title: Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population.
abstract: BACKGROUND
  Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear.
  
  
  OBJECTIVE
  We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and β-cell dysfunction, and on T2D risk.
  
  
  METHODS
  We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic β-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls).
  
  
  RESULTS
  We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (β=0.02; P-value=7.16 × 10(-9) for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased β-cell function (β=0.01; P-value=1.05 × 10(-6) and β=0.04; P-value=3.45 × 10(-4), respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 × 10(-3) and OR=1.15; P-value=9.46 × 10(-4), respectively). Adjustment for BMI abolished all significant associations.
  
  
  CONCLUSIONS
  Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased β-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.
authors.affiliation: CNRS UMR-8199, Lille Pasteur Institute, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Robiou-du-Pont
authors.forename: A
authors.initials: A
authors.lastname: Bonnefond
authors.forename: L
authors.initials: L
authors.lastname: Yengo
authors.forename: E
authors.initials: E
authors.lastname: Vaillant
authors.forename: S
authors.initials: S
authors.lastname: Lobbens
authors.forename: E
authors.initials: E
authors.lastname: Durand
authors.forename: J
authors.initials: J
authors.lastname: Weill
authors.forename: O
authors.initials: O
authors.lastname: Lantieri
authors.forename: B
authors.initials: B
authors.lastname: Balkau
authors.forename: G
authors.initials: G
authors.lastname: Charpentier
authors.forename: M
authors.initials: M
authors.lastname: Marre
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: D
authors.initials: D
authors.lastname: Meyre
mesh_terms: D000328:Adult; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics*; D012359:tRNA Methyltransferases
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases