title: The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes.
abstract: OBJECTIVE
  A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.
  
  
  METHODS
  Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.
  
  
  RESULTS
  We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).
  
  
  CONCLUSIONS
  Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Marie Neergaard
authors: MN
authors: Harder
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Emil Vincent Rosenbaum
authors: EV
authors: Appel
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Niels
authors: N
authors: Grarup
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Anette Prior
authors: AP
authors: Gjesing
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Danish Pediatric Asthma Center, Gentofte Hospital, The Capital Region, Copenhagen, Denmark.
authors: Tarunveer S
authors: TS
authors: Ahluwalia
authors: Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Torben
authors: T
authors: Jørgensen
authors: Medical Department, Lillebaelt Hospital, Vejle Hospital, Vejle, Denmark.
authors: Cramer
authors: C
authors: Christensen
authors: Department of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Vejle Hospital, Vejle, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
authors: Ivan
authors: I
authors: Brandslund
authors: Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Allan
authors: A
authors: Linneberg
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, the Capital Region, Copenhagen, Denmark.
authors: Thorkild I A
authors: TI
authors: Sørensen
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Oluf
authors: O
authors: Pedersen
authors: 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: Torben
authors: T
authors: Hansen
mesh_terms: D000483:Alleles; D001786:Blood Glucose; D016022:Case-Control Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005215:Fasting; D056726:Genetic Association Studies; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable
chemical_list: D001786:Blood Glucose; D008565:Membrane Proteins; C000603438:TMEM154 protein, human