title: TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study.
abstract: OBJECTIVE
  Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS).
  
  
  METHODS
  We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures.
  
  
  RESULTS
  As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 x 10(-7)) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92).
  
  
  CONCLUSIONS
  We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls.
authors.affiliation: Simches Research Building-CPZN 5.250, Diabetes Unit/Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Stolerman
authors.forename: A K
authors.initials: AK
authors.lastname: Manning
authors.forename: J B
authors.initials: JB
authors.lastname: McAteer
authors.forename: C S
authors.initials: CS
authors.lastname: Fox
authors.forename: J
authors.initials: J
authors.lastname: Dupuis
authors.forename: J B
authors.initials: JB
authors.lastname: Meigs
authors.forename: J C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D000368:Aged; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D008404:Massachusetts; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D011384:Proinsulin / Q000097:blood* / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D055105:Waist Circumference
chemical_list: D006442:Glycated Hemoglobin; D007328:Insulin; D011384:Proinsulin; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; C544894:TCF7L2 protein, human