3.1. Study characteristics
The primary search in web of science, Scopus, and PubMed databases yielded a total of 636 publications. After removal of duplicates and evaluation of title/abstract, only 76 studies remained for full-text examination. Eventually, 30 studies met the inclusion criteria and included for quantitative synthesis. The search workflow is shown in Figure 1. Study characteristics are summarized in Table 1. Among 30 eligible studies, 16 Studies investigated FokI SNP, 23 Studies TaqI SNP, 16 studies BsmI SNP and 20 Studies ApaI SNP. The studies were published between 1999 and 2019. Taq-Man and PCR-RFLP genotyping methods were used by the most studies.
3.2. Quantitative synthesis
The distributions of FokI, TaqI, BsmI and ApaI genotypes of the included studies are shown in Table 2. FF for FokI SNP, TT for TaqI SNP, BB for BsmI SNP and AA for ApaI were used as the reference category. The heterogeneities in the comparisons (I2<50%, fixed-effects models; I2>50%, random-effects models) ascertained the application of Fixed-effects or random-effects models.
3.3. Meta-analysis for FokI (rs2228570) polymorphism and MS
Overall 16 case-control studies with 3057 cases and 2852 controls were analyzed for assessment of FokI gene polymorphism and MS risk. Of 16 studies, 9 studies carried out in Europe continent [21, 24, 34-40] 4 studies in Asia continent [18, 19, 41, 42] one study in America continent  and finally 2 studies in Australia [17, 44] (Table 1). No significant association was observed between FokI polymorphism and MS risk across all genetic models. Additionally, subgroup analysis based on geographical location was performed which the pooled results rejected any association between FokI polymorphism and risk of MS in European and Asian populations. Since there was only one study for American, and two studies for Australian populations, these studies were excluded from the subgroup analysis. The results of pooled ORs, heterogeneity tests and publication bias tests for different analysis models are shown in table 3 (Supplementary Figure 1 and 2).
3.4. Meta-analysis for TaqI (rs731236) polymorphism and MS
There were 23 case-control studies with 3758 cases and 3992 controls concerning TaqI polymorphism and MS risk. Among them, 13 studies were conducted in European countries [21, 22, 24, 34, 36, 37, 39, 40, 45-49], 5 studies in Asian countries [18, 41, 42, 50, 51], 2 studies in each Australian [17, 44] and American [43, 52] countries, and one study in Tunisia . The TaqI polymorphism was demonstrated to be associated with MS risk under heterozygote contrast (OR = 1.27, 95%CI = 1.01–1.59, random effect) (Figure 2), whilst no significant association was detected across other genotype models (Table 3). In addition, the pooled results of subgroup analysis decline presence of significant association under all defined genetic model (Supplementary Figure 3 and 4). Groups with less than three studies were removed from subgroup analysis. The results of pooled ORs, heterogeneity tests and publication bias tests for different analysis models are shown in Table 3.
3.5. Meta-analysis for BsmI (rs1544410) polymorphism and MS
After searching databases, finally 16 case-control studies with 1793 cases and 1815 controls subjects included to examine association between BsmI polymorphism and MS risk. Among 16 studies, six studies were performed in Europe [21, 22, 36, 40, 48, 49], eight studies in Asia [18, 41, 50, 51, 53-55], and only two studies in America continent [43, 52]. The pooled results demonstrate no significant association between BsmI polymorphism and MS risk under all genetic models, but subgroup analysis revealed that BsmI polymorphism across recessive model increased the risk of MS in Asian population (OR = 1.78 , 95%CI = 1.01–2.93, random effect) compared to European population (OR = 0.84, 95%CI = 0.66–1.06, random effect) (Figure 3). The results of pooled ORs, heterogeneity tests and publication bias tests for different analysis models are shown in table 3 (Supplementary Figure 5 and 6).
3.6. Meta-analysis for Apa1 (rs7975232) polymorphism and MS
For quantitative synthesis of association between ApaI polymorphism and MS risk, 20 case-control studies with 2306 cases and 2669 controls were identified to be eligible. Overall, nine studies in Europe [21, 36, 37, 39, 40, 45, 46, 48, 49], eight studies in Asia [18, 41, 42, 50, 51, 54-56], and one study in Africa , America  and Australia were identified. There was no evidence of association between ApaI polymorphism and MS risk in the pooled results. However, subgroup analysis detected significant association between presence of ApaI SNP and risk of MS under recessive model (OR = 0.61, 95%CI = 0.42–0.89, random effect) and homozygote model (OR = 0.52, 95%CI = 0.32–0.86, random effect) in Asian population in comparison with European population (OR = 1.01, 95%CI = 0.78–1.33, recessive model) and (OR = 1.11, 95%CI = 0.76–1.63, homozygote model) (Figure 3). The results of pooled ORs, heterogeneity tests, and publication bias tests for different analysis models are shown in Table 3 (Supplementary Figure 7 and 8).
3.7. Evaluation of heterogeneity
Significant heterogeneity existed for FokI, TaqI, BsmI, and ApaI polymorphism in all of the genetic models. Furthermore, in subgroup analysis, there was a significant heterogeneity for studies carried out in Asian and European countries (Table 3).
3.8. Publication bias
Publication bias was estimated using funnel plot, Begg's and Egger's tests. No evidence of publication bias was seen for all four SNP and subgroup analysis under all genetic models. Additionally, the shape of the funnel plot appeared to be symmetrical, indicating that there was no significant publication bias (Figure 4).