title: The role of obesity-related genetic loci in insulin sensitivity.
abstract: OBJECTIVE
  Despite rapid advancements and many new diabetes susceptibility loci found in the past few years, few genetic variants associated with insulin sensitivity have been described, potentially attributable to the lack of larger cohorts examined with gold standard methods for insulin sensitivity assessment. There is a strong link between obesity and insulin sensitivity, and we hypothesized that known obesity susceptibility loci may act via effects on insulin sensitivity.
  
  
  METHODS
  A cohort of 71-year-old men without diabetes (Uppsala Longitudinal Study of Adult Men) underwent a euglycaemic-hyperinsulinaemic clamp and genotyping for genetic variants representing 32 loci recently reported to be associated with BMI (n = 926). The effect of these loci on the insulin sensitivity index (M/I ratio) was examined using linear regression. An in silico replication was performed in publically available data for the three top single-nucleotide polymorphisms from the Meta-Analyses of Glucose and Insulin-related traits Consortium analyses of homeostasis model assessment of insulin resistance (n = 37,037).
  
  
  RESULTS
  Three loci (SH2B1, MTCH2 and NEGR1) were associated with decreased insulin sensitivity at a nominal significance (P ≤ 0.05) after adjustment for BMI, but did not hold for multiple comparison correction. SH2B1 rs7359397 was also associated with homeostasis model assessment of insulin resistance in the Meta-Analyses of Glucose and Insulin-related traits Consortium data set (P = 3.9 × 10(-3)).
  
  
  CONCLUSIONS
  Our study supports earlier reports of SH2B1 to be of importance in insulin sensitivity and, in addition, suggests potential roles of NEGR1 and MTCH2.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. tove.fall@ki.se
authors.forename: T
authors.initials: T
authors.lastname: Fall
authors.forename: J
authors.initials: J
authors.lastname: Arnlöv
authors.forename: C
authors.initials: C
authors.lastname: Berne
authors.forename: E
authors.initials: E
authors.lastname: Ingelsson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000235:genetics; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; C502207:MTCH2 protein, human; D033681:Mitochondrial Membrane Transport Proteins; C485559:NEGR1 protein, human; D011506:Proteins; C518910:SH2B1 protein, human; D014157:Transcription Factors; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human