BIHAREAN BIOLOGIST 6 (2): pp.87-89 Article No.: 121112
©Biharean Biologist, Oradea, Romania, 2012 http://biozoojournals.3x.ro/bihbiol/index.html
Interaction of thymidylate synthase polymorphism with MTHFR variants modify the risk of childhood acute lymphoblastic leukemia Zohreh RAHIMI1,2,*, Mohammad-Reza AZHAR1,3, Ziba RAHIMI1 and Kheirollah YARI1 1. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. 2. Department of Biochemistry, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran. 3. Department of Pharmacology, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran. Short running title: Interaction of Thymidylate synthase with MTHFR Variants *Corresponding author, Z. Rahimi, E-mail:
[email protected] /
[email protected], Phone: 0098-831-4274618-21; Fax: 0098-831-4276471 Received: 21. January 2012 / Accepted: 04. August 2012 / Available online: 29. August 2012 / Printed: December 2012
Abstract. A genetic susceptibility to acute lymphoblastic leukemia (ALL) has been suggested. The present study was conducted to examine the influence of interaction between methylenetetrahydrofolate reductase (MTHFR) variants and thymidylate synthase (TS) 28- base pair (bp) repeat polymorphism on the risk of pediatric ALL. Sixty eight ALL children with the mean age of 8.19±4.0 years and 70 age- and sex-matched healthy children were studied for TS 28-bp repeat and MTHFR C677T and A1298C variants using PCR and PCR-RFLP, respectively. The presence of TS 2R allele had a protective effect on the risk of ALL that did not reach a statistical significance [OR=0.5 (95% CI 0.19- 1.24, p=0.13)]. Also, the effect of MTHFR 677T allele on the risk of ALL was similar to TS 2R allele [OR=0.5 (95% CI 0.18- 1.4, p=0.19)]. However, there was a trend toward increased risk of ALL in the presence of both TS 2R and MTHFR 677T alleles [OR=1.92 (95% CI 0.7- 5.3, p=0.2)]. In contrast, the overall distribution of interaction between TS 2R and MTHFR 1298C alleles in ALL patients compared to controls was not significant. Our results suggest that the interaction between polymorphisms of different genes instead of the one polymorphism in a single gene might determine the susceptibility to pediatric ALL. Key words: ALL, thymidylate synthase, MTHFR, Western Iran, leukemia.
Introduction Acute lymphoblatic leukemia (ALL) is a common pediatric malignancy accounting for 25-30% of all cancers among children with relatively high rate of mortality (Giovannetti et al. 2008, Amirghofran et al. 2011). It has been suggested that the interaction between genetic and environmental factors might be involved in the pathogenesis of ALL (Alcasabas et al. 2008, Kamel et al. 2007). Folate is a key element in the one-carbon group metabolism that is required for DNA synthesis and methylation. Its deficiency has been associated with the malignancies including susceptibility to leukemia. Thymidylate synthase (TS) converts dUMP to dTMP required for DNA synthesis. The most common polymorphism in TS is a double (2R) or triple (3R) 28-base pair (bp) repeat sequence in the promoter enhancer region of TS gene influences protein expression in cancer cells (Skibola et al. 2004). The role of TS variants on the susceptibility to ALL has been reported in various populations with inconsistency (Skibola et al. 2002, Lauten et al. 2003, Petra et al 2007, De Jong et al. 2009). Also, the possible association between the two most common polymorphisms of 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, namely MTHFR C677T and A1298C and the risk of pediatric ALL has been examined in several studies. Some studies reported a protective role for these variants on the risk of pediatric ALL (Kamel et al. 2007, De Jong et al. 2009, Zintzaras et al. 2006, Franco et al. 2001). In contrast, others reported a role for these polymorphisms on the susceptibility to ALL (Alcasabas et al. 2008). Previously, we reported the absence of association between TS variants and susceptibility to childhood ALL among Kurdish population from Western Iran (Rahimi et al. 2012). Also, recently we indicated the lack of association between MTHFR variants and the risk of ALL in our
population (Azhar et al. 2012). It seems different gene polymorphisms instead of single genetic defects play a role in the susceptibility to childhood ALL. In the study of de Jong et al (De Jong et al. 2009) the interaction between carriers of TS 2R and MTHFR 677T allele resulted in a 1.4fold reduction in ALL risk (p50000×109/l), and 35% had decreased WBC (
