TY - JOUR
T1 - Identification of minimal promoter and genetic variants of kruppel-like factor 11 gene and association analysis with type 2 diabetes in Japanese
AU - Kuroda, Eiji
AU - Horikawa, Yukio
AU - Enya, Mayumi
AU - Oda, Naohisa
AU - Suzuki, Eiji
AU - Iizuka, Katsumi
AU - Takeda, Jun
PY - 2009
Y1 - 2009
N2 - Genetic analysis of the KLF11 gene revealed two rare variants, A347S and T220M, segregating in families with early-onset type 2 diabetes, and one frequent polymorphic Q62R variant significantly associated with type 2 diabetes in Northern Europeans. Furthermore, it has been reported that over-expression of KLF11 has a deleterious effect on insulin promoter activity. Thus, an altered expression level of KLF11 may contribute to the occurrence of type 2 diabetes. To investigate the contribution of KLF11 to type 2 diabetes in Japanese, we surveyed the 5' flanking region of KLF11 by reporter assay and identified the minimal promoter region of the gene. The promoter region from -250 to +162 bp including five Spl binding sites showed basal promoter activity both in MIN6-m9 and HepG2 cells. We also examined the entire region of KLF11 to detect genetic variants. A total of 19 polymorphisms, six of which are novel, were identified, but none of them showed association with the occurrence of type 2 diabetes. Two of the identified polymorphisms, R29Q and S124F, are novel coding variants. Functional analyses of these variants were performed, and similarly reduced effects on transcriptional activities of insulin, catalasel, and the Smad7 gene were found. We conclude that variants of KLF11 are not a major factor in the occurrence of type 2 diabetes in Japanese. The promoter region of KLF11 identified in the present study should be useful in further elucidation of the transcriptional regulation mechanism of the gene and genetic analyses of type 2 diabetes.
AB - Genetic analysis of the KLF11 gene revealed two rare variants, A347S and T220M, segregating in families with early-onset type 2 diabetes, and one frequent polymorphic Q62R variant significantly associated with type 2 diabetes in Northern Europeans. Furthermore, it has been reported that over-expression of KLF11 has a deleterious effect on insulin promoter activity. Thus, an altered expression level of KLF11 may contribute to the occurrence of type 2 diabetes. To investigate the contribution of KLF11 to type 2 diabetes in Japanese, we surveyed the 5' flanking region of KLF11 by reporter assay and identified the minimal promoter region of the gene. The promoter region from -250 to +162 bp including five Spl binding sites showed basal promoter activity both in MIN6-m9 and HepG2 cells. We also examined the entire region of KLF11 to detect genetic variants. A total of 19 polymorphisms, six of which are novel, were identified, but none of them showed association with the occurrence of type 2 diabetes. Two of the identified polymorphisms, R29Q and S124F, are novel coding variants. Functional analyses of these variants were performed, and similarly reduced effects on transcriptional activities of insulin, catalasel, and the Smad7 gene were found. We conclude that variants of KLF11 are not a major factor in the occurrence of type 2 diabetes in Japanese. The promoter region of KLF11 identified in the present study should be useful in further elucidation of the transcriptional regulation mechanism of the gene and genetic analyses of type 2 diabetes.
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U2 - 10.1507/endocrj.K08E-302
DO - 10.1507/endocrj.K08E-302
M3 - Article
C2 - 19122346
AN - SCOPUS:66849131586
SN - 0918-8959
VL - 56
SP - 275
EP - 286
JO - endocrine journal
JF - endocrine journal
IS - 2
ER -