pmid: "32972375"
title: "Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis."
authors: "Li Y, Qiu S, Shi J, Guo Y, Li Z, Cheng Y, Liu Y"
journal: "BMC pediatrics"
pubdate: "2020 Sep 24"
doi: "10.1186/s12887-020-02330-3"
source: "PMC Full Text"
Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis.
Autores
Li Y, Qiu S, Shi J, Guo Y, Li Z, Cheng Y, Liu Y
Periodico
BMC pediatrics (2020 Sep 24)
Conteudo
Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis
Background
Autism spectrum disorder (ASD) is becoming increasingly prevalent of late. Methylenetetrahydrofolate reductase (MTHFR) has a significant role in folate metabolism. Owing to the inconsistencies and inconclusiveness on the association between MTHFR single nucleotide polymorphism (SNP) and ASD susceptibilities, a meta-analysis was conducted to settle the inconsistencies.
Methods
For this meta-analysis, a total of 15 manuscripts published up to January 26, 2020, were selected from PubMed, Google Scholar, Medline, WangFang, and CNKI databases using search terms “MTHFR” OR “methylenetetrahydrofolate reductase” AND “ASD” OR “Autism Spectrum Disorders” OR “Autism” AND “polymorphism” OR “susceptibility” OR “C677T” OR “A1298C”.
Results
The findings of the meta-analysis indicated that MTHFR C677T polymorphism is remarkably associated with ASD in the five genetic models, viz., allelic, dominant, recessive, heterozygote, and homozygote. However, the MTHFR A1298C polymorphism was not found to be significantly related to ASD in the five genetic models. Subgroup analyses revealed significant associations of ASD with the MTHFR (C677T and A1298C) polymorphism. Sensitivity analysis showed that this meta-analysis was stable and reliable. No publication bias was identified in the associations between MTHFRC677T polymorphisms and ASD in the five genetic models, except for the one with regard to the associations between MTHFRA1298C polymorphisms and ASD in the five genetic models.
Conclusion
This meta-analysis showed that MTHFR C677T polymorphism is a susceptibility factor for ASD, and MTHFR A1298C polymorphism is not associated with ASD susceptibility.
Background
Autism spectrum disorder (ASD) is one of the complex neurodevelopmental disorders, which has been increasingly recognized as a public health issue. It affects 9‰ of the entire population of children, and the estimated ratio between male and female (M:F) children is 4:1. The prevalence rates of ASD in terms of percentages are approximately 1.52‰ in the Middle East, 14.7‰ in the USA, 1.66‰ in China, and 6‰ in Australia.
The distinguishing features of ASD include a set of behavioral phenotypes such as social communication deficits, restrictive and repetitive behaviors, and worsened quality of life and family functioning for children with ASD and their parents. Brain and nervous system dysfunctions are indicated in ASD, which occur as a result of pathophysiological and environmental factors. Folate/homocysteine (Hcy) levels act as a risk factor in ASD, indicating the involvement of methylenetetrahydrofolate reductase (MTHFR) in ASD. Therefore, MTHFR has been the focal point of investigation on ASD, as inheritance validates the pathophysiological mechanism of ASD.
MTHFR locus has been mapped to chromosome1 (1p36.3). Conversion of 5, 10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate is performed by MTHFR, which regulates the intracellular levels of folate and Hcy. Single nucleotide polymorphisms (C677T and A1298C) are associated with the decline in MTHFR activity, which is, in turn, correlated with Folate/Hcy levels. Homocysteinemia and low plasma folate are found in individuals with C677T and A1298C alleles. A reduction of approximately 50% ~ 60% in the MTHFR activity is correlated with compound heterozygosity for both C677T and A1298C. A decline in the enzymatic activity to 35% ~ 70% in homozygotes T is linked to C677T polymorphism in MTHFR. Generally, when compared to C677T mutation, A1298C mutation feebly affects MTHFR activity and Hcy and folate levels.
Correlations between single nucleotide polymorphisms (C677T and A1298C) and susceptibility to ASD are still debatable. A correlation between MTHFR C677T polymorphism and a higher susceptibility to ASD has been reported by Boris et al. among Caucasian children. Guo et al. evidenced that MTHFR C677T polymorphism is a risk factor for ASD among Chinese Han children. El-baz et al. recognized a significant correlation between MTHFR C677T polymorphisms and ASD among Egyptian children. Nonetheless, Dos Santos et al. found no correlation between MTHFR C677T polymorphism and ASD. Studies by Khalil et al. and El-baz et al. describe MTHFR A1298C polymorphism to represent a risk factor in correlation with ASD among Egyptian children. On the contrary, Mohammad et al. evidenced that MTHFR A1298C polymorphism variant allele has no link with any independent risk of ASD. In this meta-analysis, updated articles were gathered to authenticate correlations between MTHFR polymorphism (C677T/A1298C) and susceptibility to ASD.
Methods
Search strategy and identification of studies
Scientific literature published before January 26, 2020, in PubMed, Embase, Web of Science, Medline, WanFang datebase, and CNKI database were searched using specific search terms (Supplement file 1). The equivalent Chinese terms were used in the Chinese databases. Moreover, we retrieved related articles from the selected literature references to replenish data that had not been identified in the initial search. All full-text literature were scrutinized to determine whether the papers to be included.
Selection criteria
The following criteria had to be satisfied by the studies to be incorporated in this meta-analysis: (1) Original studies on the correlation between MTHFR polymorphism (C677T/A1298C) and ASD; (2) Cohort or case-control designs; (3) All genotype frequency information is available; (4) Diagnostic criteria of ASD described in the Diagnostic and Statistical Manual of Mental Disorders (4th or 5th edition), and/or Childhood Autism Rating Scale. Certain earlier papers referred to the Manual of Mental Disorders (3rd edition). The exclusion criteria comprised the following: (1) Researches on the correlation between MTHFR polymorphism (C677T/A1298C) and ASD that are not original; (2) Studies that lack data and complete information; (3) Replicated studies; (4) Review studies.
Data extraction
Two investigators, namely, Yan Li and Shuang Qiu, extracted all the relevant data with the help of a standardized protocol and data collection form. From every qualified study, data such as the name of the first author, year of publication, country, study population (ethnicity), study design, the definition of ASD, sample size of cases and controls, genotyping method, genotype information, and allele frequencies were gathered and documented. Disparities in the study selection were resolved through discussion or consensus with the third investigator (Yawen Liu). The corresponding authors of articles with missing data were emailed for the required data.
Statistical analysis
Odds ratio (OR) and 95% confidence intervals (CI) were deduced to analyse how strongly MTHFR (C677T/A1298C) polymorphism and the risk of ASD were correlated in the five genetic models, viz., allelic, dominant, recessive, heterozygote, and homozygote. Heterogeneity among studies was assessed through Q-test and I2. Random effects model (DerSimonian-Laird methods) was selected to pool data and in case of substantial heterogeneity (Ph < 0.05 and I2 > 50%); else, fixed effect model (Mantel-Haenszel methods) was chosen. Furthermore, subgroup analyses were stratified according to the state with mandatory fortification of folate, population, sample source, and Hardy-Weinberg equilibrium (HWE). The included studies were tested for HWE in the control group utilizing Chi-square tests. Besides, the stability of the results was tested by performing a sensitivity analysis with the sequential omission of each study. To evaluate the potential publication bias in this meta-analysis, Begg’s funnel plot and Egger’s test were conducted. Stata version 12.0 (StataCorp LP, College Station, TX, USA) was used to evaluate all analyses, and p < 0.05 was considered to be statistically significant.
Results
Overall results
Flowchart of this meta-analysis
Characteristics of included studies for MTHFR C677T polymorphism
Author, year Quality Score Country Ethnicity Case Control Sample source Folate HWE N CC CT TT N CC CT TT Boris et al. 2004 6 USA Caucasian 168 35 94 39 5389 2570 2213 606 Hospital-based YES 0 James et al. 2006 7 USA Caucasian 356 134 176 46 205 93 90 22 Hospital-based YES 0.974 Mohammad et al. 2009 7 USA Asian 138 98 35 5 138 120 18 0 Population-based NO 0.412 Pasca et al. 2009 8 Romania Caucasian 39 21 14 4 80 46 28 6 Population-based NO 0.551 dos Santos et al. 2010 7 Brazil Caucasian 151 60 68 23 100 45 41 14 Hospital-based YES 0.353 Liu et al. 2011 7 Canada Caucasian 205 68 98 39 384 177 166 41 Population-based YES 0.823 Liu et al. 2011 7 Canada Caucasian 400 167 179 54 384 177 166 41 Population-based YES 0.823 Schmidt et al. 2011 8 USA Caucasian 294 128 133 33 180 74 77 29 Population-based YES 0.241 Guo et al. 2012 7 China Asian 186 79 77 30 186 87 83 16 Population-based NO 0.542 Divyakolu et al. 2013 6 India Asian 50 27 22 1 50 42 8 0 Hospital-based NO 0.539 Park et al. 2014 7 Korea Asian 249 76 136 37 423 139 204 80 Hospital-based NO 0.737 Sener et al. 2014 9 Turkey Caucasian 98 44 51 3 70 37 33 0 Population-based NO 0.009 Shawky et al. 2014 6 Egypt Caucasian 20 7 10 3 22 16 6 0 Hospital-based NO 0.459 Meguid et al. 2015 8 Egypt Caucasian 24 11 11 2 30 20 8 2 Population-based NO 0.361 El-baz et al. 2017 6 Egypt Caucasian 31 12 15 4 39 35 4 0 Hospital-based YES 0.735 Zhao et al. 2013 9 China Asian 200 91 59 50 200 144 39 17 Hospital-based NO 0
Characteristics of included studies for MTHFR A1298C polymorphism
Author, year Quality Score Country Ethnicity Case Control Sample source Folate HWE N AA AC CC N AA AC CC Boris et al. 2004 6 USA Caucasian 168 93 65 10 159 70 75 14 Hospital-based YES 0 James et al. 2006 7 USA Caucasian 356 175 147 34 204 103 77 24 Hospital-based YES 0.974 Mohammad et al. 2009 7 USA Asian 138 35 59 44 138 48 32 58 Population-based NO 0.412 Liu et al. 2011 8 Canada Caucasian 205 109 81 15 382 170 175 37 Population-based YES 0.823 Liu et al. 2011 7 Canada Caucasian 307 134 133 40 382 170 175 37 Population-based YES 0.823 Schmidt et al. 2011 8 USA Caucasian 296 160 117 19 177 89 76 12 Population-based YES 0.241 Park et al. 2014 6 Korea Asian 236 147 75 14 323 198 114 11 Hospital-based NO 0.737 Meguid et al. 2015 8 Egypt Caucasian 24 0 23 1 30 12 16 2 Population-based NO 0.361 El-baz et al. 2017 6 Egypt Caucasian 31 7 13 11 39 31 7 1 Hospital-based YES 0.451 Zhao et al. 2013 9 China Asian 200 144 19 37 200 166 21 13 Hospital-based NO 0
Upon literature search and critical screening, about 15 studies from 125 articles were included in this meta-analysis, as already discussed in the Methods section (Fig. 1). A total of 2609 cases and 7496 controls were enrolled from the 15 articles published on the correlation between MTHFR C677T polymorphism and ASD susceptibility. Of those, only nine articles that included 1961 cases and 1652 controls qualified for the evaluation of the link between MTHFR A1298C and ASD as per the selection criteria. The characteristics of each primary study are summarized and presented in Tables 1 and 2.
Association between MTHFR C677T polymorphism and ASD
Meta-analysis between MTHFR C677T polymorphism and ASD risk under genetic models
Genetic Models Fixed/ Random effectOR(95%CI) HeterogeneityP I2(%) Publication Bias P of Egger’s/Begg test Allele Contrast (T vs C) 1.63 (1.30–2.05)b* 0.000 84.3 0.029/0.017 Mandatory fortification with folate Yes 1.32 (1.00–1.75)b 0.000 86.2 0.441/0.707 No 2.08 (1.40–3.08)b* 0.000 84.4 0.044/0.032 Population Asian 1.95 (1.14–3.33)b* 0.000 90.3 0.178/0.221 Caucasian 1.51 (1.17–1.95)b* 0.000 81.5 0.130/0.087 Sample source Hospital-based 2.10 (1.34–3.14)b* 0.000 89.6 0.062/0.174 Population-based 1.33 (1.11–1.65)b* 0.006 64.3 0.267/0.386 HWE Yes 1.46 (1.18–1.81)b* 0.000 76.0 0.005/0.006 No 2.17 (1.52–3.10)b* 0.030 71.4 0.779/1.000 Heterozygote (CT vs CC) 1.66 (1.31–2.11)b* 0.000 69.2 0.017/0.008 Mandatory fortification with folate Yes 1.45 (1.05–2.00)b* 0.001 76.1 0.784/0.707 No 1.95 (1.34–2.82)b* 0.002 66.4 0.031/0.020 Population Asian 1.80 (1.15–2.80)b* 0.005 72.7 0.044/0.221 Caucasian 1.62 (1.20–2.18)b* 0.000 70.4 0.098/0.029 Sample source Hospital-based 2.23 (1.48–3.35)b* 0.000 76.3 0.048/0.108 Population-based 1.26 (1.07–1.48)a* 0.249 22.6 0.191/0.266 HWE Yes 1.49 (1.18–1.87)b* 0.005 57.9 0.007/0.009 No 2.24 (1.40–3.58)b* 0.064 63.6 0.001/0.296 Homozygote (TT vs CC) 2.03 (1.33–3.09)b* 0.000 74.6 0.048/0.053 Mandatory fortification with folate Yes 1.66 (0.94–2.94)b 0.000 84.7 0.355/0.700 No 2.78 (1.35–5.73)b* 0.001 66.5 0.044/0.074 Population Asian 2.45 (0.95–6.31)b 0.000 81.2 0.286/0.806 Caucasian 1.92 (1.16–3.16)b* 0.000 73.7 0.147/0.119 Sample source Hospital-based 2.54 (1.26–5.16)b* 0.000 82.5 0.142/0.536 Population-based 1.61 (1.01–2.58)b* 0.031 54.7 0.122/0.266 HWE Yes 1.50 (1.05–2.13)b* 0.012 53.4 0.006/0.012 No 4.72 (3.26–6.84)a* 0.988 0.0 0.291/1.000 Dominant (TT + CT vs CC) 1.82 (1.39–2.37)b* 0.000 78.6 0.021/0.010 Mandatory fortification with folate Yes 1.49 (1.04–2.15)b* 0.000 83.3 0.775/0.707 No 2.22 (1.46–3.36)b* 0.000 76.3 0.051/0.049 Population Asian 2.03 (1.21–3.42)b* 0.000 82.7 0.164/0.221 Caucasian 1.73 (1.25–2.41)b* 0.000 78.4 0.089/0.029 Sample source Hospital-based 2.51 (1.57–4.02)b* 0.000 84.6 0.050/0.108 Population-based 1.32 (1.13–1.54)a* 0.066 47.2 0.253/0.266 HWE Yes 1.59 (1.23–2.04)b* 0.000 68.3 0.008/0.003 No 2.59 (1.60–4.18)b* 0.038 69.5 0.016/0.296 Recessive (TT vs CT + CC) 1.59 (1.14–2.22)b* 0.000 65.6 0.033/0.053 Mandatory fortification with folate Yes 1.37 (0.93–2.00)b 0.003 72.3 0.114/0.707 No 2.23 (1.13–4.38)b* 0.002 65.1 0.039/0.283 Population Asian 2.07 (0.84–5.10)b* 0.000 81.5 0.243/0.806 Caucasian 1.47 (1.04–2.07)b* 0.015 54.7 0.138/0.087 Sample source Hospital-based 1.76 (1.02–3.04)b* 0.000 76.0 0.155/0.386 Population-based 1.41 (1.11–1.80)a* 0.057 48.9 0.122/0.266 HWE Yes 1.23 (1.02–1.48)a* 0.025 48.7 0.006/0.033 No 2.79 (2.05–3.80)a* 0.459 0.0 0.489/1.000
:P < 0.05
aFixed effect
bRandom effect
Association between MTHFR (C677T and A1298C) polymorphism and ASD susceptibility
Random effect model (Ph < 0.05 or I2 > 50%) was used, and MTHFR C677T polymorphism was found to be remarkably linked to ASD susceptibility in allelic (T vs C: OR = 1.63, 95% CI = 1.30–2.05, p < 0.05), heterozygote (CT vs CC: OR = 1.66, 95% CI = 1.31–2.11, p < 0.05), homozygote (TT vs CC: OR = 2.03, 95% CI = 1.33–3.09, p < 0.05), dominant (TT + CT vs CC: OR = 1.82, 95% CI = 1.39–2.37, p < 0.05), and recessive models (TT vs CT + CC: OR = 1.59, 95% CI = 1.14–2.22, p < 0.05; Table 3, Fig. 2a).
To further clarify the link between MTHFR polymorphisms and the risk of ASD, subgroup analysis was carried out. Firstly, no significant deviation of the correlation among the states with mandatory fortification of folate was recorded. MTHFR C677T polymorphism was not found to be linked to ASD susceptibility: allelic (T vs C: OR = 1.32, 95% CI = 1.00–1.75, p > 0.05), homozygote (TT vs CC: OR = 1.66, 95% CI = 0.94–2.94, p > 0.05), and recessive models (TT vs CT + CC: OR = 1.37, 95% CI = 0.93–2.00, p > 0.05). Nonetheless, it was observed to be associated with ASD susceptibility among the states without mandatory fortification of folate: allelic (T vs C: OR = 2.08, 95% CI = 1.40–3.08, p < 0.05), heterozygote (CT vs CC: OR = 1.95, 95% CI = 1.34–2.82, p < 0.05), homozygote (TT vs CC: OR = 2.78, 95% CI = 1.35–5.73, p < 0.05), dominant (TT + CT vs CC: OR = 2.22, 95% CI = 1.46–3.36, p < 0.05), and recessive models (TT vs CT + CC: OR = 2.23, 95% CI = 1.13–4.38, p < 0.05). Secondly, MTHFR C677T polymorphism was recorded to be correlated with ASD susceptibility in Caucasian population: allelic (T vs C: OR = 1.51, 95% CI = 1.17–1.95, p < 0.05), heterozygote (CT vs CC: OR = 1.62, 95% CI = 1.20–2.18, p < 0.05), homozygote (TT vs CC: OR = 1.92, 95% CI = 1.16–3.16, p < 0.05), and dominant models (TT + CT vs CC: OR = 1.73, 95% CI = 1.25–2.41, p < 0.05). Nonetheless, MTHFR C677T polymorphism was not found to be linked to ASD susceptibility among Asians: homozygote model (TT vs. CC: OR = 2.45, 95% CI = 0.95–6.31, p > 0.05). Thirdly, a hospital-based and population-based sample was adopted for this study. MTHFR C677T polymorphism was found to be linked with ASD susceptibility under five genetic models in hospital- and population-based samples, respectively (all p < 0.05). Fourthly, our results showed that MTHFR C677T polymorphism was consistent/inconsistent with HWE; however, it was significantly associated with ASD susceptibility under five genetic models (all p < 0.05) (Table 3).
Association between MTHFR A1298C polymorphism and ASD
Meta-analysis of MTHFR A1298C polymorphism to ASD risk under the five genetic models
Genetic Models Fixed/ Random effectOR(95%CI) HeterogeneityP I2(%) Publication Bias P of Egger’s/Begg test Allele Contrast (C vs A) 1.17 (0.91–1.50)b 0.000 81.7 0.210/0.010 Mandatory fortification with folate Yes 0.91 (0.81–1.03)a 0.153 40.3 0.086/0.098 No 1.84 (1.08–3.14)b 0.002 86.0 0.086/0.095 Population Asian 1.31 (0.81–2.14)b 0.002 84.4 0.296/0.380 Caucasian 1.11 (0.82–1.49)b 0.000 80.9 0.548/0.045 Sample source Hospital-based 1.45 (0.88–2.39)b 0.000 89.5 0.221/0.021 Population-based 0.96 (0.84–1.10)a 0.074 53.0 0.204/0.462 HWE Yes 1.13 (0.84–1.52)b 0.000 80.9 0.368/0.043 No 1.25 (0.73–2.15)b 0.000 87.2 0.282/0.296 Heterozygote (AC vs AA) 1.11 (0.82–1.50)b 0.000 73.5 0.001/0.049 Mandatory fortification with folate Yes 0.87 (0.74–1.02)a 0.302 17.6 0.382/0.462 No 2.23 (0.98–5.09)b 0.000 82.7 0.026/0.086 Population Asian 1.29 (0.68–2.44)b 0.015 76.3 0.532/1.000 Caucasian 1.04 (0.72–1.50)b 0.001 74.7 0.002/0.230 Sample source Hospital-based 1.11 (0.71–1.74)b 0.004 74.0 0.090/0.462 Population-based 1.15 (0.72–1.86)b 0.001 78.4 0.009/0.221 HWE Yes 1.04 (0.73–1.50)b 0.001 74.6 0.001/0.133 No 1.28 (0.66–2.47)b 0.013 76.9 0.578/1.000 Homozygote (CC vs AA) 1.31 (0.82–2.09)b 0.000 72.0 0.025/0.152 Mandatory fortification with folate Yes 0.89 (0.67–1.18)a 0.260 24.2 0.139/0.462 No 2.98 (1.17–7.58)b 0.002 75.8 0.143/0.221 Population Asian 1.78 (0.88–3.62)b 0.041 68.8 0.811/1.000 Caucasian 1.11 (0.62–2.01)b 0.002 70.5 0.073/0.368 Sample source Hospital-based 1.87 (0.74–4.77)b 0.000 83.6 0.044/0.462 Population-based 1.02 (0.76–1.34)a 0.208 32.0 0.066/1.000 HWE Yes 1.27 (0.68–2.35)b 0.001 72.5 0.072/0.230 No 1.45 (0.65–3.24)b 0.014 76.7 0.966/1.000 Dominant (CC + AC vs AA) 1.19 (0.87–1.64)b 0.002 79.6 0.000/0.049 Mandatory fortification with folate Yes 0.87 (0.74–1.02)a 0.205 32.5 0.198/0.221 No 2.45 (1.16–5.15)b* 0.000 84.5 0.005/0.086 Population Asian 1.38 (0.89–2.14)b 0.054 65.8 0.291/1.000 Caucasian 1.13 (0.75–1.72)b 0.000 82.0 0.001/0.230 Sample source Hospital-based 1.43 (0.81–2.50)b 0.000 86.6 0.019/0.462 Population-based 1.03 (0.71–1.49)b 0.011 69.2 0.014/0.221 HWE Yes 1.14 (0.76–1.73)b 0.000 81.9 0.001/0.230 No 1.34 (0.80–2.23)b 0.023 73.4 0.306/1.000 Recessive (CC vs AC + AA) 1.17 (0.76–1.78)b 0.001 69.4 0.081/0.152 Mandatory fortification with folate Yes 0.94 (0.72–1.24)a 0.363 7.7 0.192/0.462 No 1.93 (0.70–1.25)b 0.000 82.6 0.240/0.806 Population Asian 1.52 (0.54–4.33)b 0.000 87.3 0.546/1.000 Caucasian 0.99 (0.64–1.55)b 0.486 52.8 0.174/0.368 Sample source Hospital-based 1.74 (0.76–3.99)b 0.000 80.3 0.063/0.462 Population-based 0.90 (0.69–1.19) a 0.235 27.9 0.710/1.000 HWE Yes 1.12 (0.69–1.80)b 0.025 58.5 0.163/0.368 No 1.24 (0.46–3.36)b 0.001 86.6 0.676/1.000
*:P < 0.05
aFixed effect
bRandom effect
Random effect model (Ph < 0.05 or I2 ≥ 50%) was utilized, and no significant correlation between MTHFR A1298C polymorphism and ASD susceptibility in the five genetic models was identified (allelic, dominant, recessive, heterozygote, and homozygote; all p > 0.05; Table 4, Fig. 2b). As per the subgroup analyses, MTHFR A1298C polymorphism was found to be associated with ASD susceptibility among the states without mandatory fortification of folate: allelic model (C vs. A: OR = 1.84, 95% CI = 1.08–3.14, p < 0.05) and dominant model (CC + AC vs. AA: OR = 2.45, 95% CI = 1.16–5.15, p < 0.05). No significant correlation between MTHFR A1298C polymorphism and ASD susceptibility under the other genetic models in any subgroup was found (all p > 0.05) (Table 4).
Sensitivity analysis and publication bias
Sensitivity analysis between MTHFR (C677T and A1298C) polymorphism and ASD susceptibility
Publication bias between MTHFR (C677T and A1298C) polymorphism and ASD susceptibility
The stability of the findings was evaluated through sensitivity analysis conducted by sequentially omitting each study, demonstrating that this meta-analysis is relatively stable and credible (Fig. 3). To evaluate the publication bias, Begg’s funnel plot and Egger’s tests were carried out. No significant publication bias was detected in the correlation between MTHFR C677T polymorphisms and ASD risk in the five genetic models: allelic (PB = 0.029, PE = 0.017), heterozygote (PB = 0.017, PE = 0.008), homozygote (PB = 0.048, PE = 0.053), dominant: (PB = 0.021, PE = 0.010), and recessive models (PB = 0.033, PE = 0.053). However, publication bias was detected among the studies on the correlation between MTHFR A1298C polymorphisms and ASD risk in the following genetic models: allelic (PB = 0.210, PE = 0.010), heterozygote (PB = 0.001, PE = 0.049), homozygote (PB = 0.025, PE = 0.152), dominant (PB = 0.000, PE = 0.049), and recessive models (PB = 0.081, PE = 0.152) (Tables 3 and 4, Fig. 4).
Discussion
Relevant and up to date literature published prior to January 26, 2020 were selected for examining the correlation between MTHFR polymorphism (C677T and A1298C) and ASD risk in this meta-analysis. The findings of this study exhibit that MTHFR C677T polymorphism is a susceptibility factor of ASD, but MTHFR A1298C polymorphism is not linked with ASD susceptibility.
Several meta-analytic studies on the correlation between C677T polymorphism of MTHFR and ASD risk have been conducted. Frustaci et al. studied six articles, which consisted of 877 cases and 939 controls, mainly Caucasians, and found a remarkable correlation between C677T polymorphism of MTHFR and ASD risk. Pu et al. investigated eight articles involving 1672 cases and 6760 controls, also mainly Caucasians, evidenced a significant risk on the T allele mutation of MTHFR C677T in ASD. Rai et al. investigated 1978 cases and 7257 controls (Caucasians: 1355 cases and 6460 controls; Asians: 623 cases and 797 controls) in 13 studies and found that C677T polymorphism of MTHFR is a risk factor for ASD susceptibility as well. Similarly, the current meta-analysis enrolled 2609 cases and 7496 controls (Caucasian: 1786 cases and 6499 controls, Asian: 823 cases and 997 controls) from 15 selected literature, further confirmed the association between C677T polymorphism of MTHFR and ASD susceptibility.
A previous meta-analysis, conducted on the correlation between A1298C polymorphism of MTHFR and ASD risk (included five literatures; 1470 cases and 1060 controls; Caucasians: 1332 cases and 922 controls, Asians: 138 cases and 138 controls, respectively) reported that A1298C polymorphism of MTHFR is remarkably linked to reduced ASD risk but only in the recessive model.
In the present meta-analysis, eight of the selected articles had enrolled 1961 cases and 1652 controls (Caucasians: 1387 cases and 991 controls, Asians: 574 cases and 661 controls), and it was recognized that A1298C polymorphism of MTHFR was not correlated with ASD susceptibility. However, Khalil et al. (42 cases and 48 controls) and El-Baz et al. (31 cases and 39 controls) revealed that MTHFR A1298C polymorphism represented a risk factor in association with ASD. This disagreement may be caused by small samples in the study.
There are several limitations for this study. First, the subgroup analyses of environmental risk factors, sex, and gene-environment interactions were not performed owing to insufficient information. Second, this meta-analysis was mainly focused on Caucasians and Asians, thus limiting the generalization of the findings to other ethnicities. Third, in agreement with the findings of Frustaci et al., Pu et al. and Rai et al., heterogeneity exists in this exploration. Fourth, publication bias was found in the association between MTHFR A1298C polymorphisms and ASD risk.
Conclusion
To conclude, this meta-analysis confirms that C677T polymorphism of MTHFR is remarkably linked with ASD risk. Nevertheless, the findings agree that the A1298C polymorphism of MTHFR is not significantly correlated with ASD. Exploring gene-gene and gene-environment interactions could throw more light on the genetic link between MTHFR variants and ASD risk.
Supplementary information
Abbreviations
ASD
Autism spectrum disorder
MTHFR
Methylenetetrahydrofolate reductase
SNPs
Single nucleotide polymorphisms
HWE
Hardy-Weinberg equilibrium
OR
Odds ratio
CI
Confidence interval
AIC
Akaike’s information criterion
LD
Linkage disequilibrium
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Supplementary information
Supplementary information accompanies this paper at 10.1186/s12887-020-02330-3.
Authors’ contributions
Conception and design: YL, YC, and YWL; provision of study material: YL, YC, SQ, YG, JS, and ZL; collection and assembly of data: YL, SQ; data analysis and interpretation: YL, SQ, ZL, YC, and YWL; manuscript writing: YL; revision of the language/article: all authors; final approval of the manuscript: all authors.
Funding
This work was supported by the Ministry of Science and Technology of the People’s Republic of China grant 2015DFA31580, ScienAce and Technology Department of Jilin Province grant 20150101130JC, Jilin Provincial Key Laboratory of Neuronal Plasticity grant 20140622001JC and 20160622020JC, and China Postdoctoral Science Foundation grant 2013 M530989. The funding bodies had no role in the design of the study, the collection, analysis, or interpretation of the data, or writing the manuscript.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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