TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels.
OBJECTIVE
The gene encoding transcription factor 7-like 2 (TCF7L2) has been identified as a type 2 diabetes locus from genome-wide linkage studies and subsequent association analysis. We investigated the role of two common variants in TCF7L2 in a large case-control study recruited from the Tayside region of Scotland, UK.


METHODS
We genotyped 6,516 participants for rs12255372 and rs7903146 and analysed the role in type 2 diabetes susceptibility using binary logistic regression. Age, sex and obesity status were examined as covariates. The distribution of the genotypes within different treatment groups of cases was examined.


RESULTS
Both variants were associated with type 2 diabetes (p < 10(-13)). The variants were present at very similar frequencies and were in strong linkage disequilibrium (R(2) = 0.88, D' = 0.89). A gene dosage effect of the rare allele of both variants was observed, the heterozygote CT group of rs7903146 having an odds ratio of 1.36 (95% CI 1.2-1.5, p=1.54 x 10(-7)) for type 2 diabetes and the TT homozygote having a greater risk (OR = 2.03, 95% CI 1.7-2.5, p=1.40 x 10(-12)). An interaction with sex was observed, the males displaying a higher degree of genotype-associated risk compared with the females (p = 0.023). The T allele was associated with increased HbA(1c) levels in both cases and controls, and with decreased BMI and waist circumference in case but not controls. The T allele was overrepresented in individuals requiring insulin treatment and underrepresented in the patients being managed by diet alone (p = 0.006).


CONCLUSIONS
We have confirmed TCF7L2 to be a diabetes locus in a large case-control study in Tayside, UK. Our data suggest that variants of TCF7L2 may be associated with increased disease severity and therapeutic failure.
Kimber
C H
CH
Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.
Doney
A S F
AS
Pearson
E R
ER
McCarthy
M I
MI
Hattersley
A T
AT
Leese
G P
GP
Morris
A D
AD
Palmer
C N A
CN
D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D049628:Body Size; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006706:Homeostasis; D006801:Humans; D008055:Lipids / Q000097:blood; D008875:Middle Aged; D016017:Odds Ratio; D012016:Reference Values; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D001786:Blood Glucose; D017931:DNA Primers; D008055:Lipids; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein