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

Abstract

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 - 1263A > G (rs4645978), CASP9 - 712C > T (rs4645981), CASP9 - 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 - 1263 position elevates the risk of AML 1.53-fold and CT/TT genotype at CASP9 - 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 - 712C > T SNP and four loci CASP9 - 1263A > G, CASP9 - 293del, CASP9 - 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.

Caspase polymorphisms and prognosis of hepatocellular carcinoma

“…CASP9 , an important initiator CASP of the intrinsic pathway, is activated by the release of cytochrome c from mitochondria, activates downstream the effector CASP3 and CASP7 [22–23]. Many previous studies have shown that polymorphisms in CASP9 were associated with various cancer types, especially in the promoter region.…”

Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease

“…Even greater challenges relate to understanding noncoding CASP9 polymorphisms associated with hematopoietic malignancies (Hosgood et al, 2008;Lan et al, 2009;Kelly et al, 2010;Cingeetham et al, 2014), new-onset diabetes after renal transplant (McCaughan et al, 2014), and treatment efficacy for Crohn's disease (Hlavaty et al, 2005;Ferreira et al, 2010;Cravo et al, 2014). Biochemical analysis of patient samples can help identify if these noncoding variants are correlated with alterations in caspase-9 activity or expression in disease-relevant tissues.…”

Heat shock protein 70 gene polymorphisms’ influence on the electrophysiology of long QT syndrome

“…5) [17]. Table 2 (Supplementary 1) shows a small chunk of mutation analysis data produced from the ongoing study.…”