Genetic Variants in the Candidate Genes of the Apoptosis Pathway and Susceptibility to Chronic Myeloid Leukemia
Authors: Kim Dong Hwan , Kim Kyoung Ha , Chang Myung Hee , Xu Wei , Ma Clement , Liu Xiangdong , Siminovitch Katherine , Messner Hans A. , Lipton Jeffrey H. 
Published: April 2020

Abstract
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
Gene SNP ID Apoptosis pathway (n=30) BCL2 rs1801018, rs2279115 BAX rs11667351 BCL2L2 rs7042474 BCL6 rs1056932, rs11545363 BCL2L11 rs6746608, rs12613243 BIRC5 rs9904341, rs2071214 CASP1 rs580253 CASP3 rs1049253 CASP7 rs7922608 CASP8 rs1045485, rs3769818, rs3834129 CASP9 rs4645981 CASP10 rs13010627, rs13006529 FASL rs763110 FAS rs2234767, rs1800682, rs3218619, rs3218612, rs2234978 APAF1 rs1439123, rs2288713 TNFR2 rs1061622 PDCD1 rs2227981 GZMB rs7144366 Angiogenesis (n=7) VEGFA rs699947, rs833061, rs2010963, rs3025039 VEGFR2 rs1531289, rs1870377, rs2305948 Myeloid Growth (n=14) FLT3 rs35602083 CSF3 rs25645, rs1042658 CSF2 rs25882 JAK3 rs3008, rs3212713 JAK3 IL1A rs17561, rs1800587 IL1A IL1B rs1143634, rs1143633, rs1143627, rs16944 IL1R rs2228139, rs315952 WT1 signaling (n=7) WT1 rs1799937, rs2234591, rs2234590, rs2301254, rs2301252, rs2301250, rs6508 Xenobiotic metabolism (n=13) ABCB1 rs1045642, rs2032582, rs1128503 ABCG2 rs2231142, rs2231137 CYP3A5 rs776746, rs28383469, rs28383468 HOCT1 rs1867351, rs12208357, rs683369, rs2282143, rs628031 Interferon signaling (n=4) IFNG rs1861494, rs2069705 IFNGR1 rs3799488 IFNGR2 rs9808753 Others (n=5) GNB3 rs5443 ULK3 rs2290573 ORM rs1126724, rs3182041 PTK2 rs4554515