title: Is MTHFR 677 C>T Polymorphism Clinically Important in Polycystic Ovarian Syndrome (PCOS)? A Case-Control Study, Meta-Analysis and Trial Sequential Analysis.
abstract: BACKGROUND
  Optimum efficiency of the folate pathway is considered essential for adequate ovarian function. 677 C>T substitution in the 5, 10-methylene tertrahydrofolatereductase (MTHFR) gene compromises activity of the MTHFR enzyme by about 50%. The significance of correlation between 677C>T substitution and PCOS remains dubious due to the low power of published studies.
  
  
  RESULTS
  We analyzed MTHFR 677 C>T site in ethnically two different PCOS case-control groups (total 261 cases and 256 controls) from India. The data analysis revealed a lack of association between this polymorphism and PCOS [OR = 1.11 (95%CI = 0.71-1.72), P = 0.66]. Group-wise analysis on the basis of ethnicity also revealed no association in any of the ethnic groups [Indo-Europeans, P = 1; Dravidians, P = 0.70]. Homocysteine levels did not differ significantly between cases (15.51 μmol/L, SD = 2.89) and controls (15.89 μmol/L, SD = 2.23). We also undertook a meta-analysis on 960 cases and 1028 controls, which suggested a significant association of the substitution with PCOS in the dominant model of analysis (OR = 1.47 (95%CI = 1.04-2.09), P = 0.032]. Trial sequential analysis corroborated findings of the traditional meta-analysis. However, we found that the conclusions of meta-analysis were strongly influenced by studies that deviated from the Hardy Weinberg equilibrium. A careful investigation of each study and a trial sequential analysis suggested that 677 C>T substitution holds no clinical significance in PCOS in most of the populations.
  
  
  CONCLUSIONS
  In conclusion, MTHFR 677 C>T polymorphism does not affect PCOS risk in India. The association seen in the meta-analysis is due to an outlier study and studies showing deviation from the Hardy Weinberg equilibrium.
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.|Centre for Genetics and Inherited Diseases (CGID), Taibah University, Al- Madinah, Kingdom of Saudi Arabia.
authors.forename: S Justin
authors.initials: SJ
authors.lastname: Carlus
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Saumya
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sandeep Kumar
authors.initials: SK
authors.lastname: Bansal
authors.affiliation: Banaras Hindu University, Varanasi, India.
authors.forename: Vertika
authors.initials: V
authors.lastname: Singh
authors.affiliation: Banaras Hindu University, Varanasi, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Singh
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Jha
authors.affiliation: Maaruthi Medical Centre and Hospitals, Erode, Tamil Nadu, India.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Sadasivam
authors.affiliation: Maaruthi Medical Centre and Hospitals, Erode, Tamil Nadu, India.
authors.forename: Sri Revathy
authors.initials: SR
authors.lastname: Sadasivam
authors.affiliation: Yogi Vemana University, Kadapa, Andhra Pradesh, India.
authors.forename: P S
authors.initials: PS
authors.lastname: Gireesha
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Singh
authors.initials: S
authors.lastname: Rajender
mesh_terms: D016022:Case-Control Studies; D005260:Female; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D011110:Polymorphism, Genetic
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)