Genetic Polymorphisms of Methylenetetrahydrofolate Reductase Genes and Diffuse Large B-Cell Lymphoma Risk in Middle Eastern Population.
Authors: Siraj Abdul K. , Bu Rong , Ibrahim Mona , Al-Rasheed Maha , Uddin Shahab , Ezzat Adnan , Al-Kuraya Khawla 
Published: April 2020

Abstract
Diffuse large B-Cell Lymphoma (DLBCL) is one of the most common non-Hodgkin lymphoma types and increased incidence has also been reported during the past 30 years. Methylenetetrahydrofolate (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of DNA synthesis and methylation, both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate caner predisposing factor. These genetic differences are highly race specific and have never been screened in the Saudi DLBCL patients. We conducted hospital-based case control study in the Saudi DLBCL patients.
To evaluate the MTHFR C677T and A1298C functional polymorphisms in the MTHFR gene and their association with Saudi DLBCL risk. A hospital based case control study was conducted on a Saudi population- which is known for their genetic homogeneity and high consanguinity- consisting of 187 histologically confirmed DLBCL cases and 513 Saudi controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping.
Data showed that Saudi individuals carrying MTHFR 1298 CC genotype (p&lt;0.001) and genotypes carrying MTHFR 1298C allele (p= 0.012) had 4.23 and 1.73-fold higher risk of developing DLBCL, respectively. Additionally, combined genotype CCCC (MTHFR 677CC+ MTHFR 1298CC) among intermediate MTHFR activity group was associated with 3.489 fold and CTCC (MTHFR 677 CT + 1298CC) among low MTHFR activity group was related to 9.515 fold higher risk, compared with full MTHFR enzyme activity.
Our findings suggest that polymorphisms of MTHFR enzyme genes support for the important role of folate metabolism in lymphomagenesis and may be associated with the individual susceptibility to develop DLBCL in Saudi Arabian population.
Table 1 Distribution of MTHFR polymorphisms in healthy population and lymphoma patients. Polymorphism Genotype Control group Lymphoma patients p -Methylenetetrahydrofolate reductase (MTHFR) MTHFR C677T CC 372 (72.8%) 109 (68.1%) CT 126 (24.7%) 45 (28.1%) 0.346 1.219 TT 13 (2.5%) 6 (3.8%) 0.404 1.575 CT+TT 139 (27.2%) 51 (31.9%) 0.269 1.252 MTHFR A1298C AA 239 (46.8%) 38 (33.6%) AC 220 (43.1%) 40 (35.4%) 0.625 1.144 CC 52 (10.2%) 35 (31%) &lt;0.001 4.233 AC+CC 272 (53.2%) 75 (66.4%) 0.012 1.734 Table 2 Distribution of combined C677T and A1298C MTHFR genotypes in case and control group. Genotype Control Case p OR ND=Not detected Full Activity group CCAA 157 (30.8%) 22 (27.8%) Intermediate Activity group CCAC 169 (33.2%) 28 (35.4%) 0.649 1.182 CCCC 45 (8.8%) 22 (27.8%) &lt;0.001 3.489 CTAA 69 (13.6%) 13 (16.5%) 0.439 1.345 TOTAL 283 63 0.104 1.589 Low Activity Group CTAC 50 (9.8%) 5 (6.3%) 0.634 0.714 CTCC 6 (1.2%) 8 (10.1%) &lt;0.001 9.515 TTAA 12 (2.4%) 1 (1.3%) 1 0.595 TTAC 0 2 (2.5%) 0.017 ND TTCC 1 (0.2%) - - - TOTAL 69 16 0.189 1.655 Intermediate + Low 352 (69.1%) 79 0.073 1.602