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Context: 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&amp;gt;G/Gln62Arg and −1659 G&amp;gt;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&amp;gt;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&amp;gt;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&amp;gt;C variant. Overall, KLF11 variants may have a deleterious effect on insulin sensitivity, although that may not be sufficient to lead to T2D.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Genetic Analysis of Krüppel-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&amp;gt;C