Genetic Factors of Idiopathic Recurrent Miscarriage in Kazakh Population

Abstract

Background: It seems that 50% of the possible causes of recurrent miscarriage do not have any explainable etiology and they require in-depth etiopathogenesis analysis. The purpose of this research was to study polymorphisms relationship of the im-mune response genes including Val249Ile CX3CR1 (rs3732379), CT60 G/A CTLA4 (rs3087243), and HLA DQA1, DQB1, DRB1 (major histocompatibility complex, class II) with development of idiopathic form of recurrent miscarriage (iRM) in Kazakh population.
 Methods: TagMan genotyping for 302 patients with iRM and 300 women with normal reproduction was performed. Molecular genetic studies were carried out by the TaqMan method of unified site-specific amplification and real-time genotyping using test systems. Statistical tests and Chi Square were carried out using PLINK, STATA13 software and p˂0.05 was considered statistically significant.
 Results: It has been shown that carriage of unfavorable genotypes (Val/Ile, Val/Val) by the Val249Ile polymorphism of 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 increase the risk of developing iRM in Kazakh population.
 Conclusion: The highly significant associations of immune response genes with development of iRM in Kazakh population indicate the possible involvement of the immune system interaction of mother cells with syncytiotrophoblast, which is realized by vascular defects and defective embryo implantation, causing termination of pregnancy.

Maternal HLA class II alleles and haplotypes associated with altered risk of recurrent pregnancy loss: A case‐control study

“…Consistent with our earlier finding on Lebanese women, no specific DQB1 alleles were found to be linked with RPL among Tunisian women 5 . This was in prominent contrast to Chinese, 52 Danish, 27 Kazakh, 40 and South Indian 25 studies, which described an association of DQB1*03 40,52 and DQB1*05 27,53 with altered risk of RPL. On the other hand, DPB1*01:01:01 was positively associated, while both DPB1*04:01:01 and DPB1*14:01:01 were negatively associated with RPL in our study cohort.…”

“…The positive ( DRB1*04:01:01 and DRB1*08:01:01 ) and negative ( DRB1*07:01:01, DPB1*04:01:01; DPB1*14:01:01 ) class II alleles association with RPL suggest an at‐risk, or protective aspect to these alleles, respectively. This was in evident disagreement with studies on Brazilian, 47 Danish, 37,48 Japanese, 49 Kazakh, 40 and South Indian 25 women, which demonstrated the association of other DRB1 alleles with an increased risk of RPL, namely, DRB1*03:01:01 , and DRB1*07/*07 40,48 . This was further exemplified by the association of DRB1*03:01 with increased risk of RPL with a high risk of RPL in the (Central Asian) Kazakh subjects, 40 but not (Middle Eastern] Lebanese 5 or South European 33 populations.…”

“…This was in evident disagreement with studies on Brazilian, 47 Danish, 37,48 Japanese, 49 Kazakh, 40 and South Indian 25 women, which demonstrated the association of other DRB1 alleles with an increased risk of RPL, namely, DRB1*03:01:01 , and DRB1*07/*07 40,48 . This was further exemplified by the association of DRB1*03:01 with increased risk of RPL with a high risk of RPL in the (Central Asian) Kazakh subjects, 40 but not (Middle Eastern] Lebanese 5 or South European 33 populations. These contrasting associations can be associated with ethnic differences in study subjects, sample size, and typing methods (DNA‐based vs. serological assays).…”

“…1,38,39 This case-control report is the first to assess the association of spe- to the risk of RPL in distinct populations. 5,25,27,[40][41][42] There is a consensus that the diagnosis of RPL may be considered following the loss of two or more gestations, which includes miscarriages after spontaneous pregnancy and conception via ART but excluding ectopic and molar pregnancies and implantation failure. 4 The stringent definition of three or more consecutive miscarriages before the 20th week of gestation consistent with the RCOG guideline was used in this study.…”

Study on the Relationship between Unexplained Recurrent Abortion and HLA-DQ Gene Polymorphism

“…Since the discovery of the first human leukocyte antigen Mac (HLA-A2) by French physician Dausset in 1958, research on HLA has developed rapidly [ 9 ]. HLA is located in region 21.3 of the short arm of chromosome 6, with a length of 4100 kb, and is by far the most polymorphic system known in humans, accounting for about 0.1% of the genes in the human genome [ 10 ].…”