Immunogenetic aspects of idiopathic recurrent miscarriage in the Kazakh population.

Alexandra Murtazaliyeva,Gulnara Svyatova,Dinara Mirzakhmetova,Galina Berezina

doi:10.25122/jml-2021-0063

Abstract

There are numerous scientific studies of recurrent miscarriage (RM) with possible causes, such as fetal chromosomal abnormalities, infectious agents, adverse environmental factors, bad habits, anatomical defects, thrombophilic disorders, etc. However, RM causes in 50% of cases remain unknown. These RM cases do not have any explainable etiology, and they require in-depth etiopathogenesis study, thus they are considered idiopathic RM. The purpose of this research is to study polymorphisms relationship of the immune response genes CX3CR1 (rs3732379, Val249Ile), CTLA4 (rs3087243, CT60 G/A), and HLA DQA1, DQB1, DRB1 (major histocompatibility complex, class II) with the idiopathic form of recurrent miscarriage (iRM) development in Kazakh population. Independent replicative TagMan genotyping for 302 patients with iRM and 300 women with normal reproduction was performed. It has been shown that carriage of unfavorable genotypes (Val/Ile, Val/Val) by the Val249Ile polymorphism of the CX3CR1 gene increases the risk of developing iRM by 1.43 times. Search for associations of genes allelic variants of HLA class 2 complex with iRM revealed *501 allele in DQA1 locus, *0301 in DQB1 locus, *10, *12, *15, *16 alleles in DRB1 locus, which increases the risk of developing iRM in Kazakh population with OR from 1.34 to 4.5. As a result of the study, obtained highly significant associations of immune response genes with the development of iRM in the Kazakh population indicate the possible involvement of the immune system interaction of mother cells with syncytiotrophoblast, which is realized by vascularization defects, defective embryo implantation, and leads to early pregnancies’ termination.

Highlights

Recurrent miscarriage (RM) is a heterogeneous disorder in the reproductive period that affects up to 3% of couples [1,2,3]
Scientific literature discusses the role of homozygous genotypes carriage for the risk alleles of the main complex of tissue compatibility human leukocyte antigen (HLA) class II – HLA DQA1, DQB1, DRB1 genes in the development of RM, which was confirmed by studies of several other diseases
The independent replicative genotyping Genome-Wide Association Studies (GWAS) excluded the genetic contribution of coagulation and cardiovascular system, anti-inflammatory cytokines, apoptosis, and angiogenesis genes for idiopathic form of recurrent miscarriage (iRM) in the Kazakh population

Summary

Introduction

Recurrent miscarriage (RM) is a heterogeneous disorder (two or more spontaneous miscarriages) in the reproductive period that affects up to 3% of couples [1,2,3]. It has been shown that decreased expression of CTLA4 in the placenta can weaken the inhibition of activated T-lymphocytes, impair immunity, which leads to RM development [10]. Several studies have shown that CTLA4 gene rs3087243 mutant genotypes contributed to CTLA4 level decrease in the blood serum and led to RM [15,16,17,18]. During the first week of pregnancy, immunohistochemical analysis of endometrium showed maximum expression of fractalkine in uterus glandular epithelium; this activates chemokine receptors and contributes to successful blastocyst implantation [19, 20]. Mutant genotypes carriage reduces production, binding fractalkine to CX3CR1 receptor, leading to adhesion and migration disruption of fetal and maternal cells, causing spontaneous abortion [19,20,21]

Objectives

Methods

Results

Conclusion