Gene polymorphisms associated with recurrent miscarriage in Russian women / Генные полиморфизмы, ассоциированные с привычным невынашиванием беременности у русских женщин тема диссертации и автореферата по ВАК РФ 03.02.07, кандидат наук Ахмед Абдулбари Амин Махюп

• Ахмед Абдулбари Амин Махюп
• кандидат наук
• 2020

Оглавление диссертации кандидат наук Ахмед Абдулбари Амин Махюп

CONTENTS

Introduction

Chapter 1. Literature Review

1.1 Miscarriage and its causes

1.2 Genetic aspects of early miscarriage

Chapter 2. Materials and Methods

Chapter 3. Results

Chapter 4. Discussion

4.1. DNA methyltransferases

4.2. Synaptonemal complex protein

4.3. Gene polymorphisms involved in Folate and Methionine cycle

4.4. Gene polymorphisms involved in hereditary thrombophilia

4.5. Gene polymorphisms involved in impaired angiogenesis

4.6. Comparison of genotype and allele frequencies among population

group members with those among controls and case group members

Conclusion

List of abbreviations

References

Введение диссертации (часть автореферата) на тему «Gene polymorphisms associated with recurrent miscarriage in Russian women / Генные полиморфизмы, ассоциированные с привычным невынашиванием беременности у русских женщин»

INTRODUCTION

Topicality of the dissertation. A miscarriage is one of the most common medical and social issues, which affects numerous couples every year due to various reasons. Pregnancy loss represents 31% of total pregnancies [Simpson, et. al., 2013]. This rate could rise to 50-75% if those pre-embryonic losses occurring within the first 4 weeks of pregnancy are included, which ordinarily go unidentified by patients [Ramanathanpullai, et. al., 2017]. Approximately 80% of all miscarriage cases occur before the 12th week of gestation [ACOG Practice Bulletin, 2018; AgaM^H ..B. h coaBT., 2016; Pag3HHCKHH B.E. h coaBT., 2019]. The rate of clinically recognized early miscarriage increases with advancing women age [ACOG Practice Bulletin, 2018]. Early miscarriage (EM) refers to a process in which a loss of a clinically recognized fetus occurs spontaneously during the first three months of gestation [ACOG Practice Bulletin, 2018]. When this process occurs once in discontinuous rounds of pregnancies is known as sporadic early miscarriage (SEM), accounting for the majority of prevalence, but when it occurs two or more times it is defined as recurrent early miscarriage (REM), constituting for 2-5% of couples [Scott, et. al., 2003, Chaithra, et. al., 2011, Ford and Schust, 2009, Bashiri and Borick, 2016]. Miscarriage might be primary or secondary and the difference between them is that primary REM is when REM women had been without any full-term pregnancy before, while REM is referred to as secondary REM when it follows at least one full-term pregnancy [ESHRE Early Pregnancy Guideline Development Group, 2017].

Although many factors that have been involved as causes or risk agents for the occurrence of spontaneous miscarriage, the cause of early miscarriage could only be diagnosed in approximately 50% of cases [Rai and Regan, 2006]. It has been seen that genetic factors constitute around 3-5% of the etiology of recurrent miscarriage, a chromosomal abnormality 7%, hormonal disorders 15%, and anatomical defects 10-15% [Chaithra, et. al., 2011]. Virtually, cytogenetic abnormalities occur in 50-70% of sporadic spontaneous miscarriage cases, where

60% of cases are due to autosomal trisomies, 20% due to monosomy X, and 20% due to polyploidy [Hyde and Schust, 2015, AgaM^H .H.B. h coaBT., 2016].

Recurrent miscarriage arises due to miscellaneous risk factors among which some parental genetic factors tend to be more significant than others. In other words, there is no so far a single genetic predictor that might be used for the prognosis of subsequent pregnancy losses; however, the maternal risk factors are the most predictive because of their direct relationships to the development of a fetus. It has been believed that a series of differential gene expressions is essential to actuating many biological processes demanded to achieve a successful gestation, where found, more than 30 genes are responsible for the various gene expression levels between normal and RM women [Baek, 2004] and maybe implicated in REM. Several studies have reported that makeup variation in maternal genes, responsible for the regulation of some reproductive biological processes, may lead to the emergence of abnormal global DNA methylation in conceptus, embryonic chromosome abnormalities, placental thrombophilia, or deficiency of chorionic villous vascularization, which may lead to impairment of growth and development of the embryo, and as a result, the pregnancy ends up with failure [Li, et. al., 2014, Sazegari, et. al., 2014, Rodger, et. al., 2008, Sun, et. al., 2017].

DNA methylation is a type of epigenetic processes catalyzed by a family of DNA methyltransferases (DNMTs) that add a methyl group at the 5-carbon of the cytosine base in the dinucleotide sequence CpG located in gene promoters, thus often impacting the gene expression [Li and Zhang, 2014]. In early pregnancy, soon after zygote formation and before implantation, DNA undergoes global waves of demethylation, thereafter DNA in cells is remethylated. The DNA methylation patterns established earlier in the embryo are maintained for normal embryonic and placental development. Accordingly, genetic defects of the DNA methyltransferases may result in abnormal DNA methylation in growth regulatory genes impairing their functions and ultimately resulting in early fetal death and pregnancy loss [Li and Zhang, 2014]. The majority of the DNMTase gene polymorphisms were extensively investigated in a variety of human cancers, but

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only a few of them were investigated in early miscarriage and are still not enough to confirm the association of aberrant global DNA methylation with recurrent early miscarriage, as well as, to the best of our knowledge, most of DNMTase gene polymorphisms haven't been investigated in Russia, in particular in women with early miscarriage. And in keeping with the demographic Concept Policy for the Russian Federation 2025, launched in 2007 by Russian Federation to reduce maternal and infant mortality by at least 50% and strengthen population reproductive health [Reproductive Health Survey Russia, 2011], and on the purpose of the effective contribution to achieving this strategy, the present study was designed to find out new genetic risk factors that may contribute to the prognosis of recurrent early pregnancy loss through identifying several candidate genes unknown or rarely known for early miscarriage.

General objective of the study

The present study was designed to find out gene polymorphisms associated with the sporadic and recurrent early pregnancy loss in Russian women living in Central Russia.

Specific objectives

1. To investigate the association of some polymorphisms within genes implicated in DNA methylation (DNMT1 rs2228611, DNMT1 rs8101626, DNMT3A rs7590760, DNMT3B rs2424913, DNMT3B rs1569686, DNMT3L rs2276248, DNMT3L rs2070565) with recurrent early miscarriage.

2. To determine whether polymorphism rs769825641 in the synaptonemal complex protein 3 (SYCP3) gene implicated in meiosis, is associated with increased risk for early pregnancy loss.

3. To assess the following gene polymorphisms in genes of prothrombin (FII rs1799963), Factor V (FVL rs6025, Leiden), VEGFA (rs3025039, rs699947), MTHFR (rs1801133, rs1801131), MTR rs1805087, and MTRR rs1801394 previously reported underlying EM to elucidate their contribution to early miscarriage among our research participants.

4. To determine the prevalence of all the studied gene polymorphisms in Russian women and make a comparison between the polymorphisms in DNMT1, DNMT3A, DNMT3B, DNMT3L, SYCP3 genes with the prevalence of gene polymorphisms, recommended previously as genetic predictors for recurrent early miscarriage.

Novelty of research. For the first time in Russia, our study has determined the genotype and allele frequencies for eight single nucleotide polymorphisms located in DNA methyltransferase genes (DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248 and DNMT3L rs2070565) and in SYCP3 gene (SYCP3 rs769825641) among women with early pregnancy loss. Moreover, most these gene polymorphisms haven't ever been yet analyzed in any diseases in Russians and there were no even statistical data about their genotype and allele distributions in the population. This study is the first that have performed the population study and assessed the prevalence of genotypes and alleles for DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, DNMT3L rs2070565, and SYCP3 rs769825641 polymorphisms in Russian women, in addition to comparing the distribution rate of their minor genotypes and alleles with those of the common recurrent pregnancy loss (RPL) related gene polymorphisms recommended extensively as genetic predictors for RPL by previous investigators.

Theoretical and practical significance. The present research data indicate

that early miscarriage among Russian women is one of the significant

complications of aberrant fetal DNA methylation arising due to the gene makeup

variations in DNMT1, DNMT3B, or chromosomal abnormality caused by gene

structure variation in SYCP3. It is expected that the new predictive factors would

contribute to the stratification of patients with early miscarriage, in particular

REM, as well as formulating a fundamental scheme to the diagnosis and

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prophylactic management to reduce risk factors of early abortion by performing a genetic investigation.

Methodology and methods of research investigation. Determination of the prevalence of the gene polymorphisms studied in the framework of this thesis was by genotyping of DNA samples extracted from blood samples of research participants, which was carried out by using Real-Time PCR, Polymerase chain reaction for Restriction fragments length polymorphisms (PCR-RFLP) and allele-specific PCR. The results were statistically processed using the SPSS software version 22.

Statements of defense

1. The genotypes and alleles for gene polymorphisms DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626 implicated in global DNA methylation, are associated with the increased risk of occurrence of sporadic and recurrent early pregnancy loss among Russian women.

2. The heterozygous genotype and allele C for SYCP3 rs769825641 (T657C) polymorphism are associated with the occurrence of sporadic early miscarriage among Russian women.

3. The prevalence of DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 rs769825641 minor alleles are as equivalent as the prevalence of minor alleles of common RPL-associated polymorphisms among Russian women.

Reliability and validity of scientific results. The reliability and validity of research results are provided by the sufficient number of investigated samples (237), as well as that the genotyping was performed with the use of modern technologies and high-quality chemicals and kits. The statistical methods met the tasks set.

Approbation of research results. The findings of the thesis were reported at the scientific conference "Agajanyan readings" (Moscow, 2018), and the

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international congresses "43rd FEBS Congress" (Prague, 2018), "44th FEBS Congress" (Krakow, 2019) as well as at the meeting of the Department of Biology and General Genetics of the RUDN Medical Institute (2020).

Implementation of research results in practice. The results of the presented work were introduced into the educational process when studying the disciplines "Biology" "Biology with the basics of Medical Genetics", and "Molecular Genetics in practical Biology and Medicine" at the Department of Biology and General Genetics of the RUDN Medical institute.

Publications of research results. Based on the research materials, 7 scientific papers have been published, out of them, four articles, including two in scientific journals indexed in Scopus/WoS and two articles in journals from RUDN's list.

Personal contribution of the author. The author systematized the literature data on the topic of the dissertation. The author has independently established and developed new PCR protocols. Independently the author has conducted the molecular-genetic analysis. Description of the obtained results were performed by the author personally. As well as the author has taken part in analyzing and writing the published articles and abstracts. The whole dissertation was written by the author independently.

Volume and structure of the Thesis. The thesis is displayed on 138 pages of typewritten texts and consists of an introduction, a literature review, a description of materials and research methods, a chapter of results, a chapter of discussion, conclusions and a list of references. This research work is illustrated by 13 figures and 15 tables. The literature index contains 224 Russian and foreign bibliographic sources.

Заключение диссертации по теме «Генетика», Ахмед Абдулбари Амин Махюп

CONCLUSION

The studies included in this thesis were designed to investigate the genotype and allele frequencies for some gene polymorphisms (DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, DNMT3L rs2070565, SYCP3 rs769825641, FII rs1799963, FVL rs6025, MTHFR rs1801131, MTHFR rs1801133, MTRR rs1801394, MTR rs1805087, VEGFA rs699947, and VEGFA rs3025039) and detect the association between them and early pregnancy loss in Russian women. The results of the studies allow us to draw the following conclusions:

1. The minor allele T and the minor homozygous genotype TT for DNMT3B rs2424913 polymorphism are associated with the increased risk of early miscarriage.

2. The minor allele G and the minor homozygous genotype GG for DNMT1 rs2228611 polymorphism show a significant association with recurrent early miscarriage, whereas the homozygous genotype GG for DNMT1 rs8101626 is associated with both sporadic and recurrent early pregnancy loss.

3. The heterozygosity for VEGFA rs699947 polymorphism predisposes to recurrent early miscarriage.

4. The heterozygous genotype for SYCP3 rs769825641 polymorphism is significantly associated with sporadic early miscarriage.

5. No significant association was observed between DNMT3A rs7590760, DNMT3L rs2276248 polymorphisms and early pregnancy loss.

6. The distribution of genotypes and alleles for DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 rs769825641 among Russian women is comparable with that for common polymorphisms associated with increased risk of pregnancy loss.

Recommendations

1. DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626 polymorphisms may be recommended as genetic predictors for recurrent early miscarriage.

2. The heterozygosity for SYCP3 rs769825641 polymorphism may be considered as a predictive factor for sporadic early miscarriage.

For future study

1. Conducting genetic studies to investigate the distribution of alleles and genotypes for DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626 polymorphisms among the aborted fetuses and males in couples with early pregnancy loss.

2. Karyotyping of aborted fetuses from mothers that are heterozygous for SYCP3 rs769825641 polymorphism

3. Conducting genetic studies to investigate the distribution of alleles and genotypes for DNMT3B s2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 rs769825641 polymorphisms in other ethnic groups.

4. As the SYCP3 rs769825641 polymorphism is significantly associated with sporadic early miscarriage and is quite frequent among women experiencing recurrent pregnancy loss, larger prospective studies on Russian women with recurrent miscarriage are advisable.

Список литературы диссертационного исследования кандидат наук Ахмед Абдулбари Амин Махюп, 2020 год

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