HLA-G regulatory variants and haplotypes with susceptibility to recurrent pregnancy loss (original) (raw)
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Role of 14-Bp HLA-G, INDEL Polymorphism in Recurrent Miscarriage
Global Journal of Health Science, 2016
Mothers and their fetuses are hereditarily unlike. Surprisingly, no less than 50% human pregnancies reach full term despite the tendency of the immune system to eliminate of non-self units. Reduction of adaptive maternal immune answer, which is planned to reject strange factors, is essential for a pregnancy to reach full term. However, approximately 5% couples trying to conceive experience 2 recurrent miscarriages (RMs). HLA-G, which is produced by the external trophectoderm layer and has unique biological features, is involved in the implantation and maintenance of fetus. Serum HLA-G levels are correlated with the risk of RM. Recent studies indicate that a 14-bp HLA-G, INDEL polymorphism decreases the level of HLA-G mRNA, which in turn decreases the amount of HLA-G produced. An understanding of gene parameter and the function of polymorphic sites in the functioning of HLA-G products may enable the development of approaches targeting HLA-G for more detail of causes of RM.
Association of genetic variants in the 3′UTR of HLA-G with Recurrent Pregnancy Loss
Human Immunology, 2016
Human Leukocyte Antigen (HLA)-G is involved in reprogramming immune responses at fetal-maternal interface during pregnancy. We evaluated the genetic diversity of the 3 0 Un-Translated Region (UTR) of HLA-G, previously associated with HLA-G mRNA post-transcriptional regulation, in women with unexplained Recurrent Pregnancy Loss (RPL), with 2 pregnancy losses (RPL-2, n = 28), or 3 or more pregnancy losses (RPL-3, n = 24), and in 30 women with a history of successful pregnancy. Results showed in RPL-2, but not in RPL-3, women compared to controls: i) higher frequency of the 14 bp Ins allele, in single and in double copy; ii) significantly lower frequency of DelG/X genotype, iii) reduced frequency of the UTR-2, and UTR-3 haplotypes; iv) higher frequencies of the UTR-5, UTR-7, and UTR-8 haplotypes. This pilot study supports the relevance of performing 3 0 UTR HLA-G genetic screening, not limited to a specific polymorphism, but considering the extended haplotypes, as a possible predictor of pregnancy outcome.
HLA-G and Recurrent Pregnancy Loss
International Journal of Molecular Sciences
Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40–60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.
Springer eBooks, 2016
Recent findings have raised the possibility that polymorphisms within the annexin A5 gene (ANXA5) promoter contribute to the etiology of recurrent pregnancy loss (RPL). In our present study, 243 Japanese women who had suffered more than three fetal losses and a group of 119 fertile controls were genotyped for four ANXA5 gene promoter single-nucleotide polymorphisms (SNPs; SNP1-4: g.-467G .A, g.-448A.C, g.-422T.C, g.-373G.A) previously reported to be associated with this disorder. An additional two SNPs located within the 5 ′-untranslated region of the ANXA5 (SNP5 and 6: g.-302T.G, g.-1C.T) were also evaluated. Our case-control study revealed that the minor allele was significantly more frequent in the RPL group than controls for all six of these SNPs, among which SNP5 showed the highest significance (P ¼ 0.002). As with the M2 haplotype for SNP1-4 (A-CC A) for a western population in previous reports, a haplotype comprising all of the minor alleles for SNP1-6 (A-CC A -G-T), the third major haplotype in the Japanese population, showed a significantly higher frequency in our current RPL subjects than in controls (P ¼ 0.025). In addition, the second major haplotype (G-AT -G-G-C) was found to confer a significant risk of RPL (P ¼ 0.036), implicating SNP5 as a major risk determinant for this disease. Our present findings support the hypothesis that genomic variations within the ANXA5 gene upstream region impact upon the disease susceptibility to RPL. Our data indicate that SNP5 is a novel risk factor for this disease in the Japanese population.
Human Immunology, 2011
Human leukocyte antigen (HLA)-G expression is restricted, expressed on trophoblast, with a major role in fetus acceptance. In addition to the 46 HLA-G alleles, the presence or absence of a 14 bp polymorphism located in the 3= UTR contributes to gene polymorphism that may influence both HLA-G mRNA stability and HLA-G isoform's splicing and consequently could play an immunomodulatory function in pregnancy. To elucidate the role of HLA-G polymorphism in pregnancy, HLA-G allele frequencies and the 14 bp polymorphisms were analyzed and compared in 60 couples with recurrent miscarriage (RM) and 68 fertile control couples. Two haplotypes showed a significant elevated frequency in patients (HLA-G*01:01:08/ϩ14, p c Ͻ 0.0001 and HLA-G*01:04:01/Ϫ14, p c Ͻ 0.0001). The haplotype HLA-G*01:01:A/ϩ14 exhibited a significant protective effect against RM in women (p c ϭ 0.0238). Remarkably, significant differences in linkage disequilibrium were observed between patient and control groups. Two alleles showed a positive association with the ϩ14 bp segment in RM patients and a strong negative association with fertile controls (HLA-G*01: 01:08 ϭ patients D= ϭ 0.295-0.371; controls D= ϭ Ϫ0.715 to Ϫ1.000; HLAG* 01:05N ϭ patients D= ϭ 0.728Ϫ1.000; controls D= ϭ Ϫ1.000). HLA-G*01:04:01 showed a negative association with the 14 bp segment in patients and a positive association in controls (patients D= ϭ Ϫ0.249 to Ϫ 0.674; controlss D= ϭ 0.688-1.000). Our results suggest that haplotypic combinations of HLA-G alleles and the 14 bp segment may be associated with RM.
HLA-G displays immunotolerant properties and hence plays important roles in the maintenance of a successful pregnancy and maternal tolerance of the semiallogeneic fetus. HLA-G gene Polymorphism may potentially affect the biological properties of the protein, and a 14-bp insertion/deletion polymorphism in exon 8 of the 3 untranslated region (3 UTR) of the HLA-G gene is thought to influence HLA-G expression. To study the association of the 14-bp insertion/deletion (INDEL) polymorphism with the risk of recurrent pregnancy loss (RPL), polymerase chain reaction (PCR) amplification and genotyping were enrolled on 100 women in the case group (women who have had three or more unexplained RPL) and 100 women in the control group (women who have had at least two normal pregnancy). Our results showed that the frequencies of the+14 bp/+14 bp genotypes were not observed in women with RPL, while that of the +14 bp/?14 and -14 bp/-14 bp genotype was significantly increased in RPL compared with the control group of normal fertile women, in addition a significant differences in the allele frequencies of the HLA-G 14-bp polymorphism were observed. These results suggest a possible significance of the HLA-G 14-bp INDEL polymorphism in the outcome of pregnancy. However, further studies on other polymorphic sites in the 3 UTR and 5 UTR regions, as well as monitoring the serum HLA-G concentration are necessary in order to determine the potential implications of this marker in our population.
Recurrent Pregnancy Loss (RPL): An overview
Recurrent pregnancy loss (RPL) is defined as two or more pregnancies losses occurring before 20 weeks of gestation and affecting 1-3% of the couples. Chromosomal abnormalities, uterine defects, thrombophilia, immunological factors, endocrine and metabolic factors are the known risk factors involved in the causation of recurrent pregnancy loss in 50% of the cases. However, remaining 50% of the recurrent pregnancy loss cases are unexplained. A lot of research is going on in the area of recurrent pregnancy loss globally and the results are inconsistent due to study designs, sample size, ethnicity etc. The present review took an insight into the overall risk factors involved in the causation of explained recurrent pregnancy loss to help the researchers to identify the origin of pregnancy loss and to provide best investigation and treatment strategy for women with recurrent pregnancy loss.
Role of the HLA-G regulatory region polymorphisms in idiopathic recurrent spontaneous abortions (RSA
American Journal Of Reproductive Immunology, 2023
Problem: HLA-G polymorphisms have a functional impact on its expression and may cause a breakdown of maternal tolerance towards the semi-allogenic fetus, resulting in recurrent spontaneous abortions (RSA). This study reports on the association of HLA-G regulatory region polymorphisms with idiopathic RSA. Methods: Seventy-five couples with ≥2 spontaneous abortions were recruited in comparison to 75 healthy couples who had normal pregnancies. About 5 mL of blood samples were collected from all the participants, and DNA was extracted. Screening of HLA-G 5′-upstream regulatory region (5′-URR) was done by direct sequencing in 50 each of RSA and healthy couples, respectively. The 14 bp deletion/insertion polymorphism in the 3′-untranslated region (3′-UTR) was genotyped in 75 each of RSA and healthy couples, respectively, by PCR amplification of HLA-G exon 8. MedCalc, Graph-Pad Prism, Haploview, PLINK, and multifactor dimensionality reduction were used to analyze the data.