 activity might influence fasting glucose levels in a normal physiological range. This study does not exclude that other coding mutations in FFAR4 with stronger functional effect than p.R270H may be associated with T2D.
authors.affiliation: CNRS-UMR8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: Inserm U-1138, Centre de Recherche des Cordeliers, Paris, France Paris-Diderot University, Sorbonne Paris-Cité, Paris, France Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada.
authors.forename: Amel
authors.initials: A
authors.lastname: Lamri
authors.affiliation: CNRS-UMR8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Leloire
authors.affiliation: CNRS-UMR8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vaillant
authors.affiliation: Inserm U-1138, Centre de Recherche des Cordeliers, Paris, France Paris-Diderot University, Sorbonne Paris-Cité, Paris, France Department of Endocrinology-Diabetology and Nutrition, DHU-FIRE, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.affiliation: Inserm CIE 05-Department of Clinical Epidemiology, Robert Debré Hospital, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lévy-Marchal
authors.affiliation: Pediatric Endocrine Unit, Lille University Hospital, Lille, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.affiliation: Nutritional Epidemiology Research Group, Sorbonne-Paris-Cité, UMR University of Paris 13/Inserm U-557/INRA U-1125/CNAM, Bobigny, France.
authors.forename: Pilar
authors.initials: P
authors.lastname: Galan
authors.affiliation: Nutritional Epidemiology Research Group, Sorbonne-Paris-Cité, UMR University of Paris 13/Inserm U-557/INRA U-1125/CNAM, Bobigny, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Hercberg
authors.affiliation: Inserm, CIC1402 and U-1082, Poitiers, France Department of Endocrinology-Diabetology, Centre for Clinical Investigation, CHU of Poitiers, Poitiers, France University of Poitiers, UFR Medicine Pharmacy, Poitiers, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ragot
authors.affiliation: Inserm, CIC1402 and U-1082, Poitiers, France Department of Endocrinology-Diabetology, Centre for Clinical Investigation, CHU of Poitiers, Poitiers, France University of Poitiers, UFR Medicine Pharmacy, Poitiers, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.affiliation: Department of Diabetes and Endocrinology, Centre Hospitalier Sud-Francilien, Corbeil-Essonne, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.affiliation: Inserm U-1018, CESP, Team 5 (EpReC, Renal and cardiovascular Epidemiology), UVSQ-UPS, Villejuif, France.
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.affiliation: Inserm U-1138, Centre de Recherche des Cordeliers, Paris, France Paris-Diderot University, Sorbonne Paris-Cité, Paris, France Department of Endocrinology-Diabetology and Nutrition, DHU-FIRE, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.affiliation: Inserm U-1138, Centre de Recherche des Cordeliers, Paris, France Paris-Diderot University, Sorbonne Paris-Cité, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fumeron
authors.affiliation: CNRS-UMR8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes (EGID), Lille, France Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D001786:Blood Glucose / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005215:Fasting; D005260:Female; D005787:Gene Frequency; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D017354:Point Mutation / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: D001786:Blood Glucose; C519853:FFAR4 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Diabetes; Genetics; Obesity