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Is MTHFR 677 C>T Polymorphism Clinically Important in Polycystic Ovarian Syndrome (PCOS)? A Case-Control Study, Meta-Analysis and Trial Sequential Analysis

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  • S Justin Carlus
  • Saumya Sarkar
  • Sandeep Kumar Bansal
  • Vertika Singh
  • Kiran Singh
  • Rajesh Kumar Jha
  • Nirmala Sadasivam
  • Sri Revathy Sadasivam
  • P S Gireesha
  • Kumarasamy Thangaraj
  • Singh Rajender

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. Methods and 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. Conclusion: 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.

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  • S Justin Carlus & Saumya Sarkar & Sandeep Kumar Bansal & Vertika Singh & Kiran Singh & Rajesh Kumar Jha & Nirmala Sadasivam & Sri Revathy Sadasivam & P S Gireesha & Kumarasamy Thangaraj & Singh Rajend, 2016. "Is MTHFR 677 C>T Polymorphism Clinically Important in Polycystic Ovarian Syndrome (PCOS)? A Case-Control Study, Meta-Analysis and Trial Sequential Analysis," PLOS ONE, Public Library of Science, vol. 11(3), pages 1-15, March.
    • Handle: RePEc:plo:pone00:0151510
    DOI: 10.1371/journal.pone.0151510
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    References listed on IDEAS

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    1. Nishi Gupta & Saraswati Gupta & Madhukar Dama & Archana David & Geeta Khanna & Anil Khanna & Singh Rajender, 2011. "Strong Association of 677 C>T Substitution in the MTHFR Gene with Male Infertility - A Study on an Indian Population and a Meta-Analysis," PLOS ONE, Public Library of Science, vol. 6(7), pages 1-14, July.
    2. David Reich & Kumarasamy Thangaraj & Nick Patterson & Alkes L. Price & Lalji Singh, 2009. "Reconstructing Indian population history," Nature, Nature, vol. 461(7263), pages 489-494, September.
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