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Interaction of thrombophilic SNPs in patients with unexplained infertility—multifactor dimensionality reduction (MDR) model analysis

  • Genetics
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Abstract

Purpose

Our aim was to evaluate the frequency and SNP-SNP interactions between factor V Leiden (FVL) G1691A, prothrombin G20210A mutation, and C677T MTHFR and PAI-1 4G/5G gene polymorphisms in female IVF patients with unexplained infertility (UI) by using a multifactor dimensionality reduction (MDR) model analysis.

Methods

A total of 225 subjects were enrolled in the study. There were 105 females in UI group and 120 healthy controls. Designated SNPs were determined by using allele-specific PCR methods. The difference in thrombophilia prevalence was assessed by a chi-square test and logistic regression analysis. Four-locus SNP interaction model was tested using the MDR approach. A ten-fold cross-validation consistency (CVC) and permutation testing were performed.

Results

There was a significant difference of MTHFR C677T polymorphism frequency between the groups. Significantly less UI patients had MTHFR CC genotype (p = 0.005), while the risk allele T was more frequent (OR = 1.83, p = 0.0018). Logistic regression determined a significant association only for MTHFR C677T in our patients (TT genotype OR = 2.99). The MDR analysis confirmed the significance of a single-locus model for MTHFR C677T polymorphism (p = 0.015; OR = 2.93). However, the best, significant predictive model was the two-locus model comprising MTHFR C677T and FVL (CVC = 10/10, testing accuracy = 60.95%, p = 0.013; OR = 3.02).

Conclusion

The MTHFR C677T polymorphism was significantly associated with UI, with minor allele T being more frequent. Additionally, there was a significantly increased presence of MTHFR C677T with FVL mutation in these patients. Therefore, MTHFR and its interaction with FVL should be recognized as contributing factors in the pathogenesis of infertility.

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Funding

The work is supported by the Ministry of Education, Science and Technological Development of Republic of Serbia, Project No. III41018; and the Faculty of Medicine University of Nis Serbia, Project No. 3 (2017-19) and No. (2020).

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Authors and Affiliations

  1. Department of Pathophysiology, Faculty of Medicine, University of Nis, Nis, Serbia

    Jelena Milenkovic, Maja Milojkovic & Dijana Stojanovic

  2. Gyneacology and Obstetrics Clinic, Clinical Center in Nis, University of Nis, Nis, Serbia

    Dejan Mitic

  3. Department of Biochemistry, Faculty of Medicine, University of Nis, Nis, Serbia

    Tatjana Jevtovic Stoimenov

  4. Scientific Research Center for Biomedicine, Faculty of Medicine, University of Nis, Nis, Serbia

    Zaklina Smelcerovic, Stevan Vujic & Novica Bojanic

Authors
  1. Jelena Milenkovic
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  2. Maja Milojkovic
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  4. Tatjana Jevtovic Stoimenov
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  5. Zaklina Smelcerovic
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  8. Novica Bojanic
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Contributions

J. Milenkovic and M. Milojkovic conceptualized and designed the study. Material preparation, data collection, and analyses were performed by J. Milenkovic, D. Mitic, Z. Smelcerovic, S. Vujic, and N. Bojanic. T. Jevtovic-Stoimenov coordinated and supervised data collection and processing. The first draft of the manuscript was written by J. Milenkovic and D. Stojanovic. M. Milojkovic, D. Mitic, and T. Jevtovic-Stoimenov critically reviewed the manuscript. All authors read, commented, and approved the final manuscript.

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Correspondence to Jelena Milenkovic.

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Milenkovic, J., Milojkovic, M., Mitic, D. et al. Interaction of thrombophilic SNPs in patients with unexplained infertility—multifactor dimensionality reduction (MDR) model analysis. J Assist Reprod Genet 37, 1449–1458 (2020). https://doi.org/10.1007/s10815-020-01808-4

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  • DOI: https://doi.org/10.1007/s10815-020-01808-4

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