title: 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.
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Cingeetham
authors.forename: Sugunakar
authors.initials: S
authors.lastname: Vuree
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Dunna
authors.forename: Manjula
authors.initials: M
authors.lastname: Gorre
authors.forename: Santhoshi Rani
authors.initials: SR
authors.lastname: Nanchari
authors.forename: Prajitha Mohandas
authors.initials: PM
authors.lastname: Edathara
authors.forename: Phannibhusan
authors.initials: P
authors.lastname: Mekkaw
authors.forename: Sandhya
authors.initials: S
authors.lastname: Annamaneni
authors.forename: Raghunadha Rao
authors.initials: RR
authors.lastname: Digumarthi
authors.forename: Sudha
authors.initials: S
authors.lastname: Sinha
authors.forename: Vishnupriya
authors.initials: V
authors.lastname: Satti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D053453:Caspase 9 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007194:India; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D053453:Caspase 9