title: Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased β-cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort.
abstract: BACKGROUND
  Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry.
  
  
  OBJECTIVE
  The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants.
  
  
  METHODS
  A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes.
  
  
  RESULTS
  We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 with T2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14 rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation.
  
  
  CONCLUSIONS
  BCAR1 rs7202877 may mediate its diabetogenic impact through impaired β-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance.
authors: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. marie.harder@sund.ku.dk
authors: Marie N
authors: MN
authors: Harder
authors: Rasmus
authors: R
authors: Ribel-Madsen
authors: Johanne M
authors: JM
authors: Justesen
authors: Thomas
authors: T
authors: Sparsø
authors: Ehm A
authors: EA
authors: Andersson
authors: Niels
authors: N
authors: Grarup
authors: Torben
authors: T
authors: Jørgensen
authors: Allan
authors: A
authors: Linneberg
authors: Torben
authors: T
authors: Hansen
authors: Oluf
authors: O
authors: Pedersen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000483:Alleles; D017487:Ankyrins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D050719:Crk-Associated Substrate Protein / Q000235:genetics*; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011236:Prediabetic State / Q000235:genetics / Q000503:physiopathology*; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors
chemical_list: C110202:ANK1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D017487:Ankyrins; C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; C099655:GRB14 protein, human; D007328:Insulin