(CML) is a chronic myeloproliferative disorder resulted from pleuripotent hematopoietic stem cell transformation and characterized by diverse clinical and biological features (Zheng et al., 2018). However, till now, little is known about individual’s susceptibility to CML (Lordelo et al., 2012) Genetic variations in the MTHFR gene; C677T, and A1298C result in decreased MTHFR activity (Ince et al., 2016). MTHFRC677T and A1298C SNPs are good candidates not only for CML etiology, but also for disease progression through their possible impact on the chromosomal abnormalities that are associated with clonal evolution of CML (Miranda-Vilela, 2012). These polymorphisms vary among ethnic groups and populations worldwide.
Variation in human populations may also reflect natural selection and adaptation to environmental conditions (Suarez-Kurtz, 2004). This varies considerably in their predisposition to diseases and in the allele frequencies of pharmacogenetically important loci (Barreiro et al., 2008). Limited number of studies has investigated the possible association between MTHFR polymorphisms and CML with inconsistent results varying among different ethnic groups (Jakovljevic et al., 2012). Our work aimed to investigate the association between MTHFR (677 C>T and 1298 A>C) genetic variations and CML as regards to disease susceptibility and progression in Sudanese population. In present study we found that no significant difference in the prevalence of C677T MTHFR polymorphism regarding to gender and age. The frequency of 23.0% heterozygous, 20% homozygous mutant and 56.5 wild type of C677T MTHFR polymorphism. While the prevalence of heterozygous 57.0%.
Homozygous mutant 22.0% and normal genotype 32.2 for A1298C, among representing Sudanese CML patient is consistent with the data from literature. Most of the studies reviewed did not comment on differences in genotype frequencies by gender , or reported that genotype frequency was not significantly different in males and females (Variants, 2000 (.Moreover the case-control analysis conducted by Aly etal .,(Aly etal.,2014) and study carried out by Amela etal .,(Amela, 2013) found that there was no significant difference between males and females. Our study showed a statistically significant association between both of the two common MTHFR gene polymorphism 677 C>T and 1298 A>C), and susceptibility to CML. The association was very clear in homozygous mutant for each MTHFR polymorphism, 677TT and 1298CC. Geographical and ethical variations in 677T allele of the MTHFR gene polymorphisms were present in a previous study includes 16 different areas worldwide, the 677T allele varied from 26.6–46% in Italy and 25.7in the Middle East to –44.2% in northern China (Asn et al., 2003).
Moreover , a study in Lebanon reported the frequency of the MTHFR 677TT homozygous genotype to be 7.66% and 13.08% in Muslim Arabs and Christians, respectively( (Almawi et al., 2004). The current study showed a relationship of MTHFR C677T polymorphism, with CML patient. The frequency of CT, TT genotype and T allele is more prevalent in CML patient, 23.5%, 20% and 31.75 respectively. Our results were in agreement with the Caucasian and Asian populations where the frequency of T allele was approximately10–15%(Lordelo et al., 2012). In addition This is in accordance with that previously reported by Ismail et al. (Ismail etal,.2009) in Jordon, Al-achkar etal., (Al-achkar et al., 2018) in Syria and Bănescu et al., (Bănescu et al., 2015) in Romania. All these results in harmony with that of Aly(Aly et al., 2014) who found that an association between TT genotype of the MTHFR C677T polymorphism and a risk of CML .
On the other hand, several studies found there is no significant association of 1p36.3 MTHFR (C677T) locus with CML. These were obviously described by Moon etal. (Moon et al., 2007) in Korea ,Miranda-vilela (Miranda-Vilela, 2013) , Hur etal, (Hur et al., 2006) also in Korea ,Barbosa etal. (BARBOSA, et al., 2008), vahid etal .,((P. Vahid et al., 2010) in Iran, Hussain eta(Hussain al., 2012)in India , lordelo etal. (Lordelo et al., 2012 in a Brazilian population and Khorshied etal., (Khorshied et al., 2014) in Egypt. Our finding results conflicting with these studies. In our contrary there is no published studies focused on the role of MTHFR genes s C677T (dbSNP rs1801133) and A1298C (dbSNP rs1801131) in risk of CML, but some recent study conducted by El-hadidy etal .(El-hadidy et al., 2014) found that there was an association of MTHFR C677T polymorphism with schizophrenia and bipolar disorder (BD). Hamad and Fadi (Hamad and Fadl, 2016) also both indicate a possible association of Cardiac syndrome X( CSX ) with MTHFR C677T in Sudanese population. Regarding MTHFRA1298C, our result revealed that there was significant difference in genotype and allele frequencies between control and diagnostic group has been studied (CML).
Moreover Several studies revealed an association of the MTHFR 1298 A>C polymorphism (homozygous CC genotype) patients and an increased CML (Moon et al., 2007; Aly et al., 2014; Ismail et al., 2009; Al-achkar et al. 2018 and Dorgham et al., 2014.Our results are in agreement with these observations and evidenced that both heterozygous AC and homozygous CC genotypes of the MTHFR 1298 A>C polymorphism an increased susceptibility to development of CML risk especially in Sudanese population. The frequency of AC and CC among patient was 55.5% and 11.0% respectively. Insofar the variant C allele is Signiant higher in CML patient than control group (38.5% and 22%) respectively. Such a high frequency for the A1298C allele had been observed among the Lebanese, Syrian, Egyptian and the Iranian population(Sabbagh et al., 2008;Al-achkar et al., 2018 ;Aly etal ., 2014; Vahid et al., 2010).Furthermore, we could consider the finding of variant allele may play a role in the risk of CML.
In another studies , Lordelo etal (Lordelo et al., 2012) found that the MTHFR 1298AA genotype was statistically significant increased the risk of developing CML, while 1298 AC significantly decreased this risk. Also Khoshied and collagenous found that there no significate difference in A1298C genotype distribution or allele frequency between control and an Egyptian CML patient (Khorshied et al., 2014). This result is in accordance with that of valid et al (Vahid et al., 2010)did not find any statically Signiant association between the distribution of MTHFR poly morphism (C677T andCA1298C) in myeloid leukemia (AML and CML )and the control .Moreover, in our study, MTHFR A1298C showed no signifi¬cant difference between the control and CML groups for age and gender. This is in contrast to a study conducted by Lordelo et al. who found that the 1298AA genotype frequency was higher in the CML group and the genotypes containing the variant allele (AC and CC) predominated in the control and also showed significant differ¬ence between the control and CML groups for age(Lordelo et al., 2012).
Aly etal. reveled that no correlation between patient or control subject and different laboratory measurement (hemoglobin level, total white blood cells, platelets count and blast percentage ) regarding to MTHFR 677 C →T and 1298 A →c ,these results are in accordance with our finding results there is no significant association between hematological parameters (Aly etal ,.2014). In addition case- control study by Khorshied et al. assumed that an association between homozygous TT genotype of MTHFR 677 C>T polymorphism and the risk of disease progression to accelerated and blastic transformation phase(Khorshied et al., 2014). But Aly etal found that there was a significant dif¬ference in CML phase’s distribution among patients according to C677T and A1298C gen¬otypes. Higher trend of chronic phase was pres¬ent among cases with 766CC genotype but higher frequency of blastic crises was present in cases with 677CT genotype. Also, Patients with 1298AA genotype showed higher frequency of chronic phase but cases with 1298AC genotype showed higher trend toward blastic crises(Aly et al., 2014). While, in our study it difficult to compare CML and MTHFR genotype regarding to disease phases as only one sample was accelerate and no crisis phase.