Genetic analysis of Kruppel-like zinc finger 11 variants in 5864 Danish individuals: potential effect on insulin resistance and modified signal transducer and activator of transcription-3 binding by promoter variant -1659G>C.
BACKGROUND
The transcription factor Krüppel-like zinc finger 11 (KLF11) has been suggested to contribute to genetic risk of type 2 diabetes (T2D). Our previous results showed that four KLF11 variants, in strong linkage disequilibrium (LD block including +185 A>G/Gln62Arg and -1659 G>C) were associated with T2D in a north European case-control study. Here we further analyzed these variants for T2D association in a general Danish population and assess their possible effect on gene function.


METHODS
We genotyped Gln62Arg variant, representative for the LD block, in 5864 subjects of the INTER99 study to assess association to T2D and glucose metabolism-related quantitative traits. We studied effects of LD-block variants on KLF11 function and in particular, the effect of -1659G>C on transcriptional regulation of KLF11 using EMSA, chromatin immunoprecipitation, gene reporter assays, and small interfering RNA transfection.


RESULTS
We could not confirm T2D association of the KLF11 LD block, however, in glucose-tolerant subjects; it was significantly associated with higher fasting serum insulin and C-peptide levels and increased homeostasis model assessment insulin resistance indexes (P = 0.00004, P = 0.006, and P = 0.00002, respectively). In addition, binding of signal transducer and activator of transcription (STAT)-3 to the wild-type (-1659G>C) allele stimulated gene transcription, whereas STAT3 did not bind onto the mutant allele.


CONCLUSIONS
We showed that KLF11 may interfere with glucose homeostasis in a Danish general population and that STAT3-mediated up-regulation of KLF11 transcription was impaired by the -1659G>C variant. Overall, KLF11 variants may have a deleterious effect on insulin sensitivity, although that may not be sufficient to lead to T2D.
Gutiérrez-Aguilar
Ruth
R
Centre National de la Recherche Scientifique Unit Mixte de Recherche 8090-Institute of Biology, Lille, France.
Froguel
Philippe
P
Hamid
Yasmin H
YH
Benmezroua
Yamina
Y
Jørgensen
Torben
T
Borch-Johnsen
Knut
K
Hansen
Torben
T
Pedersen
Oluf
O
Neve
Bernadette
B
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D007333:Insulin Resistance; D015810:Linkage Disequilibrium; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C115117:KLF11 protein, human; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013937:Thymidine Kinase