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
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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. / Gutiérrez-Aguilar, Ruth; Froguel, Philippe; Hamid, Yasmin H; Benmezroua, Yamina; Jørgensen, Torben; Borch-Johnsen, Knut; Hansen, Torben; Pedersen, Oluf; Neve, Bernadette.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 8, 2008, p. 3128-35.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Gutiérrez-Aguilar, Ruth
AU - Froguel, Philippe
AU - Hamid, Yasmin H
AU - Benmezroua, Yamina
AU - Jørgensen, Torben
AU - Borch-Johnsen, Knut
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Neve, Bernadette
N1 - Keywords: Cell Cycle Proteins; Cells, Cultured; Humans; Insulin Resistance; Linkage Disequilibrium; Promoter Regions, Genetic; Repressor Proteins; STAT3 Transcription Factor; Thymidine Kinase; Transcription, Genetic
PY - 2008
Y1 - 2008
N2 - 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>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.
AB - 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>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.
U2 - 10.1210/jc.2007-2504
DO - 10.1210/jc.2007-2504
M3 - Journal article
C2 - 18505768
VL - 93
SP - 3128
EP - 3135
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 8
ER -
ID: 10001406