Skip to main content
NCBI home page
Disease Markers logoLink to Disease Markers
. 2022 May 31;2022:4568145. doi: 10.1155/2022/4568145

Association between Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Risk of Autoimmune Diseases: A Systematic Review and Meta-Analysis

Mao Lu 1,2, Ke Peng 1,2, Li Song 1, Li Luo 1, Peng Liang 3, Yundan Liang 3,✉
PMCID: PMC9173919  PMID: 35686035

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a critical rate-limiting enzyme in the homocysteine/methionine metabolism pathway that is implicated in the pathogenesis and progression of autoimmune diseases. Previous association studies have been performed to investigate the effect of polymorphisms in MTHFR on the risk of autoimmune diseases with inconsistent results. Therefore, this meta-analysis was designed to assess the association between the MTHFR 677 C/T and 1298 A/C polymorphisms and the susceptibility to autoimmune diseases. We identified reports by a literature search in the following electronic databases: PubMed, Ovid, Web of science, and China National Knowledge Infrastructure. Statistical analyses of the summary odds ratios (ORs) and 95% confidence intervals (CIs) were done using STATA software. In a recessive genetic model, the MTHFR 677 C/T polymorphism was associated with an increased risk of Behcet's disease (OR = 1.97, 95% CI, 1.31-2.97), multiple sclerosis (OR = 1.57, 95% CI, 1.03-2.38), and ankylosing spondylitis (OR = 2.90, 95% CI, 1.92-4.38). The MTHFR 1298 A/C polymorphism was associated an increased risk of multiple sclerosis in a heterozygote comparison (OR = 2.36, 95% CI, 1.29-4.30) and in a dominant model (OR = 2.31, 95% CI, 1.24-4.29). This meta-analysis demonstrated that the MTHFR 677 C/T was a risk factor for Behcet's disease, multiple sclerosis, and ankylosing spondylitis, and the 1298 A/C was a risk factor for multiple sclerosis.

1. Introductions

Autoimmune diseases are a group of diseases characterized by abnormal immune response to autoantigens and self-tissue destruction [1, 2]. It is estimated that 7.6-9.4% of global population is affected by autoimmune diseases, causing the cost of treatment great than 100 billion annually [3, 4]. Despite the high price of treatment, autoimmune diseases cannot be cured but only temporarily reduce symptoms. The major reason for the therapeutic problem may be that the exact mechanism of triggering the disease is not yet fully known. A previous work has demonstrated that environmental exposure may help individuals with a genetic predisposition to develop autoimmune diseases, suggesting the combination of genetic and environmental factors may contribute to the risk of the disorder [5, 6].

Increasing evidence has shown that abnormal metabolism of folate and homocysteine is involved in the pathogenesis of autoimmune diseases [7, 8]. Homocysteine (Hcy), first discovered in 1969, is a nonproteinogenic α-amino acid that is an intermediary product in methionine metabolism [9]. Elevated levels of total Hcy were observed in some autoimmune diseases, such as psoriasis [10], multiple sclerosis (MS) [11], Behcet's disease (BD) [12], ankylosing spondylitis (AS) [13, 14], and Graves' disease (GD) [15]. A critical rate-limiting enzyme in Hcy/methionine metabolism is methylenetetrahydrofolate reductase (MTHFR). Several mutations of the gene coding the MTHFR enzyme, such as the substitution of proline to leucine, threonine to methionine, and alanine to valine were found to be associated with low activity of MTHFR, resulting in impaired folate metabolism and accumulation of Hcy [16, 17].

MTHFR, located on the long arm of chromosome 1 (chr1p36.3) in humans, contains several missense mutations that caused altered amino acid in the protein product. Among them, rs1801133 (677 C/T) and rs1801131 (1298 A/C) were studied widely [18]. The rs1801133 consists of a transition of C to T at the residue 677, leading to an alanine to valine substitution and the rs1801131 consists of a transition of A to C at the nucleotide position 1298, leading to a glutamate to alanine substitution. Both the single-nucleotide polymorphisms (SNPs) were related to the reduction of MTHFR enzymatic activity and higher levels of Hcy [19–23]. The MTHFR, catalyzing the synthesis of 5-methyltetrahydrofolate, is required for vitamin B12-dependent enzyme methionine synthase and Hcy regulation [24, 25]. Vitamin B12 deficiency and Hcy imbalance have been identified to play a role in the pathology of psoriasis [26], MS [27], BD [28], AS [29], and GD [30]. Previously, some authors reported that the two genetic variants were risk factors for psoriasis [31], MS [32], and GD [33]. Not all reports, however, supported these findings. For example, Chorąży et al. reported that there was no statistically significant association between the MTHFR 677 C/T and 1298 A/C polymorphisms and MS risk [34]. The conflict results might be caused by inadequate statistical power, ethnic diversities, and publication bias. In this meta-analysis, we aimed to evaluate the association between the MTHFR 677 C/T and 1298 A/C polymorphisms with the susceptibility of autoimmune diseases, including psoriasis, MS, BD, AS, and GD.

2. Materials and Methods

2.1. Search Strategy

The systematic review and meta-analysis followed the PRISMA 2020 statement guideline [35]. Reports investigating the association of MTHFR polymorphisms with autoimmune diseases, including psoriasis, BD, GD, AS, and MS were identified before July 2021. The literature search was performed in the following electronic databases: PubMed, Ovid, Web of science, and China National Knowledge Infrastructure. The following items were used: “methylenetetrahydrofolate reductase”, “MTHFR”, “polymorphism”, “variant”, “SNP”, “psoriasis”, “Behcet's disease”, “Graves' disease”, “ankylosing spondylitis”, and “multiple sclerosis”. Additional articles were retrieved by checking references that were cited in the selected articles. No language restrictions were applied for the search strategy.

2.2. Inclusion and Exclusion Criteria

We included case-control and case-cohort studies that investigated the association of the MTHFR 677 C/T or 1298 A/C polymorphism with the following autoimmune diseases, including psoriasis, BD, GD, AS, and MS. We excluded studies that were case report, review articles, and records with insufficient data for calculating odds ratio (OR) and 95% confidence interval (CI). Studies that presented overlapping cases or controls were also excluded.

2.3. Data Extraction

LM and PK reviewed and extracted simultaneously the data using a predefined form. The following information was extracted: the first author's name, year of publication, country of origin, ethnicity, sample size, definition of cases and controls, genotyping technique, and quality control of genotyping technique. Interreviewer disagreements were resolved by discussion with the third author (LY) who double checked the raw data.

2.4. Assessment of Study Quality

With reference to the Newcastle-Ottawa Scale, we assessed the quality of included studies by dividing them into two groups: high-quality (equal or more than 4 stars) and low- quality (less than 4 stars) studies. The assessment was performed independently by LM and PK, and discrepancies were resolved by consultation with LY.

2.5. Statistical Analysis

Hardy-Weinberg equilibrium (HWE) was assessed using a chi-squared test. The Q-statistic test and I2 metric were used to assess the heterogeneity across studies [36]. If the P value was more than 0.10 and I2 was less than 50%, indicating that there was no heterogeneity, the fixed-effect model was used; otherwise, the random-effect model was used [37, 38]. To compare the association between MTHFR polymorphisms and the risk of autoimmune diseases, four comparisons (i.e., heterozygote, homozygote, dominant, and recessive genetic models) were used by computing summary OR and 95% CI. Subgroup analyses based on racial decent (Asians and Caucasians) and study quality were also done. The robustness of results was evaluated using a sensitivity analysis when removing a single study at a time. Egger's linear regression asymmetry test was used to assess publication bias of included studies [39]. A two-tailed P value < 0.05 was considered significant. All the statistical analyses were performed using STATA software version 11.0 (Stata Corporation, College Station, TX).

2.6. Trial Sequential Analysis

Trial sequential analysis (TSA) software version 0.9.5.10 beta was used to assess the reliability of the results from meta-analysis [40]. The O'Brien-Fleming boundary, futility boundary, and Z-curve were constructed with a type I error of 5%, power of 80%, and relative risk reduction of 5-20%. Required information size (RIS) was also estimated. For the MTHFR 677 C/T polymorphism, TSA was performed under a recessive genetic model; for the 1298 A/C polymorphism, TSA was performed under a dominant genetic model.

3. Results

3.1. Eligible Studies

The literature review identified 262 citations. After duplicating removing, 161 appeared to be relevant to the meta-analysis and were selected for further analysis. Among them, 78 were excluded after review of title and abstract. The full texts of the remained studies were read, and 40 were excluded due to different reasons, such as no MTHFR polymorphisms, lack of autoimmune diseases, absence of controls and available data, review articles, overlapping data, and case report. Finally, 43 studies met the inclusion criteria and were enrolled in the meta-analysis, including 14 investigating psoriasis, 10 investigating BD, 9 investigating MS, 5 investigating AS, and 3 investigating GD (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Flow diagram of selection studies.

Detailed characteristics extracted from the eligible studies are summarized in Table 1. Of the 43 included studies, 15 were carried out in Asians and 28 were carried out in Caucasians. Publication date ranged 1997–2020 and the number of sample sizes ranged 60–844. In summary, less than 40% (17/43) records were perceived as high-quality studies and more than 90% (40/43) studies were in agreement with HWE.

Table 1.

Characteristics of literatures included in the meta-analysis.

First author Year Country Ethnicity Diagnosis of cases Controls Number of cases/controls Matching criteria Genotyping method Quality control Polymorphisms Newcastle-Ottawa scale Diseases
Agha 2018 Pakistan Caucasian — Adults unrelated to cases and without a history of psoriasis 200/200 — PCR-RFLP — 677 C/T; 1298 A/C ★★ Psoriasis
Alatab 2011 Iran Caucasian According to the McDonald criteria Healthy volunteers 194/230 Age and sex PCR-RFLP DNA sequencing. 677 C/T ★★★★★ MS
Arakawa 2012 Japan Asian According to a clinical history of thyrotoxicosis and a positive test for anti-thyrotrophin receptor antibody Healthy volunteers 160/83 — PCR-RFLP — 677 C/T; 1298 A/C ★★★ GD
Asefi 2014 Iran Caucasian Psoriasis area and severity index Healthy subjects 100/100 Age, gender, and race DNA sequencing Genotyping was performed without knowledge of cases and controls. 677 C/T ★★★★★ Psoriasis
Beranek 2019 Czech Republic Caucasian — Healthy subjects 35/60 — TaqMan — 677 C/T; 1298 A/C ★★ Psoriasis
Bin 2019 Saudi Arabia Caucasian Plaque psoriasis for at least 1 year Healthy subjects 106/280 Age and sex PCR-RFLP Positive, negative control and repeated genotyping were used. 677 C/T ★★★★ Psoriasis
Cakina 2019 Turkey Caucasian According to the McDonald criteria Healthy subjects 80/80 Age and sex PCR-RFLP — 677 C/T; 1298 A/C ★★★ MS
Canataroglu 2003 Turkey Caucasian The criteria of the International Study Group for BD Healthy subjects 40/60 — Light Cycler real-time PCR — 677 C/T ★★★ BD
Caramaschi 2010 Italy Caucasian The criteria of the International Study Group for BD Healthy subjects 30/30 — PCR-allele specific oligonucleotide — 677 C/T; 1298 A/C ★★★★ BD
Cevik 2014 Turkey Caucasian According to the 2005 Revised McDonald MS criteria Healthy subjects 130/150 Age and sex PCR-RFLP — 677 C/T ★★★★★ MS
Chorąży 2019 Poland Caucasian According to the McDonald criteria Healthy volunteers without a family history of any autoimmune disease 174/186 — TaqMan — 677 C/T; 1298 A/C ★★★ MS
Dashti 2020 Kuwait Caucasian — Healthy volunteers 170/311 Age and sex TaqMan — 1298 A/C ★★★ MS
Espinosa 2002 Spain Caucasian The criteria of the International Study Group for BD Healthy subjects 38/100 — PCR-RFLP — 677 C/T ★★★★ BD
Fekih Mrissa 2013 Tunisia Caucasian According to the McDonald criteria Healthy subjects 80/200 Age and sex PCR and reverse hybridization — 677 C/T; 1298 A/C ★★★★ MS
Gecene 2013 Turkey Caucasian A modified New York criteria for AS (1984) Subjects with noninflammatory low back pain 50/50 Age, sex, and body mass index Light Cycler real-time polymerase chain reaction — 677 C/T ★★★★ AS
Huang 1997 Sweden Caucasian — Healthy volunteers and healthy partners of patients 150/110 Ethnicity PCR-RFLP — 677 C/T ★★ MS
Izmirli 2016 Turkey Caucasian — Psoriasis-free individuals 96/77 — PCR-RFLP — 677 C/T ★★ Psoriasis
Jin 2012 China Asian — Subjects without any history and clinical evidence of autoimmune diseases 108/102 Age and sex PCR-RFLP — 677 C/T ★★★ Psoriasis
Karakus 2012 Turkey Caucasian The international criteria of BD for classification Healthy subjects 318/207 Age and geographic area PCR-RFLP — 677 C/T ★★★★ BD
Kilic 2017 Turkey Caucasian — Healthy subjects 84/212 Age and sex Light cycler real-time PCR — 677 C/T; 1298 A/C ★★★ Psoriasis
Kim 2013 South Korea Asian The criteria of the Behcet's research Committee of Japan Healthy subjects unrelated to each other or to the patients 32/59 — TaqMan — 677 C/T ★★★ BD
Klotz 2010 Switzerland Caucasian According to the McDonald criteria Healthy subjects 138/138 Age and sex PCR-RFLP — 677 C/T; 1298 A/C ★★★★ MS
Koubaa 2008 Tunisia Caucasian The criteria of the International Study Group for BD Healthy volunteers 35/39 — PCR-RFLP — 677 C/T ★★★ BD
Lee 2016 Korea Asian The presence of hyperthyroidism, serum antithyroid-stimulating hormone receptor antibody (+), and/or a higher radioactive 131I uptake ratio with diffuse uptake. Healthy subjects 50/100 — PCR-RFLP — 677 C/T; 1298 A/C ★★★★ GD
Liew 2012 Malaysia Asian According to clinical examination Healthy subjects 200/167 Age, gender, and ethnicity PCR-RFLP — 677 C/T ★★★★★ Psoriasis
Luo 2018 China Asian Psoriasis Area and Severity Index Healthy volunteers 420/424 Age and sex PCR-RFLP — 677 C/T; 1298 A/C ★★★★★ Psoriasis
Mao 2020 China Asian A modified New York criteria for AS (1984) Healthy subjects 200/120 Age and sex PCR-RFLP — 677 C/T ★★★ AS
Mao 2010 China Asian The presence of hyperthyroidism, serum antithyroid-stimulating hormone receptor antibody (+), and/or a higher radioactive 132I uptake ratio with diffuse uptake. Healthy subjects 199/235 — PCR-RFLP Genotyping was performed without knowledge of cases and controls, and repeated genotyping was used. 677 C/T; 1298 A/C ★★★ GD
Messedi 2013 Tunisia Caucasian The criteria of the International Study Group for BD Healthy subjects 142/172 Age and sex PCR-RFLP — 677 C/T; 1298 A/C ★★★ BD
Naghibalhossaini 2015 Iran Caucasian According to the McDonald criteria Healthy subjects 180/231 Age, gender and ethnicity Mutagenically separated PCR and PCR-RFLP — 677 C/T; 1298 A/C ★★★ MS
Ozkul 2005 Turkey Caucasian The criteria of the International Study Group for BD Healthy subjects 59/42 Age and sex PCR-RFLP — 677 C/T ★★★ BD
Pi 2014 China Asian — Healthy subjects 120/100 — PCR-RFLP — 677 C/T ★★ Psoriasis
Ricart 2006 Spain Caucasian The criteria of the International Study Group for BD Healthy subjects 79/84 Age and sex PCR-RFLP — 677 C/T ★★★★★ BD
Szvetko 2007 Australia Caucasian — Healthy subjects 140/140 Age, gender, and ethnicity PCR-RFLP — 1298 A/C ★★ MS
Tajouri 2006 Australia Caucasian — Healthy subjects 104/104 Age, gender, and ethnicity PCR-RFLP — 677 C/T ★★★ MS
Toydemir 2000 Turkey Caucasian The international criteria of BD for classification Subjects without a history of venous or arterial thrombosis 60/100 — PCR-RFLP Positive and negative control were used. 677 C/T ★★★ BD
Vasku 2009 Czech Caucasian — Healthy subjects 410/244 — PCR-RFLP — 677 C/T ★★ Psoriasis
Wang 2000 China Asian — Healthy subjects 39/79 — PCR-RFLP — 677 C/T ★★ Psoriasis
Weger 2008 Austria Caucasian According to clinical findings Subjects without any history and clinical evidence of psoriasis 310/247 Age and sex TaqMan — 677 C/T ★★★★ Psoriasis
Wu 2007 China Asian — Healthy subjects 123/129 Age and sex PCR-RFLP — 677 C/T; 1298 A/C ★★ Psoriasis
Xu 2005 China Asian A New York criteria for AS (1980) Healthy volunteers 60/62 — PCR-RFLP — 677 C/T ★★ AS
Xu 2016 China Asian A modified New York criteria for AS (1984) Healthy subjects 113/120 Age and sex PCR-RFLP — 677 C/T; 1298 A/C ★★★★ AS
Yigit 2015 Turkey Caucasian A modified New York criteria for AS (7th edition) Healthy subjects 122/150 Age and ethnicity PCR-RFLP — 677 C/T ★★★★ AS
Open in a new tab

PCR-RFLP: polymerase chain reaction–restriction fragment length polymorphism; MS: multiple sclerosis; GD: Graves' disease; BD: Behcet's disease; AS: ankylosing spondylitis.

3.2. Association of MTHFR Polymorphisms with Psoriasis Risk

Fourteen studies investigated the association of the MTHFR 677 C/T polymorphism with psoriasis risk, involving 2351 cases and 2421 controls (Figure 2). Meta-analysis showed a borderline statistical significance between the MTHFR 677 TT genotype and the presence of psoriasis in overall analysis (OR = 1.57, 95% CI, 1.00-2.45). The borderline statistical significance was also observed in Caucasians (CT vs. CC: OR = 1.93, 95% CI, 1.01-3.69; CT/TT vs. CC: OR = 2.06, 95% CI, 1.04-4.05, respectively) rather than in Asians. In subgroup analysis based on study quality, no significant association of the MTHFR 677 C/T polymorphism with psoriasis risk was found in both high-quality and low-quality studies (Table 2). Sensitivity analysis revealed that the exclusion of the study by Izmirli et al., Luo et al., or Wang et al. yielded a different result for the association of the MTHFR 677 C/T polymorphism with psoriasis risk [41–43].

Figure 2.

Figure 2

Open in a new tab

Forest plots of MTHFR 677 C/T with the risk of psoriasis (a), Behcet's disease (b), multiple sclerosis (c), ankylosing spondylitis (d), and Graves' disease (e).

Table 2.

Meta-analysis of MTHFR 677 C/T polymorphism with the risk of autoimmune diseases.

Diseases Variables n CT versus CC TT versus CC Dominant model Recessive model
OR (95% CI) P Q OR (95% CI) P Q OR (95% CI) P Q OR (95% CI) P Q
Psoriasis Total 14 1.33 (0.88-2.00) <0.001 1.67 (0.94-2.97) <0.001 1.44 (0.94-2.20) <0.001 1.57 (1.00-2.45) <0.001
Asian 6 0.85 (0.52-1.40) <0.001 1.33 (0.65-2.74) 0.003 0.94 (0.56-1.58) <0.001 1.53 (0.95-2.47) 0.07
Caucasian 8 1.93 (1.01-3.69) <0.001 2.43 (0.92-6.40) <0.001 2.06 (1.04-4.05) <0.001 1.91 (0.84-4.32) <0.001
Study quality
High 5 1.41 (0.96-2.06) 0.003 2.73 (1.00-7.48) 0.008 1.51 (0.99-2.29) <0.001 2.34 (0.98-5.58) 0.03
Low 9 1.34 (0.69-2.61) <0.001 1.34 (0.67-2.68) <0.001 1.46 (0.74-2.86) <0.001 1.33 (0.78-2.27) 0.003
BD Total 10 1.05 (0.85-1.30) 0.21 2.00 (1.30-3.07) 0.11 1.06 (0.78-1.43) 0.09 1.97 (1.31-2.97) 0.12
Caucasian 9 1.07 (0.86-1.34) 0.20 1.82 (0.83-4.00) 0.07 1.06 (0.77-1.46) 0.07 1.84 (1.19-2.86) 0.10
Study quality
High 4 0.85 (0.46-1.56) 0.09 — — 1.09 (0.82-1.45) 0.30 — —
Low 6 1.01 (0.75-1.36) 0.37 1.56 (0.97-2.52) 0.23 0.86 (0.43-1.72) 0.04 1.62 (1.03-2.54) 0.20
MS Total 9 1.25 (0.89-1.75) <0.001 1.69 (1.00-2.84) 0.004 1.33 (0.94-1.89) <0.001 1.57 (1.03-2.38) 0.05
Study quality
High 4 1.34 (0.91-1.98) 0.05 1.22 (0.76-1.96) 0.21 1.32 (0.90-1.92) 0.05 1.08 (0.69-1.71) 0.25
Low 5 1.17 (0.66-2.09) <0.001 2.18 (1.04-4.55) 0.008 1.33 (0.72-2.46) <0.001 2.21 (1.53-3.19) 0.14
AS Total 5 1.00 (0.76-1.32) 0.55 3.09 (1.99-4.80) 0.57 1.33 (1.04-1.72) 0.19 2.90 (1.92-4.38) 0.51
Asian 3 1.16 (0.81-1.66) 0.90 2.91 (1.82-4.65) 0.50 1.60 (1.16-2.19) 0.45 2.67 (1.73-4.14) 0.44
Caucasian 2 0.80 (0.51-1.25) 0.27 4.55 (1.27-16.27) 0.25 0.96 (0.63-1.48) 0.28 5.14 (1.44-18.33) 0.31
Study quality
High 3 0.90 (0.63-1.29) 0.37 2.61 (1.42-4.82) 0.36 1.11 (0.79-1.55) 0.33 2.48 (1.42-4.32) 0.31
Low 2 1.18 (0.76-1.85) 0.67 3.65 (1.94-6.90) 0.72 1.72 (1.16-2.53) 0.27 3.45 (1.86-6.42) 0.68
GD Total 3 1.03 (0.43-2.47) 0.003 1.45 (0.50-4.16) 0.004 1.15 (0.49-2.72) 0.002 1.42 (0.78-2.60) 0.07
Study quality
Low 2 0.85 (0.27-2.71) 0.003 0.81 (0.52-1.27) 0.10 0.88 (0.31-2.47) 0.004 1.07 (0.75-1.53) 0.94
Open in a new tab

MTHFR: methylenetetrahydrofolate reductase; OR: odds ratio; CI: confidence interval; PQ: Q-statistic for heterogeneity test among studies; BD: Behcet's disease; MS: multiple sclerosis; AS: ankylosing spondylitis; GD: Graves' disease.

Five studies investigated the association of the MTHFR 1298 A/C polymorphism with psoriasis risk, involving 862 cases and 1024 controls (Table 3, Figure 3). Two studies were carried out in Asians, and 3 studies were carried out in Caucasians. A significant association was found between the MTHFR 1298 CC genotype and the presence of psoriasis in Asians (CC vs. AA: OR = 3.25, 95% CI, 1.68-6.31; CC vs. AA/AC: OR = 2.68, 95% CI, 1.39-5.16, respectively). In overall analysis, no significant association of the MTHFR 1298 A/C polymorphism with psoriasis risk was found. In sensitivity analysis, however, the exclusion of the study by Agha et al., Beranek et al., or Wu et al. yielded a significant result [44–46].

Table 3.

Meta-analysis of MTHFR 1298 A/C polymorphism with the risk of autoimmune diseases.

Diseases Variables n AC versus AA CC versus AA Dominant model Recessive model
OR (95% CI) P Q OR (95% CI) P Q OR (95% CI) P Q OR (95% CI) P Q
MS Total 7 2.36 (1.29-4.30) <0.001 1.48 (0.72-3.04) <0.001 2.31 (1.24-4.29) <0.001 1.08 (0.54-2.16) <0.001
Study quality
High 3 4.64 (1.08-19.88) <0.001 3.04 (0.45-20.77) 0.001 4.42 (0.84-23.42) <0.001 1.64 (0.30-8.83) 0.002
Low 4 1.50 (1.05-2.15) 0.06 1.27 (0.55-2.91) 0.002 1.50 (1.09-2.07) 0.09 1.02 (0.44-2.37) <0.001
Psoriasis Total 5 1.96 (0.79-4.86) <0.001 1.85 (0.54-6.38) 0.002 2.02 (0.80-5.12) <0.001 1.60 (0.58-4.47) 0.02
Asian 2 1.23 (0.56-2.72) 0.02 3.25 (1.68-6.31) 0.68 1.31 (0.57-2.97) 0.01 2.68 (1.39-5.16) 0.84
Caucasian 3 3.29 (0.30-35.92) <0.001 1.61 (0.23-11.58) 0.007 3.33 (0.30-36.50) <0.001 1.30 (0.27-6.35) 0.03
Study quality
Low 4 2.18 (0.50-9.49) <0.001 1.57 (0.33-7.52) 0.02 2.23 (0.51-9.80) <0.001 1.33 (0.37-4.79) 0.06
GD Total 3 0.91 (0.65-1.26) 0.91 1.72 (0.56-5.23) 0.31 0.94 (0.68-1.30) 0.71 1.77 (0.58-5.38) 0.32
Study quality
Low 2 0.93 (0.65-1.35) 0.88 2.46 (0.65-9.26) 0.28 0.99 (0.70-1.42) 0.66 2.50 (0.67-9.38) 0.29
Open in a new tab

MTHFR: methylenetetrahydrofolate reductase; OR: odds ratio; CI: confidence interval; PQ: Q-statistic for heterogeneity test among studies; MS: multiple sclerosis; GD: Graves' disease.

Figure 3.

Figure 3

Open in a new tab

Forest plots of MTHFR 1298 A/C with the risk of multiple sclerosis (a), psoriasis (b), and Graves' disease (c).

3.3. Association of MTHFR Polymorphisms with BD Risk

Ten studies investigated the association of the MTHFR 677 C/T polymorphism with BD risk, involving 825 cases and 892 controls (Figure 2). Among them, 9 were performed in Caucasians. Meta-analysis showed a statistical significance between the MTHFR 677 TT genotype and the presence of BD in overall analysis (TT vs. CC: OR = 2.00, 95% CI, 1.30-3.07; TT vs. CT/CC: OR = 1.97, 95% CI, 1.31-2.97, respectively) and Caucasians (TT vs. CT/CC: OR = 1.84, 95% CI, 1.19-2.86). After subgroup analysis based on study quality, the significant association of the MTHFR 677 C/T polymorphism with BD risk was also found in low-quality studies (TT vs. CT/CC: OR = 1.62, 95% CI, 1.03-2.54) (Table 2). Sensitivity analysis revealed that the exclusion of the study by Karakus et al. generated a nonsignificant result for the association of the MTHFR 677 C/T polymorphism with BD risk [47].

3.4. Association of MTHFR Polymorphisms with MS Risk

Nine studies investigated the association of the MTHFR 677 C/T polymorphism with MS risk, involving 1227 cases and 1426 controls (Figure 2). Meta-analysis showed a borderline statistical significance between the polymorphism and the presence of MS in a recessive genetic model (OR = 1.57, 95% CI, 1.03-2.38). In subgroup analysis based on study quality, the borderline significant association of the MTHFR 677 C/T polymorphism with MS risk was also found in low-quality studies (TT vs. CC: OR = 2.18, 95% CI, 1.04-4.55; TT vs. CT/CC: OR = 2.21, 95% CI, 1.53-3.19, respectively) (Table 2).

Seven studies investigated the association of the MTHFR 1298 A/C polymorphism with MS risk, involving 952 cases and 1232 controls (Table 3, Figure 3). All the studies were conducted in Caucasians. Meta-analysis showed a statistical significance between the MTHFR 1298 A/C polymorphism and the presence of MS in overall analysis (AC vs. AA: OR = 2.36, 95% CI, 1.29-4.30; AC/CC vs. AA: OR = 2.31, 95% CI, 1.24-4.29, respectively) and subgroup analysis, such as high-quality studies (AC vs. AA: OR = 4.64, 95% CI, 1.08-19.88) and low-quality studies (AC vs. AA: OR = 1.50, 95% CI, 1.05-2.15; AC/CC vs. AA: OR = 1.50, 95% CI, 1.09-2.07, respectively) (Table 3). Sensitivity analysis revealed that the exclusion of an individual study at a time did not change the findings of the MTHFR 677 C/T and 1298 A/C polymorphisms increasing MS risk.

3.5. Association of MTHFR Polymorphisms with as Risk

Five studies investigated the association of the MTHFR 677 C/T polymorphism with AS risk, involving 545 cases and 502 controls (Figure 2). Among them, 3 were performed in Asians and 2 were performed in Caucasians. Meta-analysis showed a statistical significance between the MTHFR 677 C/T polymorphism and the presence of AS in overall analysis (TT vs. CC: OR = 3.09, 95% CI, 1.99-4.80; CT/TT vs. CC: OR = 1.33, 95% CI, 1.04-1.72; TT vs. CT/CC: OR = 2.90, 95% CI, 1.92-4.38, respectively). In subgroup analysis, the significant association of the MTHFR 677 C/T polymorphism with MS risk was also found in Asians (TT vs. CC: OR = 2.91, 95% CI, 1.82-4.65; CT/TT vs. CC: OR = 1.60, 95% CI, 1.16-2.19; TT vs. CT/CC: OR =2.67, 95% CI, 1.73-4.14, respectively), Caucasians (TT vs. CC: OR = 4.55, 95% CI, 1.27-16.27; TT vs. CT/CC: OR = 5.14, 95% CI, 1.44-18.33, respectively), high-quality studies (TT vs. CC: OR = 2.61, 95% CI, 1.42-4.82; TT vs. CT/CC: OR = 2.48, 95% CI, 1.42-4.32, respectively), and low-quality studies (TT vs. CC: OR = 3.65, 95% CI, 1.94-6.90; CT/TT vs. CC: OR = 1.72, 95% CI, 1.16-2.53; TT vs. CT/CC: OR = 3.45, 95% CI, 1.86-6.42, respectively) (Table 2). Sensitivity analysis showed that the result was not affected when excluding a single study each time.

3.6. Association of MTHFR Polymorphisms with GD Risk

Three studies investigated the association of the MTHFR 677 C/T and 1298 A/C polymorphisms with GD risk (Tables 2 and 3, Figures 2 and 3). All the studies were conducted in Asians. No statistical significance between the MTHFR 677 C/T and 1298 A/C polymorphisms and the presence of GD were observed. Sensitivity analysis showed that the result was not changed when excluding a single study each time.

3.7. TSA Analysis

The cumulative Z-curve in Figure 4(a) crossed the futility boundary and the RIS boundary, indicating that it is unnecessary for additional studies to investigate the association between the MTHFR 677 C/T and psoriasis risk. The cumulative Z-curve in Figures 4(b)–4(d) and 4(f) crossed the traditional boundary and the O'Brien-Fleming boundary, indicating that the results from the meta-analysis may be conclusive. However, the cumulative Z-curve in Figures 4(e), 4(g), and 4(h) did not cross any boundary, indicating that the findings of the MTHFR 1298 A/C with psoriasis risk and the 677 C/T and 1298 A/C with GD risk are inconclusive.

Figure 4.

Figure 4

Open in a new tab

Trial sequential analysis of the association between MTHFR 677 C/T and the risk of psoriasis (a), Behcet's disease (b), multiple sclerosis (c), ankylosing spondylitis (d), and Graves' disease (e) under a recessive model. Trial sequential analysis of the association between MTHFR 1298 A/C and the risk of multiple sclerosis (f), psoriasis (g), and Graves' disease (h) under a dominant model.

3.8. Heterogeneity Analysis and Publication Bias

During pooled analysis of MTHFR 677 C/T and 1298 A/C polymorphisms with psoriasis and MS risk, the between-study heterogeneity was found. Metaregression was then used to analyze whether some factors such as sample size, ethnicity, HWE, and study quality affected the source of between-study heterogeneity. None of these factors, however, influenced the heterogeneity. Publication bias was evaluated using Egger's linear regression asymmetry test, and no evidence of publication bias was found (P > 0.05) (Figure 5).

Figure 5.

Figure 5

Open in a new tab

Egger's funnel plot for evaluating publication bias of MTHFR 677 C/T with the risk of psoriasis (a–d) and Behcet's disease (e–h). (a, e) 667CT vs. CC. (b, f) 667TT vs. CC. (c, g) 667CT/TT vs. CC. (d, h) 667TT vs. CC/CT.

4. Discussion

Autoimmune disease is a pathological state that occurs when self- or autoantigens are misidentified as foreign entities by the immune system, resulting in tissue destruction and chronic inflammation [1, 2]. Although it is unknown exactly what triggers the disturbance of the immune system, there are several predisposing and precipitating factors, such as genetic and environmental factors [5, 6]. As one of the most frequent types of DNA sequence variation in the human genome, SNPs play an important role in individuals' susceptibility to autoimmune diseases [48, 49]. Previous genetic association studies have demonstrated that autoimmune diseases may share a common genetic background [49].

MTHFR is a crucial enzyme in Hcy/folate metabolism, and the MTHFR deficiency is related to the development and progression of autoimmune diseases [16, 17]. Previously, two important polymorphisms 677 C/T and 1298 A/C in MTHFR were considered to contribute to the occurrence of autoimmune diseases [31–33]. The results, however, are contradictory to the findings from other authors. For example, Asefi et al. reported that the MTHFR 677 T allele was associated with an increased risk of psoriasis [50], whereas Beranek et al. failed to find any association between the SNP and risk of psoriasis [45]. Two previous meta-analyses were conducted, and no significant association of the MTHFR 677 C/T with the etiology of psoriasis was found [51, 52]. It is necessary to update the data as many more studies appeared during the past years [31, 42, 44, 45, 53]. In this meta-analysis, we did not find any relationship of the SNP with psoriasis in overall comparison. TSA confirmed this finding. Nevertheless, subgroup analyses showed that the association was a borderline statistical significance in Caucasians. Further investigations are of great importance to exclude the possibility of the results occurring by chance.

Apart from psoriasis, the MTHFR 677 C/T has been examined extensively whether it influences individuals' susceptibility to BD and MS. However, conflicting results were also obtained. Karakus et al. and Naghibalhossaini et al. reported that subjects carrying the 677 T allele had an increased susceptibility to BD and MS [32, 47], whereas Chorąży et al. and Koubaa et al. reported that the MTHFR 677 C/T was not a risk factor for BD and MS [34, 54]. The negative results were verified by subsequent meta-analysis [48, 55]. However, in this updated meta-analysis involving 825 BD cases (892 controls) and 1227 MS cases (1426 controls), we found that the MTHFR 677 TT genotype was associated with a higher risk of BD and MS. The discordant results may be due to small sample sizes in the meta-analysis reported by Chamorro et al. that included 494 BD patients and 374 controls [48], and the meta-analysis reported by Lee et al. that included 830 MS patients and 893 controls [55].

Regarding the association between the MTHFR 677 C/T and AS risk, 5 studies were included in this meta-analysis. The pooled analysis showed a significant association between AS and the MTHFR 677 TT genotype in overall comparison. Subgroup analyses based on ethnicity and study quality also showed the significant association. Notably, carriers with the MTHFR 677 TT genotype had a 2.48-increased risk of AS risk in high-quality studies under a recessive genetic model. To the best of our knowledge, this is the first meta-analysis to assess the effect of the MTHFR 677 C/T polymorphism on AS risk, which provides stronger evidence than any previous case-control study.

To date, only 3 studies investigated the association between the MTHFR 677 C/T and GD risk. When we pooled all data together, only 409 cases and 418 controls were included in the current meta-analysis. TSA also showed that the findings may be not conclusive, and thus, the negative results in the current study should be interpreted with caution. Additional studies are needed to be performed to clarify the exact role of the MTHFR 677 C/T in the pathogenesis of GD.

Besides the MTHFR 677 C/T, the 1298 A/C polymorphism was reported to be associated significantly with MS risk [56–58]. However, Chorąży et al. did not find any link between the 1298 A/C polymorphism and MS risk [34]. A meta-analysis including 3 studies was performed in 2015, and no association between the MTHFR 1298 A/C polymorphism and MS was found [55]. In the present meta-analysis, we enrolled additional studies [32, 34, 56, 59] and found that the MTHFR 1298 AC and AC/CC genotypes were associated with increased risks of MS both in overall comparison and subgroup analysis according to study quality. Sample size is an important issue for a sound association study because small samples may result in insufficient power to obtain the real effect. Our study has more samples than previous meta-analysis reported by Lee et al. [55], indicating that we provided more statistical power and stronger evidence to support the positive findings in this study.

The MTHFR 1298 A/C polymorphism was also analyzed in psoriasis and GD patients. Not surprisingly, inconsistent results were also observed. Kilic et al. reported that the prevalence of the 1298 C allele was higher by 17.0-fold in patients with psoriasis compared to the control group [31], whereas Luo et al. reported that the genotype distribution of the 1298 A/C was not different significantly between psoriasis patients and controls [42]. In this meta-analysis, although a significantly increased association of the CC and AC/CC genotypes was observed in Asians, there was no significant relationship between the 1298 A/C and psoriasis risk in overall analysis and Caucasians. As only 2 studies were conducted in Asians, the positive results might not be robust enough. When analyzing the association between the MTHFR 1298 A/C polymorphism and GD risk, only 3 studies were included in this meta-analysis and no significant association was observed. According to the data from TSA, however, we cannot conclude that the 1298 A/C was not a risk factor for GD since the limited samples may lead to false negative error.

In this meta-analysis, heterogeneity across studies was observed in some comparisons. Unfortunately, we did not identify what caused the heterogeneity. Despite the disadvantages, no publication bias is present, suggesting there is no evidence of publication selection bias in the literature.

This study contains some limitations that should be discussed. The association of the MTHFR 677 C/T with psoriasis was borderline significant. After the exclusion of the study by Izmirli et al., Luo et al., or Wang et al., the findings were changed [41–43], suggesting that heterogeneity among studies might affect the result. However, the possible reason for explaining the heterogeneity was not identified. Furthermore, the relationship between the MTHFR 677 C/T and 1298 A/C polymorphisms and GD risk was investigated only in a few studies [33, 60, 61]; thus, we were unable to perform stratification analysis by ethnicity. Although we pooled all data from observational studies together, the sample size is still moderate, especially in subgroup analyses, which may lead to lower power for providing strong evidence of the effect of SNPs in MTHFR on the risk of autoimmune diseases.

In conclusion, this meta-analysis demonstrated that the MTHFR 677 C/T was a risk factor for BD, MS, and AS and the 1298 A/C was a risk factor for MS. Considering the small number of studies included in some certain subgroups, further larger-sample investigations performed in diverse ethnic groups are necessary to confirm these findings. Functional analyses are also required to elucidate whether and how the SNPs in MTHFR impact the etiology of autoimmune diseases.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81901379) and Research Fund of The First Affiliated Hospital of Chengdu Medical College (No. CYFY2019ZD05).

Data Availability

All data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors report no conflicts of interest.

Authors' Contributions

LM and PK extracted data and drafted the manuscript. SL and LL performed statistical analysis. LP helped to collect data. LY designed and revised the manuscript. Mao Lu and Ke Peng contributed equally to this work.

References

  • 1.Marrack P., Kappler J., Kotzin B. L. Autoimmune disease: why and where it occurs. Nature Medicine . 2001;7(8):899–905. doi: 10.1038/90935. [DOI] [PubMed] [Google Scholar]
  • 2.Wang L., Wang F. S., Gershwin M. E. Human autoimmune diseases: a comprehensive update. Journal of Internal Medicine . 2015;278(4):369–395. doi: 10.1111/joim.12395. [DOI] [PubMed] [Google Scholar]
  • 3.Cooper G. S., Bynum M. L., Somers E. C. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. Journal of Autoimmunity . 2009;33(3-4):197–207. doi: 10.1016/j.jaut.2009.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Julian M. K. Autoimmune disease. Nursing Management . 2014;45(11):24–29. doi: 10.1097/01.NUMA.0000455740.32485.9c. [DOI] [PubMed] [Google Scholar]
  • 5.Javier E., Lu X., Kottyan L. C. Noncoding variants as genetic contributors to autoimmune disease pathogenesis. The Journal of Investigative Dermatology . 2020;140(2):277–278. doi: 10.1016/j.jid.2019.07.698. [DOI] [PubMed] [Google Scholar]
  • 6.Dooley M. A., Hogan S. L. Environmental epidemiology and risk factors for autoimmune disease. Current Opinion in Rheumatology . 2003;15(2):99–103. doi: 10.1097/00002281-200303000-00002. [DOI] [PubMed] [Google Scholar]
  • 7.McDonald I., Connolly M., Tobin A. M. A review of psoriasis, a known risk factor for cardiovascular disease and its impact on folate and homocysteine metabolism. Journal of Nutrition and Metabolism . 2012;2012:4. doi: 10.1155/2012/965385.965385 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Jamroz-Wisniewska A., Beltowski J., Wojcicka G., Bartosik-Psujek H., Rejdak K. Cladribine treatment improved homocysteine metabolism and increased total serum antioxidant activity in secondary progressive multiple sclerosis patients. Oxidative Medicine and Cellular Longevity . 2020;2020:7. doi: 10.1155/2020/1654754.1654754 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Finkelstein J. D. Methionine metabolism in mammals. The Journal of Nutritional Biochemistry . 1990;1(5):228–237. doi: 10.1016/0955-2863(90)90070-2. [DOI] [PubMed] [Google Scholar]
  • 10.Kim J. E., Lee H. J., Lee J. S., et al. Association between homocysteine levels and psoriasis: a meta-analysis. Annals of Dermatology . 2019;31(4):378–386. doi: 10.5021/ad.2019.31.4.378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Li X., Yuan J., Han J., Hu W. Serum levels of homocysteine, vitamin B12 and folate in patients with multiple sclerosis: an updated meta-analysis. International Journal of Medical Sciences . 2020;17(6):751–761. doi: 10.7150/ijms.42058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.La Regina M., Orlandini F., Prisco D., Dentali F. Homocysteine in vascular Behcet disease: a meta-analysis. Arteriosclerosis, Thrombosis, and Vascular Biology . 2010;30(10):2067–2074. doi: 10.1161/ATVBAHA.110.207068. [DOI] [PubMed] [Google Scholar]
  • 13.Baskan B. M., Sivas F., Aktekin L. A., Dogan Y. P., Ozoran K., Bodur H. Serum homocysteine level in patients with ankylosing spondylitis. Rheumatology International . 2009;29(12):1435–1439. doi: 10.1007/s00296-009-0875-x. [DOI] [PubMed] [Google Scholar]
  • 14.Capkin E., Karkucak M., Akyuz A., Alver A., Turkyilmaz A. K., Zengin E. The relationship between plasma homocysteine level and different treatment modalities in patients with ankylosing spondylitis. Rheumatology International . 2012;32(8):2349–2353. doi: 10.1007/s00296-011-1972-1. [DOI] [PubMed] [Google Scholar]
  • 15.Li F., Aji G., Wang Y., Lu Z., Ling Y. Thyroid peroxidase antibody is associated with plasma homocysteine levels in patients with Graves' disease. German Society of Endocrinology [and] German Diabetes Association . 2020;128(1):8–14. doi: 10.1055/a-0643-4692. [DOI] [PubMed] [Google Scholar]
  • 16.Frosst P., Blom H. J., Milos R., et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics . 1995;10(1):111–113. doi: 10.1038/ng0595-111. [DOI] [PubMed] [Google Scholar]
  • 17.Goyette P., Frosst P., Rosenblatt D. S., Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. American Journal of Human Genetics . 1995;56(5):1052–1059. [PMC free article] [PubMed] [Google Scholar]
  • 18.Goyette P., Sumner J. S., Milos R., et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature Genetics . 1994;7(4):195–200. doi: 10.1038/ng0694-195. [DOI] [PubMed] [Google Scholar]
  • 19.Mahmud N., Molloy A., McPartlin J., et al. Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications. Gut . 1999;45(3):389–394. doi: 10.1136/gut.45.3.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Kang S. S., Zhou J., Wong P. W., Kowalisyn J., Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. American Journal of Human Genetics . 1988;43(4):414–421. [PMC free article] [PubMed] [Google Scholar]
  • 21.van der Put N. M., Gabreëls F., Stevens E. M., et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? American Journal of Human Genetics . 1998;62(5):1044–1051. doi: 10.1086/301825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Castro R., Rivera I., Ravasco P., et al. 5,10-Methylenetetrahydrofolate reductase 677C-->T and 1298A-->C mutations are genetic determinants of elevated homocysteine. QJM : Monthly Journal of the Association of Physicians . 2003;96(4):297–303. doi: 10.1093/qjmed/hcg039. [DOI] [PubMed] [Google Scholar]
  • 23.Weisberg I. S., Jacques P. F., Selhub J., et al. The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis . 2001;156(2):409–415. doi: 10.1016/S0021-9150(00)00671-7. [DOI] [PubMed] [Google Scholar]
  • 24.Blaise S., Alberto J. M., Nédélec E., et al. Mild neonatal hypoxia exacerbates the effects of vitamin-deficient diet on homocysteine metabolism in rats. Pediatric Research . 2005;57(6):777–782. doi: 10.1203/01.PDR.0000161406.19231.98. [DOI] [PubMed] [Google Scholar]
  • 25.Olafsson S., Stridh P., Bos S. D., et al. Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations. NPJ Genomic Medicine . 2017;2(1):p. 24. doi: 10.1038/s41525-017-0027-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Lin X., Meng X., Song Z. Homocysteine and psoriasis. Bioscience Reports . 2019;39(11) doi: 10.1042/BSR20190867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Ramsaransing G. S., Fokkema M. R., Teelken A., Arutjunyan A. V., Koch M., De Keyser J. Plasma homocysteine levels in multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry . 2006;77(2):189–192. doi: 10.1136/jnnp.2005.072199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Bitik B., Tufan A., Elbeg Ş., et al. Serum vitamin B12, homocysteine and methylmalonic acid levels in patients with parenchymal neuro-Behçet’s syndrome. Archives of Rheumatology . 2017;32(2):118–122. doi: 10.5606/ArchRheumatol.2017.6070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Wei J. C., Jan M. S., Yu C. T., et al. Plasma homocysteine status in patients with ankylosing spondylitis. Clinical Rheumatology . 2007;26(5):739–742. doi: 10.1007/s10067-006-0396-x. [DOI] [PubMed] [Google Scholar]
  • 30.Ness-Abramof R., Nabriski D. A., Shapiro M. S., et al. Prevalence and evaluation of B12 deficiency in patients with autoimmune thyroid disease. The American Journal of the Medical Sciences . 2006;332(3):119–122. doi: 10.1097/00000441-200609000-00004. [DOI] [PubMed] [Google Scholar]
  • 31.Kilic S., Ozdemir O., Silan F., et al. Possible association between germline methylenetetrahydrofolate reductase gene polymorphisms and psoriasis risk in a Turkish population. Clinical and Experimental Dermatology . 2017;42(1):8–13. doi: 10.1111/ced.12909. [DOI] [PubMed] [Google Scholar]
  • 32.Naghibalhossaini F., Ehyakonandeh H., Nikseresht A., Kamali E. Association between MTHFR genetic variants and multiple sclerosis in a southern Iranian population. International Journal of Molecular and Cellular Medicine . 2015;4(2):87–93. [PMC free article] [PubMed] [Google Scholar]
  • 33.Lee J. Y., Kim N. K., Cho Y. W., Lew H. Association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and susceptibility to Graves' ophthalmopathy. Molecular Medicine Reports . 2016;14(3):2276–2282. doi: 10.3892/mmr.2016.5458. [DOI] [PubMed] [Google Scholar]
  • 34.Chorąży M., Wawrusiewicz-Kurylonek N., Gościk J., et al. Association between polymorphisms of a folate - homocysteine - methionine - SAM metabolising enzyme gene and multiple sclerosis in a polish population. Neurologia I Neurochirurgia Polska . 2019;53(3):194–198. doi: 10.5603/PJNNS.a2019.0019. [DOI] [PubMed] [Google Scholar]
  • 35.Page M. J., McKenzie J. E., Bossuyt P. M., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ . 2021;372, article n71 doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Higgins J. P., Thompson S. G. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine . 2002;21(11):1539–1558. doi: 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 37.DerSimonian R., Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials . 1986;7(3):177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  • 38.Mantel N., Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute . 1959;22(4):719–748. [PubMed] [Google Scholar]
  • 39.Egger M., Davey Smith G., Schneider M., Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ . 1997;315(7109):629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Kang H. Trial sequential analysis: novel approach for meta-analysis. Anesthesia and Pain Medicine . 2021;16(2):138–150. doi: 10.17085/apm.21038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Izmirli M., Sen B. B., Rifaioglu E., et al. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in psoriasis in southern Turkey. Anais Brasileiros de Dermatologia . 2016;91(5):611–613. doi: 10.1590/abd1806-4841.20164766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Luo Q., Zeng J., Li W., et al. Interaction of MTHFR gene with smoking and alcohol use and haplotype combination susceptibility to psoriasis in Chinese population. Immunologic Research . 2018;66(4):543–547. doi: 10.1007/s12026-018-9017-4. [DOI] [PubMed] [Google Scholar]
  • 43.Wang B., Fu S., Zhang G., Li P. Study of the relationship between psoriasis and the polymorphic site C677T of methylenetetrahydrofolate reductase. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih . 2000;15(2):119–120. [PubMed] [Google Scholar]
  • 44.Agha Z., Shaiq P. A., Ahmed S., et al. A study of _ACE_ , _eNOS_ and _MTHFR_ association with psoriasis in Pakistani population. Meta Gene . 2018;15:65–69. doi: 10.1016/j.mgene.2017.12.001. [DOI] [Google Scholar]
  • 45.Beranek M., Malkova A., Fiala Z., et al. Goeckerman therapy of psoriasis: genotoxicity, dietary micronutrients, homocysteine, and MTHFR gene polymorphisms. International Journal of Molecular Sciences . 2019;20(8, article 1908) doi: 10.3390/ijms20081908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Wu J., Li Y., Ma H., Bai J., Chen F., Fu S. Association between single nucleotide polymorphisms of MTHFR gene and susceptibility of psoriasis. International Journal of Genetics . 2007;30:173–177. [Google Scholar]
  • 47.Karakus N., Yigit S., Kalkan G., et al. Association between the methylene tetrahydrofolate reductase gene C677T mutation and colchicine unresponsiveness in Behcet's disease. Molecular Vision . 2012;18:1696–1700. [PMC free article] [PubMed] [Google Scholar]
  • 48.Chamorro A. J., Marcos M., Hernández-García I., et al. Association of allelic variants of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase with thrombosis or ocular involvement in Behçet's disease: a systematic review and meta-analysis. Autoimmunity Reviews . 2013;12(5):607–616. doi: 10.1016/j.autrev.2012.11.001. [DOI] [PubMed] [Google Scholar]
  • 49.Lettre G., Rioux J. D. Autoimmune diseases: insights from genome-wide association studies. Human Molecular Genetics . 2008;17(R2):R116–R121. doi: 10.1093/hmg/ddn246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Asefi M., Vaisi-Raygani A., Khodarahmi R., et al. Methylentetrahydrofolatereductase (rs1801133) polymorphism and psoriasis: contribution to oxidative stress, lipid peroxidation and correlation with vascular adhesion protein 1, preliminary report. Journal of the European Academy of Dermatology and Venereology . 2014;28(9):1192–1198. doi: 10.1111/jdv.12262. [DOI] [PubMed] [Google Scholar]
  • 51.Wu D., Shi D., Yang L., Zhu X. Association between methylenetetrahydrofolate reductase C677T polymorphism and psoriasis: a meta-analysis. The Journal of Dermatology . 2016;43(2):162–169. doi: 10.1111/1346-8138.13039. [DOI] [PubMed] [Google Scholar]
  • 52.Qi J. H., Qi J. H., Shi N., Chen Y. J., Nie G. Association between MTHFR 677C/T polymorphism and psoriasis risk: a meta-analysis. Genetics and Molecular Research : GMR . 2015;14(2):3869–3876. doi: 10.4238/2015.April.22.16. [DOI] [PubMed] [Google Scholar]
  • 53.Bin H. G., Al H. F., Misbahul A., Al K. A., Sadaf R., Abdulrahman A.-A. Methylenetetrahydrofolate reductase C677T gene polymorphism as risk factor for psoriasis in Saudis. Biomarker Insights . 2019;14, article 1177271919830973 doi: 10.1177/1177271919830973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Koubaa N., Hammami S., Nakbi A., et al. Relationship between thiolactonase activity and hyperhomocysteinemia according to MTHFR gene polymorphism in Tunisian Behçet's disease patients. Clinical Chemistry and Laboratory Medicine . 2008;46(2):187–192. doi: 10.1515/CCLM.2008.046. [DOI] [PubMed] [Google Scholar]
  • 55.Lee Y. H., Seo Y. H., Kim J. H., Choi S. J., Ji J. D., Song G. G. Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis. Neurological Sciences . 2015;36(11):2089–2096. doi: 10.1007/s10072-015-2318-7. [DOI] [PubMed] [Google Scholar]
  • 56.Dashti M., Ateyah K., Alroughani R., Al-Temaimi R. Replication analysis of variants associated with multiple sclerosis risk. Scientific Reports . 2020;10(1):p. 7327. doi: 10.1038/s41598-020-64432-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Klotz L., Farkas M., Bain N., et al. The variant methylenetetrahydrofolate reductase c.1298A > C (p.E429A) is associated with multiple sclerosis in a German case-control study. Neuroscience Letters . 2010;468:183–185. doi: 10.1016/j.neulet.2009.10.057. [DOI] [PubMed] [Google Scholar]
  • 58.Fekih Mrissa N., Mrad M., Klai S., et al. Association of methylenetetrahydrofolate reductase A1298C polymorphism but not of C677T with multiple sclerosis in Tunisian patients. Clinical Neurology and Neurosurgery . 2013;115(9):1657–1660. doi: 10.1016/j.clineuro.2013.02.025. [DOI] [PubMed] [Google Scholar]
  • 59.Cakina S., Ocak O., Ozkan A., Yucel S., Ozısık Karaman H. I. Relationship between genetic polymorphisms MTHFR (C677T, A1298C), MTR (A2756G) and MTRR (A66G) genes and multiple sclerosis: a case-control study. Folia Neuropathologica . 2019;57(1):36–40. doi: 10.5114/fn.2019.83829. [DOI] [PubMed] [Google Scholar]
  • 60.Arakawa Y., Watanabe M., Inoue N., Sarumaru M., Hidaka Y., Iwatani Y. Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clinical and Experimental Immunology . 2012;170(2):194–201. doi: 10.1111/j.1365-2249.2012.04646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Mao R., Fan Y., Zuo L., et al. Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease. Cell Biochemistry and Function . 2010;28(7):585–590. doi: 10.1002/cbf.1694. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data used to support the findings of this study are included within the article.

Articles from Disease Markers are provided here courtesy of Wiley

RESOURCES