Association of methylenetetrahydrofolate reductase gene C677T polymorphism with polycystic ovary syndrome risk: a systematic review and meta-analysis update

Eur J Obstet Gynecol Reprod Biol. 2014 Jan:172:56-61. doi: 10.1016/j.ejogrb.2013.10.001. Epub 2013 Oct 10.


Objectives: To re-estimate the association between methylenetetrahydrofolate reductase gene (MTHFR) C677T polymorphism and polycystic ovary syndrome (PCOS) risk by critically reviewing, analyzing and updating the current evidence. MTHFR C677T polymorphism has been studied as a possible risk factor for a variety of common conditions including heart disease, stroke and hypertension. Its association with PCOS was negative in a previous meta-analysis which had possible shortcomings. More studies have now been done but their results remain inconclusive.

Study design: Available case-control studies containing genotype frequencies of MTHFR C677T were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. Statistical analyses were performed using software Review Manager (Version 5. 2) and Stata (Version 11.0).

Results: Nine case-control studies including 638 PCOS and 759 healthy controls were identified. Meta-analysis showed a significant effect in the dominant model (TT+CT vs. CC: OR=1.65, 95%CI=1.28-2.12, P<0.0001) and heterozygote comparison (CT vs. CC: OR=1.83, 95%CI=1.17-2.87, P=0.008). In subgroup analysis stratified by ethnicity, MTHFR C677T variant was statistically significantly relevant to PCOS risk in European populations (TT+CT vs. CC: OR=2.16, 95%CI=1.50-3.12, P<0.0001; CT vs. CC: OR=2.11, 95%CI=1.15-3.87, P=0.02) but not in Asian populations (TT+CT vs. CC: OR=1.29, 95%CI=0.91-1.82, P=0.15; CT vs. CC: OR=1.31, 95%CI=0.91-1.90, P=0.15).

Conclusions: This meta-analysis indicates that the 677T allele increases PCOS susceptibility, and this relevance seems to be more intense in Europeans than in Asians.

Keywords: CI; HWE; Hardy–Weinberg equilibrium; MTHFR; Meta-analysis; Methylenetetrahydrofolate reductase; OR; PCOS; Polycystic ovary syndrome; Polymorphism; confidence interval; methylenetetrahydrofolate reductase; odds ratio; polycystic ovary syndrome.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Asian People / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Odds Ratio
  • Polycystic Ovary Syndrome / genetics*
  • Polymorphism, Genetic
  • White People / genetics


  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)