title: Discovery of coding genetic variants influencing diabetes-related serum biomarkers and their impact on risk of type 2 diabetes.
abstract: BACKGROUND
  Type 2 diabetes (T2D) prevalence is spiraling globally, and knowledge of its pathophysiological signatures is crucial for a better understanding and treatment of the disease.
  
  
  OBJECTIVE
  We aimed to discover underlying coding genetic variants influencing fasting serum levels of nine biomarkers associated with T2D: adiponectin, C-reactive protein, ferritin, heat shock 70-kDa protein 1B, IGF binding protein 1 and IGF binding protein 2, IL-18, IL-2 receptor-α, and leptin.
  
  
  METHODS
  A population-based sample of 6215 adult Danes was genotyped for 16 340 coding single-nucleotide polymorphisms and were tested for association with each biomarker. Identified loci were tested for association with T2D through a large-scale meta-analysis involving up to 17 024 T2D cases and up to 64 186 controls.
  
  
  RESULTS
  We discovered 11 associations between single-nucleotide polymorphisms and five distinct biomarkers at a study-wide P < 3.4 × 10(-7). Nine associations were novel: IL18: BIRC6, RAD17, MARVELD2; ferritin: F5; IGF binding protein 1: SERPING1, KLKB, GCKR, CELSR2, and heat shock 70-kDa protein 1B: CFH. Three of the identified loci (CELSR2, HNF1A, and GCKR) were significantly associated with T2D, of which the association with the CELSR2 locus has not been shown previously.
  
  
  CONCLUSIONS
  The identified loci influence processes related to insulin signaling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (T.S.A., K.H.A., C.H.S., T.H.A., T.H., N.G., O.P.), Section of Metabolic Genetics, Faculty of Health and Medical Sciences, Department of Clinical Medicine (A.L.), Faculty of Health and Medical Sciences, and Institute of Public Health (T.J.), University of Copenhagen, 2100 Copenhagen, Denmark; Copenhagen Prospective Studies on Asthma in Childhood (T.S.A.), Faculty of Health and Medical Sciences, University of Copenhagen, 2820 Copenhagen, Denmark; The Danish Paediatric Asthma Center (T.S.A.), Gentofte Hospital, The Capital Region, 2820 Copenhagen, Denmark; Steno Diabetes Center (E.J.), 2820 Gentofte, Denmark; Tethys Bioscience Inc (M.R.), Emeryville, California 94608; Departments of Internal Medicine and Endocrinology (C.C.) and Clinical Biochemistry (I.B.), Vejle Hospital, 7100 Vejle, Denmark; Institute of Regional Health Research (I.B.), and Faculty of Health Sciences (T.H.), University of Southern Denmark, 5230 Odense, Denmark; Department of General Practice (T.L.), Aarhus University, 8000 C Aarhus, Denmark; Research Centre for Prevention and Health (A.L., L.L.H., T.J.), The Capital Region of Denmark, Copenhagen, Denmark; Department of Clinical Experimental Research (A.L.), Glostrup University Hospital, 2600 Glostrup, Denmark; and Faculty of Medicine (T.J.), University of Aalborg, 9220 Aalborg, Denmark.
authors.forename: Tarunveer Singh
authors.initials: TS
authors.lastname: Ahluwalia
authors.forename: Kristine Højgaard
authors.initials: KH
authors.lastname: Allin
authors.forename: Camilla Helene
authors.initials: CH
authors.lastname: Sandholt
authors.forename: Thomas Hempel
authors.initials: TH
authors.lastname: Sparsø
authors.forename: Marit Eika
authors.initials: ME
authors.lastname: Jørgensen
authors.forename: Michael
authors.initials: M
authors.lastname: Rowe
authors.forename: Cramer
authors.initials: C
authors.lastname: Christensen
authors.forename: Ivan
authors.initials: I
authors.lastname: Brandslund
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.forename: Lise Lotte
authors.initials: LL
authors.lastname: Husemoen
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D015415:Biomarkers