Journal
CANCER SCIENCE
Volume 102, Issue 8, Pages 1462-1468Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1349-7006.2011.01965.x
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Funding
- National Natural Scientific Foundation of China [81001278, 81072366]
- Suzhou Science and Technology Agency [SYS201052]
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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. (Cancer Sci 2011; 102: 1462-1468)
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