The MTHFR C677T polymorphism and protection against Legg-Calvé-Perthes disease in children: an updated systematic review and meta-analysis

Legg-Calvé-Perthes disease (LCPD) is a multifactorial pediatric hip disorder with complex genetic underpinnings. The methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) polymorphism influences folate metabolism and vascular function and has been investigated as a potential genetic modifier of LCPD susceptibility, though individual study findings remain inconsistent. A comprehensive systematic search was conducted across PubMed, EMBASE, Web of Science, Cochrane Library, and Chinese biomedical databases (China National Knowledge Infrastructure [CNKI], Wanfang, VIP) to identify eligible case-control studies published through October 2025 examining the association between the MTHFR C677T polymorphism and LCPD. No language restrictions were applied. Meta-analyses were conducted under five genetic models using random-effects approaches. The Hartung-Knapp-Sidik-Jonkman (HKSJ) adjustment with t-distribution-based inference was used as the primary analysis. Bonferroni correction (α = 0.01) was applied as a secondary conservative adjustment. Six case-control studies encompassing 222 LCPD cases and 529 controls were included. The T allele demonstrated a protective association in the dominant model (TT + CT vs. CC: odds ratio [OR] = 0.581, 95% confidence interval [CI]: 0.360–0.938, HKSJ p = 0.033), which remained significant after Bonferroni correction (p = 0.005). The heterozygous model (CT vs. CC) also showed significance (OR = 0.567, 95% CI: 0.359–0.894, HKSJ p = 0.024), surviving Bonferroni correction (p = 0.007). Heterogeneity was minimal across most models (I²=0-21.1%), though the Asian subgroup exhibited substantial heterogeneity (I²>80%). Meta-regression identified minor allele frequency (MAF) as a significant moderator in the dominant model (p = 0.047, R²=66.9%), though this analysis is limited by few studies. No evidence of publication bias was detected, though statistical power for bias detection was limited. This updated meta-analysis suggests that the MTHFR rs1801133 (C677T) T allele may confer protection against LCPD, predominantly through dominant and heterozygous inheritance patterns. The dominant model finding remained robust after conservative statistical adjustments. These results require replication in larger, ethnically diverse cohorts before clinical application. The findings highlight the importance of considering population-specific genetic backgrounds and methodological rigor in genetic association meta-analyses of rare diseases.