title: Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population.
abstract: p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gαq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucose-related traits in the Danish population.
  
  
  
  Surface expression, Gq and Gi coupled signalling as well as β-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals.
  
  
  
  p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect β-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population (p>0.05).
  
  
  
  We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark Section for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Vestmar
authors.affiliation: Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ehm A
authors.initials: EA
authors.lastname: Andersson
authors.affiliation: Section for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Christensen
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark Section for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Hauge
authors.affiliation: Department of Health Science and Technology, Aalborg University, Aalborg, Denmark Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Glümer
authors.affiliation: Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.affiliation: Section for General Practice, Department of Public Health, Aarhus University, Denmark.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Marit E
authors.initials: ME
authors.lastname: Jørgensen
authors.affiliation: Department of Internal Medicine and Endocrinology, SLB, Vejle Hospital, Vejle, Denmark.
authors.forename: Cramer
authors.initials: C
authors.lastname: Christensen
authors.affiliation: Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Ivan
authors.initials: I
authors.lastname: Brandslund
authors.affiliation: Section for General Practice, Department of Public Health, Aarhus University, Denmark.
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.affiliation: Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark Section for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark Section for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.affiliation: Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005947:Glucose / Q000235:genetics; D005951:Glucose Tolerance Test / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008024:Ligands; D008055:Lipids / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000071557:beta-Arrestins / Q000235:genetics
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C519853:FFAR4 protein, human; D008024:Ligands; D008055:Lipids; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D005947:Glucose
keywords: FFAR4; GPR120; Genetics; Molecular genetics; Obesity