Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme that converts 5,10-methylenetetrahydrofolate into 5-methylenetetrahydrofolate, which provides the methyl group to convert homocysteine to methionine. Two common MTHFR gene polymorphisms, C677T (rs1801133) and A1298C (rs1801131), are associated with decreased MTHFR enzyme activity, and several studies have demonstrated the involvement of these polymorphisms in susceptibility to diseases, including autoimmune diseases (1). Vitiligo is a common cutaneous hypopigmentation disease resulting from the loss of functional melanocytes due to autoreactive CD8+ T cells or oxidative stress in genetically predisposed individuals (2). Available studies have reported inconsistent results regarding the relationship between MTHFR polymorphisms and vitiligo; therefore this study investigated this topic in a systematic review and meta-analysis.
METHODS AND RESULTS
A systematic search was performed of PubMed, Embase, Cochrane Library, and Web of Science for case-control studies published before 9 December 2019 that compared the expression of MTHFR polymorphisms in patients with vitiligo and healthy controls. The keywords were “methylenetetrahydrofolate reductase” or “MTHFR” combined with “vitiligo.” Study quality was assessed using the Newcastle–Ottawa Scale. A random effects model was employed for pooled analysis. Heterogeneity across studies was assessed using the I2 statistic, and the risk of publication bias was assessed using Egger’s test. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized as summary statistics and were calculated using Comprehensive Meta-Analysis Version 3 (Biostat, Inc., Englewood, NJ, USA). A p-value < 0.05 was considered statistically significant.
Twenty-five relevant studies were initially identified, most of which were sequentially excluded because they were duplicates, concerned an unrelated topic, or were a review (Fig. 1). A final total of 5 case-control studies, which had recruited 1,703 patients with vitiligo and 1,708 controls, were included in the meta-analysis (3–7). Table I presents the basic characteristics of the included studies, all of which investigated the association between the MTHFR polymorphisms of C677T and A1298C and vitiligo susceptibility. Fig. 2 presents the results of combined analysis for codominant, homozygous, dominant, recessive, and allele models (8). Pooled analysis of 5 included studies revealed no difference in the prevalence of MTHFR C677T gene polymorphisms in patients with vitiligo from that in controls, and meta-analyses of the prevalence of MTHFR A1298C gene polymorphisms also showed no significant difference between patients with vitiligo and controls. High heterogeneity across the studies was found for all analyses. No publication bias was detected in any measurement.
Fig. 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow-chart of study selection.
Table I.
Basic characteristics of included studies for meta-analysis
| Studies Country | Groups | Age, years Mean ± SD/ range | C677T (n) | A1298C (n) | Significant results from original study | Quality of study* | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CC | CT | TT | C | T | AA | AC | CC | A | C | |||||
| Yasar et al., Turkey 2012 (3) | Case | 27.77 ± 13.44 | 25 | 13 | 2 | 63 | 17 | 10 | 25 | 5 | 45 | 35 | AC of A1298C with higher susceptibility | 7 |
| Control | 25.42 ± 4.48 | 20 | 15 | 5 | 55 | 25 | 18 | 11 | 11 | 47 | 33 | |||
| Chen et al., China 2014 (4) | Case | 24.9 ± 12.8 | 422 | 471 | 107 | 1,315 | 685 | 701 | 272 | 27 | 1,674 | 326 | TT of C677T with lower susceptibility | 8 |
| Control | 25.9 ± 10.8 | 363 | 477 | 160 | 1,203 | 797 | 719 | 262 | 19 | 1,700 | 300 | |||
| Jadeja et al., India 2018 (5) | Case | 5-60 | 377 | 131 | 12 | 885 | 155 | 181 | 241 | 98 | 603 | 437 | CC of A1298C with higher susceptibility | 8 |
| Control | 406 | 136 | 16 | 948 | 168 | 211 | 274 | 73 | 696 | 420 | ||||
| Benincasa et al., Italy 2019 (6) | Case | NA | 9 | 29 | 5 | 47 | 39 | NA | CT/TT of C677T with higher susceptibility | 5 | ||||
| Control | 17 | 12 | 1 | 46 | 14 | |||||||||
| El Tahlawi et al., Egypt 2020 (7) | Case | 34.96 ± 13.84 | 71 | 20 | 9 | 162 | 38 | 56 | 40 | 4 | 152 | 48 | CT/TT of C677T with higher susceptibility | 8 |
| Control | Matched | 40 | 40 | 0 | 120 | 40 | 30 | 42 | 8 | 102 | 58 | AC/CC of A1298C with lower susceptibility | ||
Newcastle-Ottawa Scale, total score: 9. SD: standard deviation; NA: not available.
C: cytosine; T: thymine; A: adenine; CC/AA: wild type homozygosity; CT/AC: heterozygosity; TT/CC: mutant homozygosity.
Fig. 2.
Meta-analysis of the association between MTHFR gene polymorphisms and risk of vitiligo in different genetic models. CI: confidence interval; OR: odds ratio.
DISCUSSION
The interaction between genetic susceptibility and environmental factors contributes to the central pathophysiology of vitiligo. Decreased MTHFR enzyme activity in the heterozygous and homozygous MTHFR variants of C677T and A1298C is associated with hyperhomocysteinaemia and folate deficiency (1). A previous meta-analysis found significantly higher homocysteine levels, but the same serum folate levels, in patients with vitiligo compared with controls (9). Elevated homocysteine levels may trigger several events related to the pathophysiology of vitiligo, including the production of inflammatory cytokines, oxidative stress, endoplasmic reticulum stress, and neo-self-antigen formation (5). All the included studies drew different conclusions regarding the association between the MTHFR gene polymorphisms and the risk of vitiligo in the original study (Table I), and pooled analysis found no significant association between MTHFR C677T or A1298C gene polymorphisms and vitiligo susceptibility. Consistently, previous reports by genome-wide association study of vitiligo had also not identified MTHFR gene as one of the susceptible genes (10, 11). In addition to the MTHFR gene, several non-immune-related genes have been identified as risk factors for vitiligo. These genes are responsible for the development and function of melanocytes, cell growth and survival, and defence against oxidative stress. Although genetic risk is not the only determining factor for vitiligo, these candidate genes increase vitiligo susceptibility by coordinating biological networks involved in immune-mediated melanocyte destruction (12).
The limitations of this analysis include the lack of information for other MTHFR polymorphism variants and insufficient data on different ethnicities or vitiligo subtypes.
In conclusion, this meta-analysis demonstrated no significant association between MTHFR C677T or A1298C gene polymorphisms and the risk of vitiligo.
Footnotes
The authors have no conflicts of interest to declare.
REFERENCES
- 1.Toffoli G, De Mattia E. Pharmacogenetic relevance of MTHFR polymorphisms. Pharmacogenomics 2008; 9: 1195–1206. [DOI] [PubMed] [Google Scholar]
- 2.Bleuel R, Eberlein B. Therapeutic management of vitiligo. J Dtsch Dermatol Ges 2018; 16: 1309–1313. [DOI] [PubMed] [Google Scholar]
- 3.Yasar A, Gunduz K, Onur E, Calkan M. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo. Dis Markers 2012; 33: 85–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Chen JX, Shi Q, Wang XW, Guo S, Dai W, Li K, et al. Genetic polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and risk of vitiligo in Han Chinese populations: a genotype-phenotype correlation study. Br J Dermatol 2014; 170: 1092–1099. [DOI] [PubMed] [Google Scholar]
- 5.Jadeja SD, Mansuri MS, Singh M, Patel H, Marfatia YS, Begum R. Association of elevated homocysteine levels and Methylene-tetrahydrofolate reductase (MTHFR) 1298 A>C polymorphism with Vitiligo susceptibility in Gujarat. J Dermatol Sci 2018; 90: 112–122. [DOI] [PubMed] [Google Scholar]
- 6.Benincasa G, Di Spigna G, Cappelli C, Di Francia R, Ottaiano M, Sansone M, et al. High incidence of MTHFR, CBS, and MTRR polymorphisms in vitiligo patients. Preliminary report in a retrospective study. Eur Rev Med Pharmacol Sci 2019; 23: 471–478. [DOI] [PubMed] [Google Scholar]
- 7.El Tahlawi S, Abdel Halim DM, El Hadidi H, Fawzy MM, Hegazy RA, Ezzat M, et al. Estimation of homocysteine level and methylenetetrahydrofolate reductase (MTHFR) gene and cystathionine B synthase (CBS) gene polymorphisms in vitiligo patients. Skin Pharmacol Physiol 2020; 33: 38–43. [DOI] [PubMed] [Google Scholar]
- 8.Lee YH. Meta-analysis of genetic association studies. Ann Lab Med 2015; 35: 283–287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tsai TY, Kuo CY, Huang YC. Serum homocysteine, folate, and vitamin B12 levels in patients with vitiligo and their potential roles as disease activity biomarkers: a systematic review and meta-analysis. J Am Acad Dermatol 2019; 80: 646–654.e645. [DOI] [PubMed] [Google Scholar]
- 10.Jin Y, Andersen G, Yorgov D, Ferrara TM, Ben S, Brownson KM, et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 2016; 48: 1418–1424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shen C, Gao J, Sheng Y, Dou J, Zhou F, Zheng X, et al. Genetic susceptibility to vitiligo: GWAS approaches for identifying vitiligo susceptibility genes and loci. Front Genet 2016; 7: 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Rahman R, Hasija Y. Exploring vitiligo susceptibility and management: a brief review. Biomedical Dermatology 2018; 2: 20. [Google Scholar]