title: Functional variant (-1304T>G) in the MKK4 promoter is associated with decreased risk of acute myeloid leukemia in a southern Chinese population.
abstract: As a member of the MAPK kinase family, mitogen-activated protein kinase kinase (MKK) 4 (NM_003010.2) is know to be involved in the regulation of apoptosis, inflammation, and tumorigenesis. Several polymorphisms have been identified in the promoter region of the MKK4 gene and we hypothesized that genetic variations in this region may alter gene expression, and thus cancer risk. In the present study, we genotyped two polymorphisms in the promoter of the MKK4 gene, namely -1304T>G (rs3826392) and -1044A>T (rs3809728), in 433 patients with AML and 600 controls, and assessed the association between those polymorphisms and the risk of AML. Compared with the -1304TT genotype, patients with the -1304TG genotype had a significantly decreased risk of AML (adjusted odds ratio (OR) 0.67; 95% confidence interval (CI) 0.51-0.87), with the risk decreased even further in those carrying -1304GG (OR 0.56; 95% CI 0.31-0.97). Additional experiments, which focused on reporter gene expression driven by MKK4 promoters, demonstrated that the presence of a -1304G allele led to greater transcriptional activity than the presence of a -1304T allele. However, no significant association was observed between the MKK4-1044A>T polymorphism and the risk of AML. These findings suggest that the functional -1304G>T variant may contribute to the risk of AML by enhancing the transcriptional activity of MKK4. Thus, this polymorphism may be a genetic modifier for the development of AML.
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Aining
authors.initials: A
authors.lastname: Sun
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Yonghe
authors.initials: Y
authors.lastname: You
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D005260:Female; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000517:prevention & control; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012306:Risk
chemical_list: D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human