Association of three missense mutations in the homocysteine-related MTHFR and MTRR gene with risk of polycystic ovary syndrome in Southern Chinese women

Wanqin Feng,Yuan Pan,Yuanling Xiao,Minjuan Liu,Yi Zhang,Junjie Jiao,Wenyu Mo,Yuxin Huang,Xiaoyang Wang,Lixia Yang,Dan Tian,Yan Zhang,Ying Ma

doi:10.1186/s12958-020-00688-8

Abstract

BackgroundThe etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. In humans, the level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). This study aims to examine the association between the three missense mutations and PCOS and investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level.MethodsA case-control study was designed, comprising 150 people with PCOS and 300 controls. Logistic regression analysis was used to assess the association between the three missense mutations and PCOS. Linear regression analysis was used to assess the association between the three missense mutations and the homocysteine level. Mediation analysis was used to investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level.ResultsFollowing adjustments and multiple rounds of testing, MTHFR A1298C was found to be significantly associated with PCOS in a dose-dependent manner (compared to AA, OR = 2.142 for AC & OR = 3.755 for CC; P < 0.001). MTRR A66G was nominally associated with PCOS. Mutations in MTHFR A1298C and MTRR A66G were significantly associated with the homocysteine level. Mediation analysis suggested the effect of MTHFR A1298C on PCOS was mediated by homocysteine.ConclusionsMTHFR A1298C and MTRR A66G were associated with PCOS, and MTHFR A1298C might affect the risk of PCOS by influencing the homocysteine level.

Highlights

The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear
For the Hardy–Weinberg equilibrium, no significant deviation from the expected population genotype proportions was detected at the methylene tetrahydrofolate reductase (MTHFR) C677T (χ2 = 2.41, P = 0.12), MTHFR A1298C (χ2 = 3.65, P = 0.06), and Methionine synthase reductase (MTRR) A66G (χ2 = 3.42, P = 0.06)
The MTRR A66G was nominally associated with PCOS (0.016 < p < 0.05) under the additive and recessive models, but not the dominant model

Summary

Introduction

The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. The level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease that affects women of childbearing age. The etiology of PCOS is not yet completely understood, increasing evidence suggests that it is a multifactorial disease caused by environmental and genetic factors [4,5,6,7]. Mutations, polymorphisms, and differential regulation of genes may contribute to the genetic pathogenesis of PCOS [11, 12]. While a limited number of studies have reported relationships between PCOS and several candidate genes [13,14,15], no single gene has yet been identified as a biomarker

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