title: A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans.
abstract: BACKGROUND
  Experiments in mice initially suggested a role for the protein angiopoietin-like 8 (ANGPTL8) in glucose homeostasis. However, subsequent experiments in model systems have challenged this proposed role. We sought to better understand the importance of ANGPTL8 in human glucose homeostasis by examining the association of a null mutation in ANGPTL8 with fasting glucose levels and risk for type 2 diabetes.
  
  
  METHODS
  A naturally-occurring null mutation in human ANGPTL8 (rs145464906; c.361C > T; p.Q121X) is carried by ~1 in 1000 individuals of European ancestry and is associated with higher levels of plasma high-density lipoprotein cholesterol, suggesting that this mutation has functional significance. We examined the association of p.Q121X with fasting glucose levels and risk for type 2 diabetes in up to 95,558 individuals (14,824 type 2 diabetics and 80,734 controls).
  
  
  RESULTS
  We found no significant association of p.Q121X with either fasting glucose or type 2 diabetes (p-value = 0.90 and 0.65, respectively). Given our sample sizes, we had >98 % power to detect at least a 0.23 mmol/L effect on plasma glucose and >95 % power to detect a 70 % increase in risk for type 2 diabetes.
  
  
  CONCLUSIONS
  Disruption of ANGPTL8 function in humans does not seem to have a large effect on measures of glucose tolerance.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Clapham
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.|National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA, 01702, USA.
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Chu
authors.affiliation: Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN, 46202, USA.|Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wessel
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.|Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.affiliation: Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Sartori
authors.affiliation: Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
authors.forename: Usman
authors.initials: U
authors.lastname: Baber
authors.affiliation: Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0SL, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.|Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. gpeloso@bu.edu.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA. gpeloso@bu.edu.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. gpeloso@bu.edu.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA. gpeloso@bu.edu.|, 801 Massachusetts Ave, Crosstown Center, Third Floor, Boston, MA, 02118, USA. gpeloso@bu.edu.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
mesh_terms: D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D001786:Blood Glucose / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005951:Glucose Tolerance Test; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D036361:Peptide Hormones / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: C576683:ANGPTL8 protein, human; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D001786:Blood Glucose; D008055:Lipids; D036361:Peptide Hormones
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