TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program.
BACKGROUND
Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo.


METHODS
We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year.


RESULTS
Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372.


CONCLUSIONS
Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992. [ClinicalTrials.gov]).
Florez
Jose C
JC
Diabetes Prevention Program Outcomes Study Coordinating Center, George Washington University, Rockville, Md 20852, USA. dppmail@biostat.bsc.gwu.edu
Jablonski
Kathleen A
KA
Bayley
Nick
N
Pollin
Toni I
TI
de Bakker
Paul I W
PI
Shuldiner
Alan R
AR
Knowler
William C
WC
Nathan
David M
DM
Altshuler
David
D
D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D018450:Disease Progression; D019858:Enteroendocrine Cells / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D044882:Glucose Metabolism Disorders / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein