Minor contribution of SMAD7 and KLF10 variants to genetic susceptibility of type 2 diabetes.
BACKGROUND
Transgenic mice over-expressing SMAD7 in pancreatic beta-cells develop type 2 diabetes (T2D). The expression of SMAD7 is affected by KLF11, which contains gene variants that have previously been shown to be involved in genetic susceptibility to T2D, and by the highly homologous KLF10. This study aims to assess the genetic contribution of SMAD7 and KLF10 gene variants to T2D susceptibility in the French population.


METHODS
We screened both genes to identify rare and frequent variants by direct sequencing and then genotyped these variants. Six frequent variants of SMAD7 and six of KLF10 were analyzed in 349 T2D patients and 349 normoglycaemic adult subjects. Variants with statistically significant differences in allele and/or genotype distribution were further analyzed in a population sample of 1.712 T2D patients and 1.072 normoglycaemic subjects.


RESULTS
Two variants showed a significant association under a recessive model: The intronic SMAD7 IVS2 -21 had an odds ratio of 0.62 (P=0.007, 95% CI=0.44-0.88; P=0.034 when adjusting for age, sex and BMI by logistic regression), and the KLF10 3'UTR +1002 variant had an Odds Ratio of 0.81 (P=0.009, 95% CI=0.69-0.95; P=0.042 when adjusting for age, sex and BMI).


CONCLUSIONS
Although the observed association of SMAD7 and KLF10 gene variants with T2D is modest, they may weakly contribute to a particular genetic background that increases the susceptibility to development of T2D.
Gutierrez-Aguilar
R
R
CNRS, UMR8090, Institute of Biologie, Institut Pasteur de Lille and Université de Lille 2, Lille, France.
Benmezroua
Y
Y
Balkau
B
B
Marre
M
M
Helbecque
N
N
Charpentier
G
G
Polychronakos
C
C
Sladek
R
R
Froguel
P
P
Neve
B
B
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D051906:Smad7 Protein / Q000235:genetics*; D044465:White People / Q000235:genetics
D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D051906:Smad7 Protein