Association of caspase9 promoter polymorphisms with the susceptibility of AML in south Indian subjects

作者：Cingeetham Anuradha; Vuree Sugunakar; Dunna Nageswara Rao; Gorre Manjula; Nanchari Santhoshi Rani; Edathara Prajitha Mohandas; Mekkaw Phannibhusan; Annamaneni Sandhya; Digumarthi Raghunadha Rao; Sinha Sudha; Satti Vishnupriya^*

来源：Tumor Biology, 2014, 35(9): 8813-8822.

DOI：10.1007/s13277-014-2096-5

• Acute myeloid leukemia
• Caspase9
• Apoptosis
• PCR-RFLP

Abnormal apoptosis is one of the hallmarks of cancers including acute myeloid leukemia (AML), as it plays a pivotal role in precisely maintaining self-renewal, proliferation, and differentiation properties of hematopoietic stem cells (HSCs). Caspase9 (CASP9), an initiator caspase activated by mitochondrial-mediated apoptotic pathway (intrinsic pathway), triggers cascade of effector caspases and executes apoptosis. Functional SNPs in CASP9 might influence the gene expression leading to altered apoptosis which confer the risk to AML. To test this hypothesis, we have analyzed four CASP9 gene polymorphisms [CASP9 -aEuro parts per thousand 1263A > G (rs4645978), CASP9 -aEuro parts per thousand 712C > T (rs4645981), CASP9 -aEuro parts per thousand 293_275del CGTGAGGTC AGTGCGGGGA (-293del) (rs4645982), and CASP9 Ex5 + 32G > A (rs1052576)] in 180 AML cases and 304 age- and sex-matched healthy controls. We performed various statistical analyses to determine the potential interactions between these SNPs and AML. The study revealed that presence of G allele at CASP9 -aEuro parts per thousand 1263 position elevates the risk of AML 1.53-fold and CT/TT genotype at CASP9 -aEuro parts per thousand 712 position by 2.60-fold under dominant model of inheritance. Two CASP9 haplotypes, G-del(+)-C-A and G-del(+)-T-A, were found to be significantly associated with increased AML risk by 2.19- (95 % confidence interval (CI), 1.09-4.39; p = 0.028) and 11.75-fold (95 % CI, 1.01-136.57; p = 0.05), respectively. Further, multidimensionality reduction (MDR) analysis had revealed single locus CASP9 -aEuro parts per thousand 712C > T SNP and four loci CASP9 -aEuro parts per thousand 1263A > G, CASP9 -aEuro parts per thousand 293del, CASP9 -aEuro parts per thousand 712C > T, and CASP9 Ex5 + 32G > A SNPs as highest predicting models for AML development. Our results revealed a significant association of two SNPs in CASP9 (-1263A > G and -712C > T) and two haplotypes of the four SNP combinations with AML susceptibility.

• 出版日期2014-9
• 单位河北医科大学