Genetic Variants in the Candidate Genes of the Apoptosis Pathway and Susceptibility to Chronic Myeloid Leukemia

Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder, characterized by the presence of BCR/ABL fusion gene. It is unclear which cellular events drive BCR/ABL gene translocation or initiate leukemogenesis in CML. Bcl-2 promotes survival of hematopoietic stem cells. Accordingly, apoptosis–related pathway may involve in the leukemogenesis of CML. In the current study, we evaluated 80 SNP markers (Table 1) involved in the pathways of apoptosis (n=31; BCL2, BAX, BCL2L2, BCL6, BCL2L11, BIRC5, CASP1, CASP3, CASP7, CASP8, CASP9, CASP10, FAS, FASL, APAF1, TNFR2, PDCD1, GZMB), angiogenesis (n=7; VEGFA, VEGFR2), myeloid cell growth (n=13; FLT2, CSF3, CSF2, JAK3, IL1A, IL1B, IL1R), xenobiotic metabolism (n=13; ABCB1, ABCG2, CYP3A5, HOCT1), WT1 signaling (n=7), interferon signaling (n=4; IFNG, IFNGR1, IFNGR2) and others (n=5; GNB3, ULK3, ORM, PTK2) in 170 CML patients and 182 healthy controls with European ancestry. In a single marker analysis, following SNPs were identified including VEGFA, BCL2, CASP7, JAK3, CSF3 and HOCT1. In the multivariate logistic model with these 7 SNPs and covariates, only BCL2 (rs1801018) was significantly associated with the susceptibility to CML (p=0.05; adj-OR 2.16, [1.00–4.68]). In haplotype analyses, haplotype block of BCL2 consistently showed significant association with the susceptibility to CML. Risk allele analysis showed that a greater number of risk alleles from BCL2 SNP correlated to increasing risk of CML (overall p=0.1, OR 1.84, [1.06–3.22] for 3–4 risk alleles vs. 0–1 risk alleles). The current study indicated that BCL2 SNP seemed to be associated with increasing susceptibility to CML.

Table 1. Summary of 80 candidate gene single nucleotide polymorphisms