Methylenetetrahydrofolate Reductase (MTHFR) A1298C Polymorphism and Risk of Lung Cancer

Review Article

Austin Hepatol. 2020; 5(1): 1011.

Methylenetetrahydrofolate Reductase (MTHFR) A1298C Polymorphism and Risk of Lung Cancers

Vandana Rai*

Department of Biotechnology, VBS Purvanchal University, Jaunpur-222003, UP, India

*Corresponding author: Vandana Rai, Department of Biotechnology, VBS Purvanchal University, Jaunpur-222003, UP, India

Received: April 20, 2020; Accepted: May 09, 2020; Published: May 16, 2020


Recent epidemiological studies have reported association between Methylenetetrahydrofolate Reductase (MTHFR) gene polymorphism and lung cancer. The aim of the present study to perform a meta-analysis of published studies to validate the association between MTHFR A1298C polymorphism and risk of lung cancer.

PubMed, Springer Link. Elsevier and Google Scholar databases were searched for eligible studies. Of the 78 initially identified studies, 11 case– control studies with 5,996 patients and 7,404 healthy controls were finally included in the present meta-analysis. Odds ratios (ORs) with 95% Confidence Intervals (CIs) were estimated to assess the association, and meta-analysis was performed using MIX software (Version 1.7).

No statistically significant associations were found between the MTHFR A1298C polymorphism and lung cancer risk in the genetic additive, co-dominant, homozygote, dominant and recessive models (C vs. A: OR= 0.95, 95% CI= 0.83-1.08; CC vs. AA: OR= 1.13, 95% CI= 0.83-1.5; AC vs. AA: OR= 0.86, 95% CI= 0.70-1.02; AC+CC vs. AA: OR= 0.89, 95% CI= 0.75-1.05; CC vs. AA+AC: OR= 1.20, 95% CI= 0.89-1.40). A significant heterogeneity between individual studies was evident in all five models. In conclusion, present meta-analysis results indicated that there in no significant association between MTHFR A1298C polymorphism and risk of lung cancer.

Keywords: Methylenetetrahydrofolate Reductase; Lung Cancer; MTHFR; A1298C; Meta-analysis; Polymorphism


Lung cancer is the leading cause of cancer-related death worldwide. The incidence and mortality of lung cancer have been significantly and constantly increasing [1-3]. Lung cancer is still the most common cancer in men worldwide (1.1 million cases, 16.5% of the total), with high rates in Central-eastern and Southern Europe, Northern America and Eastern Asia. Very low rates are still estimated in Middle and Western Africa (2.8 and 3.1 per 100,000, respectively) [4]. Lung cancer is a common disease that results from a complex interplay of genetic and environmental risk factors [5]. Many epidemiological studies have provided evidence that high consumption of vegetables and fruits is associated with a reduced risk of lung cancer [6]. Folate is one of the constituents found in vegetables and fruits, and dietary folate may be one of the micronutrients that provide protection against lung carcinogenesis [6].

5,10-Methyl Enetetrahydrofolate Reductase (MTHFR) gene (OMIM*607093; chromosome 1p36.3) is an important enzyme involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. The low enzymatic activity of the MTHFR C677T genotypic variant is associated with DNA hypomethylation, which may induce genomic instability or randomly reactivates the proto-oncogenes to oncogenes [7]. Two common and clinically important polymorphisms (C677T and A1298C) identified in the MTHFR gene [8-10]. Substitution at nucleotide 1,298 (exon 7) results in an amino acid substitution of glutamate for alanine at codon 429 [11]. A1298C (glutamate to alanine) polymorphism, has been associated with decreased enzyme activity (40%), although to a lesser extent than C677T [9]. A1298C allele frequency differs greatly in various ethnic groups of the world. The prevalence of the A1298C homozygote variant genotype ranges from 7 to 12% in White populations from North America and Europe. Lower frequencies have been reported in Hispanics (4 to 5 %), Chinese (1 to 4 %) and Asian populations (1 to 4%) [12,13].

To date, several studies have shown that the MTHFR A1298C polymorphism are associated with either increased or decreased risk of lung cancer, whereas others observed no association between the MTHFR A1298C genotype and lung cancer. Small sample size, various ethnic groups, diet, environment, and methodologies might be responsible for the discrepancy. Therefore, a meta-analysis is required to evaluate MTHFR A1298C polymorphism as risk factor for lung cancer.


Present meta-analysis was conducted according to Moose guidelines. PubMed, Google Scholar, Springer Link and Elsevier database s were searched for eligible studies. The last search was conducted on January 20, 2014. Following terms were used for search: ‘Methylenetertahydrofolate reductase’, ‘MTHFR’, ‘A1298C’, and ‘lung cancer’.

Inclusion criteria

The following inclusion criteria were used: (i) study should be case control and should evaluate MTFR A1298C polymorphism, (ii) study should be published, (iii) study should be in English language, (iv) study should contained sufficient data to calculate Odds Ratio (OR) with 95% Confidence Interval (CI), and (v)study should not contained duplicated data.

Data Extraction

The following information was extracted from each included study: first author’s name, journal name, year of publication, country name, number of cases and controls. Number of alleles or genotypes in both cases and controls were extracted or calculated from published data to recalculate ORs.

Statistical analysis

The associations were indicated as a pooled Odd Ratio (OR) with the corresponding 95% Confidence Interval (CI). The heterogeneity between studies was tested using the Q-statistic, which is a weighted sum of the squares of the deviations of individual study OR estimates from the overall estimate [14]. When the ORs are homogeneous, Q follows a chi-squared distribution with r – 1 (r is the number of studies) degrees of freedom (df). When P<0.05 then the heterogeneity was considered to be statistically significant. Heterogeneity was quantified with the I2 metric (I2 = (Q – df)/Q), which is independent of the number of studies in the meta-analysis. I2 takes values of between 0 and 100%, with higher values denoting a greater degree of heterogeneity [15-16]. The pooled OR was estimated using Fixed Effect (FE) [17] and Random Effect (RE) [18] models. Random effect modelling assumes a genuine diversity in the results of various studies, and it incorporates a between-study variance into the calculations. Hence, when there is heterogeneity between studies then the pooled OR is preferably estimated using the RE model [19,16]. Genetic models were chosen based on the method described by briefly calculating and comparing the ORs of C vs A (allele contrast), CC vs. AA (homozygote), AC vs. AA (co-dominant) and CC+AC vs. AA (dominant) and CC vs. AC+AA (recessive), checking the heterogeneity and significance, then determining the best model [20,21]. The Hardy–Weinberg equilibrium of genotypes of controls was tested and if P >0. 05, then it suggests that the controls followed the Hardy–Weinberg Equilibrium (HWE) balance.

Publication bias

Egger’s test [22] and Begg’s test [23] described for funnel plot asymmetry were applied to evaluate the evidence for publication bias. All p values are two tailed with a significance level at 0.05. All statistical analyses were undertaken by MIX version 1.7 [24].


Characteristics of included studies

Information extracted from the studies included in the metaanalysis is provided in (Tables 1 and 2). Total 78 articles were retrieved using search strategies, but 57 articles did not meet the inclusion criteria after reviewing full articles. Out of remaining twenty-one articles, ten studies were also excluded because reported only C677T polymorphism details. Eleven articles were suitable for the inclusion in the meta-analysis [25-32] [5-7]. Out of eleven studies five studies were from Asian population [26,29,31] [5,6] and remaining studies were from Caucasian population [25,27,28,30,32,7].