Edathara Prajitha Mohandas, Gorre Manjula, Kagita Sailaja, Cingeetham Anuradha, Annamaneni Sandhya, Digumarti Raghunadharao, Satti Vishnupriya
Department of Genetics, Osmania University, Hyderabad, Telangana, India.
Department of Biochemistry, Osmania University, Hyderabad, Telangana, India.
Gene. 2019;721S:100002. doi: 10.1016/j.gene.2018.100002. Epub 2018 Dec 17.
Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder, characterized by the overproduction of myeloid cells in all stages of maturation. It is usually defined by three sequential stages (Chronic, Accelerated and Blast-crisis) where the transition from chronic to accelerated to blast phases is presumed to occur due to secondary genetic changes, viz. accumulation of mutations, activation of downstream pathways and failure of apoptosis. Caspase 9 is the initiator caspase involved in mitochondrial-mediated apoptotic pathway. Polymorphisms in the promoter (-1263 A>G, -712C>T, -293 del) and coding (Ex5 +32G>A) regions of CASP9 gene are found to influence the expression levels by either impairing the activation or loss of expression of CASP9 or insufficient formation of apoptosome.
The present case-control study was carried out on 999 individuals, comprised of 485CML cases reported at Nizams Institute of Medical Sciences (NIMS), Hyderabad and 514 age and gender-matched healthy individuals from local population. DNA was isolated by non-enzymatic/salting-out method and was genotyped using RFLP technique.
It was observed that the presence of G allele of CASP9 -1263A>G polymorphism enhanced the risk for CML while CASP9 -712C>T and CASP9 -293del SNPs conferred protection against development of CML. Haplotype analysis of promoter and exonic polymorphisms had revealed increased risk associated with two haplotypes G_C_del (+)_G (OR-1.61, 95% CI-0.97-2.65, p-0.06#) and G_C_del (-)_G (OR-2.09, 95% CI-0.94-4.66, p-0.07#) suggesting the role of G allele of CASP9 -1263A>G in conferring risk independent of other SNPs. Pairwise LD analysis performed for all the four SNPs revealed the presence of LD among the SNPs.
The results of the present study therefore concludes the role of CASP9 -1263A>G polymorphism in increasing the risk for the development and progression while CASP9 -712C>T and CASP9 -293del SNPs conferred protection and CASP9 Ex5 +32G>A was involved in conferring resistance which could be in combination with other SNPs or factors affecting them.
慢性粒细胞白血病（CML）是一种骨髓增殖性疾病，其特征是各成熟阶段的髓系细胞过度增殖。它通常由三个连续阶段（慢性期、加速期和急变期）定义，从慢性期到加速期再到急变期的转变被认为是由于继发性基因改变，即突变积累、下游通路激活和凋亡失败所致。半胱天冬酶9是参与线粒体介导的凋亡途径的起始半胱天冬酶。已发现CASP9基因启动子（-1263 A>G、-712C>T、-293 del）和编码区（Ex5 +32G>A）的多态性通过损害CASP9的激活或表达缺失或凋亡小体形成不足来影响表达水平。
本病例对照研究对999名个体进行，其中包括在海得拉巴尼扎姆医学科学研究所（NIMS）报告的485例CML病例以及来自当地人群的514名年龄和性别匹配的健康个体。采用非酶法/盐析法分离DNA，并使用限制性片段长度多态性（RFLP）技术进行基因分型。
观察到CASP9 -1263A>G多态性的G等位基因的存在增加了患CML的风险，而CASP9 -712C>T和CASP9 -293del单核苷酸多态性（SNP）对CML的发生具有保护作用。启动子和外显子多态性的单倍型分析显示，与两种单倍型G_C_del(+)_G（比值比-1.61，95%置信区间-0.97-2.65，p-0.06#）和G_C_del(-)_G（比值比-2.09，95%置信区间-0.94-4.66，p-0.07#）相关的风险增加，表明CASP9 -1263A>G的G等位基因在赋予风险方面的作用独立于其他SNP。对所有四个SNP进行的成对连锁不平衡（LD）分析显示这些SNP之间存在LD。
因此，本研究结果得出结论，CASP9 -1263A>G多态性在增加发病和进展风险中起作用，而CASP9 -712C>T和CASP9 -293del SNP具有保护作用，并且CASP9 Ex5 +32G>A参与赋予抗性，这可能与其他SNP或影响它们的因素共同作用。
