Human Leukocyte antigen-G Gene Research Articles

Combined maternal KIR2DL4 and fetal HLA-G polymorphisms were associated with preeclampsia in a Han Chinese population.

Preeclampsia is the main cause of maternal and infant mortality and morbidity during pregnancy. Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4) and human leukocyte antigen G (HLA-G) play crucial roles in immune tolerance at the maternal-fetal interface. In this case‒control study, 154 maternal-fetal pairs were recruited, including 74 pairs with preeclampsia (56 of 74 pairs from family triads) and 80 pairs with a normal pregnancy (78 of 80 pairs from family triads). SNaPshot technology was used to detect genetic polymorphisms for 7 TagSNPs in the KIR2DL4 and HLA-G genes. Among the fetal HLA-G gene polymorphisms, rs9380142 (A vs. G: OR = 2.802, 95% CI = 1.761-4.458) and rs1063320 (G vs. C: OR = 1.807, 95% CI = 1.144-2.852) differed between the preeclampsia group and the control group. The transmission disequilibrium test (TDT) suggested that the differences in the rs9380142G/A polymorphism in foetuses between preeclampsia triads and control triads were due to differences in transmission from the parents (P = 0.001). There was no significant difference in the distribution of maternal KIR2DL4 alleles or genotype frequency between the preeclampsia group and the control group. Gene‒gene interaction analysis revealed that the combined genotypes of maternal rs649216-CC and fetal rs9380142-GG, maternal rs1051456-CG/GG and fetal rs9380142-GG, maternal rs34785252-CC and fetal rs9380142-AA/GA, and maternal rs34785252-CC/AA and fetal rs9380142-GG were associated with a significantly lower risk of preeclampsia. Therefore, this study suggested that the combination of maternal KIR2DL4 and fetal HLA-G polymorphisms was associated with preeclampsia in a Han Chinese population.

The correlation between soluble human leukocyte antigen (sHLA-G) levels and +3010 polymorphism.

Human leukocyte antigen-G (HLA-G) is classified as non-classical HLA, located in the short arm of chromosome 6 and composed of seven introns and eight exons. The HLA-G gene has a lower frequency polymorphism in the coding area and higher variability at the regulatory 5'- and 3'-untranslated regions linked to HLA-G microRNA regulation. HLA-G molecule is known to have an immunomodulatory and tolerogenic features role. In 199 Saudi individuals, we examined the association between plasma soluble HLA-G (sHLA-G) levels and eight polymorphic different sites, including 14bp ins/del/+3003T-C/+3010C-G/+3027C-A/+3035C-T/+3142C-G/+3187A-G/+3196C-G single nucleotide polymorphisms (SNPs) in exon 8 in the HLA-G gene. Our results revealed higher frequency for rs17179101C (97%), rs1707T (92%) and rs9380142A (73%) alleles. Greater frequencies for the tested genotypes were observed in 3027C/C (rs17179101) (93%), 14bp (rs1704) ins/del (92%), +3003T/T (rs1707) (85%) and +3035C/T (rs17179108) (79%) SNP genotypes. Moreover, we observed a significant association of sHLA-G with +3010G/C (rs1710) SNP. In conclusion, we showed a significant association between 3010G/C (rs1710) SNP and the sHLA-G level among our sample for Saudi populations. Our findings demonstrated that specific SNP within the HLA-G gene is linked to sHLA-G molecule secretion, suggesting sHLA-G levels may be regulated genetically.

Evaluation of the relationships between HLA-G 14 bp polymorphism and two acute leukemia in a Saudi population

The non-classical Human Leukocyte Antigen G (HLA-G) is an immunomodulatory molecule, with low polymorphism frequency and restricted tissue distribution. Its higher expression was associated with immunoinhibitory properties causing tolerance for cancer progression. The rs371194629 is a 14 bp insertion/deletion polymorphism (Ins/Del) in exon 8 of the 3′ untranslated region (3′-UTR) of the HLA-G gene, has been associated with the stability and the expression level of HLA-G mRNA. In this study, we evaluated the relationship between the HLA-G 14-bp Ins/Del polymorphism and two common blood cancers including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a population from Riyadh in Saudi Arabia. The study groups include 145 patients diagnosed for ALL, 98 patients diagnosed for AML and 115 healthy individuals. For all these individuals, the 14 bp Ins/Del polymorphism was genotyped using PCR methodology. mRNA gene expression of the HLA-G was assessed using quantitative RT-PCR. Logistic regression model analysis for HLA-G 14 bp Ins/Del polymorphism shows no statistically significant correlation with AML and ALL. For the HLA-G mRNA expression, while slightly increased level among healthy individuals compared to patients was observed, no statistically significant differences were obtained. Although our results did not show association between HLA-G with the two leukemia cancer diseases, the role of HLA-G gene awaits further investigations including large number of subjects with more clinical data combinations.

Study of HLA-G gene 14-bp ins/del and codon 93 (CAC/CAT) polymorphisms association with spontaneous abortion in a Tunisian population.

In the recent years, spontaneous abortion (SA) frequency increased awareness about medical and social-economic related problems. Human leukocyte antigen-G (HLA-G) is a non-classic HLA I molecule initially described in trophoblastic tissue in foeto-maternal interface. HLA-G polymorphism association with SA has been extensively studied. One amongst the foremost studied variants was HLA-G 14-bp Insertion (Ins)/Deletion (Del) polymorphism. Nevertheless, such a study was not performed in Tunisian population yet. We aim to investigate two HLA-G polymorphisms, 14-bp Ins/Del 3'UTR, and for the first time, codon 93 (CAC/CAT) polymorphisms association with SA risk in the Tunisian population. The results revealed HLA-G 14-bp Ins/Del polymorphism and CIns haplotype association with SA. No association of the HLA-G codon 93 (CAC/CAT) polymorphism to SA was observed. Considering both polymorphism together, female's homozygosity for 14-bp Ins/Del and for codon 93 (CAC/CAT) polymorphism may increase the risk of SA susceptibility.

Immunogenetic Relationship of HLA-G 14 bp Insertion/Deletion Polymorphism and Toll-Like Receptor 9 with Systemic Lupus Erythematosus in Egyptian Patients: A Case-Control Study.

IntroductionThe level of expression of the immunoregulatory human leukocyte antigen-G (HLA-G) has been suggested to play a role in the immunopathogenesis of systemic lupus erythematosus (SLE). A 14 bp insertion/deletion (ins/del) polymorphism in the 3ˊuntranslated region of HLA-G gene may influence the level of expression. The role of Toll-like receptor 9 (TLR9) in the pathogenesis of SLE has been highlighted. Data among Egyptian patients are quite limited.PurposeTo detect the association of HLA-G 14 bp ins/del gene polymorphism with the susceptibility to SLE and to correlate TLR9 serum level with disease activity among Egyptian patients.Patients and MethodsA case-control study that included 102 SLE female patients and 102 healthy matched volunteers as controls was carried out. Disease activity in patients was determined using the modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). HLA-G 14 bp ins/del genotype was detected by polymerase chain reaction (PCR). TLR9 serum level was estimated using enzyme-linked immunosorbent assay (ELISA) technique.ResultsThe ins/ins genotype was significantly increased among SLE patients compared to healthy subjects (58.8% vs 9.8%; odds ratio [OR] = 11.79, P < 0.001). The 14 bp ins allele was significantly more frequent in SLE patients than in healthy subjects (65.7% vs 27.9%, respectively) and significantly associated with an increased risk of SLE (OR 4.94, P < 0.001). The mean TLR9 serum level showed a significant increase in SLE patients compared to healthy subjects (397.04±137.86 vs 195.22±45.14 ng/L, p < 0.001) and was significantly associated with disease activity as well as to patients’ HLA-G genotypes (p < 0.001).ConclusionAmong Egyptian population, HLA-G 14 bp ins/ins homozygous genotype and ins allele may constitute a potential risk for SLE susceptibility, while TLR9 serum level is significantly associated with disease activity.

Association between maternal single-nucleotide polymorphisms in HLA-G gene and risk of preeclampsia

Aim To determine the relationship between the maternal single-nucleotide polymorphisms (SNPs) in human leukocyte antigen G (HLA-G) gene and preeclampsia (PE), so as to provide guidance for the early risk prediction of PE. Methods From October 2017 to October 2019, a total of 99 pregnant women were enrolled in this cross-sectional study. The PE group included 51 pregnant women with severe PE, and the control group included 48 pregnant women with normal delivery during the same period. DNA was extracted and the SNPs in HLA-G gene of the two groups were sequenced. Maternal SNPs in HLA-G gene affecting the occurrence of the PE were determined. Results In this study, patients with PE had increased gravidity (p = .002), increased BMI before delivery (p = .004), reduced neonatal weight (p < .001), reduced gestational weeks (p < .001), reduced placental weight (p < .001), and increased proportion of cesarean section (p < .001). There were significant differences in SNPs at locus 29794467, 29796376, and 29799440 between the two groups (p < .05). In locus 29799440, patients with genotype CC had a lower risk of PE than patients with genotype TT (p = .047), with an odds ratio (OR) of 0.347(95%CI: 0.031, 3.881). And there was no significant difference in the risk of PE between patients with genotype CT, and those with genotype TT (p = .090) (OR = 2.344 95%CI: 0.187, 29.344) Conclusion There is an association between a SNP in locus 29799440 of the HLA-G gene and susceptibility of PE in Han Chinese pregnant women, and the risk of PE increases with genotype CT/TT in pregnant women.

HLA-G 14bp Ins/Del Polymorphism in the 3'UTR Region and Acute Rejection in Kidney Transplant Recipients: An Updated Meta-Analysis.

Background and Objectives: Acute kidney injury (AKI) affects the survival rate of kidney transplant organs and patients. Acute rejection (AR) due to AKI may lead to kidney transplantation failure. It is known that there is a relationship between human leukocyte antigen-G (HLA-G), which is involved in immune regulation, and AR in transplant patients. Moreover, 14-bp insertion/deletion polymorphism in the 3′ untranslated region (UTR) region of the HLA-G gene is known to affect HLA-G expression. However, its relationship to AR is still controversial. The aim of this study was to investigate whether HLA-G 14-bp insertion/deletion polymorphism contributed to the development of AR in kidney transplant patients using a meta-analysis. Materials and Methods: To perform our meta-analysis, eligible studies about HLA-G 14-bp insertion/deletion polymorphism and AR were searched in electronic databases until 1 June 2021. Finally, a total of 336 patients with AR and 952 patients without AR in relation to kidney transplantation were analyzed from a total of nine studies. Results: In our results, the Del allele and Ins/Del+Del/Del and Del/Del genotypes significantly increased susceptibility of AR in Asian populations [odds ratio (OR) = 2.359, 95% confidence interval (CI) = 1.568–3.550, p = 3.8 × 10−5; OR = 3.357, 95% CI = 1.769–6.370, p = 0.002; OR = 2.750, 95% CI = 1.354–5.587, p = 0.0052 in each model, respectively]. Conclusions: Evidence of the present results indicate that HLA-G 14-bp insertion/deletion polymorphism is associated with susceptibility to AR in the Asian population.

Comprehensive Transcriptomic Analysis Reveals the Role of the Immune Checkpoint HLA-G Molecule in Cancers.

Human leukocyte antigen G (HLA-G) is known as a novel immune checkpoint molecule in cancer; thus, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. The aim of this study was to systematically identify the roles of checkpoint HLA-G molecules across various types of cancer. ONCOMINE, GEPIA, CCLE, TRRUST, HAP, PrognoScan, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, STRING, GeneMANIA, DAVID, TIMER, and CIBERSORT were utilized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In this study, we comprehensively analysed the heterogeneous expression of HLA-G molecules in various types of cancer and focused on genetic alterations, coexpression patterns, gene interaction networks, HLA-G interactors, and the relationships between HLA-G and pathological stage, prognosis, and tumor-infiltrating immune cells. We first identified that the mRNA expression levels of HLA-G were significantly upregulated in both most tumor tissues and tumor cell lines on the basis of in-depth analysis of RNAseq data. The expression levels of HLA-G were positively associated with those of the other immune checkpoints PD-1 and CTLA-4. Abnormal expression of HLA-G was significantly correlated with the pathological stage of some but not all tumor types. There was a significant difference between the high and low HLA-G expression groups in terms of overall survival (OS) or disease-free survival (DFS). The results showed that HLA-G highly expressed have positive associations with tumor-infiltrating immune cells in the microenvironment in most types of tumors (P<0.05). Additionally, we identified the key transcription factor (TF) targets in the regulation of HLA-G expression, including HIVEP2, MYCN, CIITA, MYC, and IRF1. Multiple mutations (missense, truncating, etc.) and the methylation status of the HLA-G gene may explain the differential expression of HLA-G across different tumors. Functional enrichment analysis showed that HLA-G was primarily related to T cell activation, T cell regulation, and lymphocyte-mediated immunity. The data may provide novel insights for blockade of the HLA-G/ILT axis, which holds potential for the development of more effective antitumour treatments.

New markers for predictions of acute and chronic rejection and graft outcomes in kidney transplant recipients; HLA-G gene 3'UTR 14bp polymorphism and sHLA-G.

The aim of this study was to evaluate the relation of Human Leukocyte Antigen-G (HLA-G) 14bp ins/del (insertion/deletion) polymorphism and soluble HLA-G (sHLA-G) level with rejection in kidney transplant recipients. The study was planned as a case-control study involving two hundred fifty kidney transplant recipients. The case group consisted of 125 (female/male: 56/69) kidney transplant recipients diagnosed with acute (n=52) and chronic rejection (n=73). The control group consisted of one hundred twenty-five kidney transplant patients with no acute or chronic rejection matched by gender and age in the case group. The sHLA-G level in the recipient's plasma (at the time of rejection for the case, the same time as the case after the transplant for control) was analyzed by Enzyme-Linked Immunosorbent Assay (ELISA). HLA-G 3' untranslated region (3'UTR) polymorphism of recipient and donor was determined using agarose gel electrophoresis and DNA sequencing method. In our study, it was shown that acute rejection rate increased 1.06 times and chronic rejection rate increased 1.14 times in kidney transplant recipients with low serum sHLA-G levels. The rejection patients with the HLA-G 14bp del/del genotype had higher sHLA-G levels post-transplantation. The frequency of acute rejection was lower in patients with HLA-G 14bp del/del polymorphism than those with ins/ins and ins/del polymorphisms. This study proposes that HLA-G 3'UTR polymorphism and sHLA-G level might be useful in prediction of rejection in kidney transplant recipients.

The Effect of INDEL Polymorphism of the Human Leukocyte Antigen G (HLA-G) and the Season of Birth on the Risk of Schizophrenia and Its Clinical Features

By modulating the immunological relationship between the mother and the fetus, as well as interacting with various environmental factors, HLA-G plays an important role in the development of the brain of the embryo and is therefore considered as one of the risk factors for schizophrenia. We studied the relationship of INDEL HLA-G gene polymorphism with schizophrenia and its clinical features, taking into account the season of birth. The sample of patients included 1171 people with schizophrenia; the control group consisted of 575 mentally healthy people without a family history of mental disorders. The interaction of INDEL polymorphism and the season of birth was revealed. It has been found that, in men with the D/D genotype born in the summer, the risk of schizophrenia increases (OR = 1.95, 95% CI: 1.01–3.78). Our analysis has shown that the INDEL polymorphism does not interact with the season of birth as an environmental factor and does not affect the clinical features of schizophrenia: the age of onset of the disease and the severity of symptoms.

Analysis of HLA-G 5'URR regulatory polymorphisms in Slovak women with pre-eclampsia.

The objective of this study was to identify the impact of the selected HLA-G gene polymorphisms in the 5'URR region on the risk to develop pre-eclampsia. Pre-eclampsia (PE) is a serious multisystem disorder that affects women during pregnancy. Despite many research studies, the pathology of PE is not fully understood. Human leukocyte antigen G (HLA-G) belongs to the molecules that induce immune tolerance at the fetal-maternal interface. HLA-G expression was found to be impaired in the women suffering from PE suggesting its involvement in the development of PE. 116 women with pre-eclampsia and 130 women with normotensive pregnancy were included in the study. The 16 gene polymorphisms in the HLA-G 5'URR region (promoter) affecting HLA-G expression were typed by direct sequencing. The -201AA genotypes in recessive model were significantly more frequent in women with pre-eclampsia than in the controls (p = 0.047). Furthermore, the analysis of HLA-G 5'URR variants with clinical findings of PE showed a significant association of the -533delA-/+ genotype with a higher mean level of diastolic blood pressure (p = 0.02). Our results suggest a genetic association of selected HLA-G 5'URR variants with a risk of developing pre-eclampsia and possible contribution of HLA-G to disease pathology (Tab. 4, Ref. 51).

Haplotype Effect of Two Human Leukocyte Antigen-G Polymorphisms of rs1736933 and rs2735022 on the Recurrent Pregnancy Loss

Background: Recurrent Pregnancy Loss (RPL) is a multifactorial disease that affects 1-3% of couples. Since Human Leukocyte Antigen-G (HLA-G) gene is involved in fetal maternal immune tolerance, mutations in the HLA-G gene can affect the success rate of pregnancy. Objective: The present study aims to investigate the haplotype effect of rs1736933 and rs2735022 polymorphisms found in the HLA-G gene on the RPL. Methods In this case-control study, participants were 100 women with RPL and 80 women with normal fertility in northwestern Iran. The HLA-G gene promoter was amplified by Polymerase Chain Reaction (PCR) method and sequenced. The genotype and allele frequencies of the two polymorphisms were compared between the two groups by using t-test in SPSS software version 22. Haplotype analysis was performed using PHASE 2.1 and Haploview 4.2 applications Findings: C allele and CC genotype in rs2735022 polymorphism and the G allele and GG genotype in rs1736933 polymorphism showed a significant association with the RPL (P&lt;0.05). Frequency of haplotypes AA, AC, GA, GC were 0.72, 0.23, 0.01, 0.03 in patients and 0.39, 0.01, 0.02, 0.59 in the control group (P&lt;0.05). The linkage disequilibrium score was 94. Conclusion: Analysis of GC haplotype in rs2735022 and rs1736933 polymorphisms of the HLA-G gene can be helpful in genetic studies of women with RPL.

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

BackgroundThe Human Leukocyte Antigen G (HLA-G) protein is an immune tolerogenic molecule with 7 isoforms. The change of expression level and some polymorphisms of the HLA-G gene are involved in various pathologies. Therefore, this study aimed to predict the most deleterious missense non-synonymous single nucleotide polymorphisms (nsSNPs) in HLA-G isoforms via in silico analyses and to examine structural and functional effects of the predicted nsSNPs on HLA-G isoforms.ResultsOut of 301 reported SNPs in dbSNP, 35 missense SNPs in isoform 1, 35 missense SNPs in isoform 5, 8 missense SNPs in all membrane-bound HLA-G isoforms and 8 missense SNPs in all soluble HLA-G isoforms were predicted as deleterious by all eight servers (SIFT, PROVEAN, PolyPhen-2, I-Mutant 3.0, SNPs&GO, PhD-SNP, SNAP2, and MUpro). The Structural and functional effects of the predicted nsSNPs on HLA-G isoforms were determined by MutPred2 and HOPE servers, respectively. Consurf analyses showed that the majority of the predicted nsSNPs occur in conserved sites. I-TASSER and Chimera were used for modeling of the predicted nsSNPs. rs182801644 and rs771111444 were related to creating functional patterns in 5′UTR. 5 SNPs in 3′UTR of the HLA-G gene were predicted to affect the miRNA target sites. Kaplan-Meier analysis showed the HLA-G deregulation can serve as a prognostic marker for some cancers.ConclusionsThe implementation of in silico SNP prioritization methods provides a great framework for the recognition of functional SNPs. The results obtained from the current study would be called laboratory investigations.

Plasma soluble HLA-G levels in a cohort of heart failure patients exposed to chemicals

Heart failure (HF) is a syndrome caused by structural and/or functional cardiac abnormalities, resulting in a reduced cardiac output and/or elevated intracardiac pressures. Several studies reported a crucial role of immune activation and inflammation in the chronic heart failure (HF) pathogenesis, suggesting that pro-inflammatory and anti-inflammatory mediators could be predictive markers of the HF development and/or progression. Human Leukocyte Antigen-G (HLA-G), a tolerogenic and anti-inflammatory class I non-classical major histocompatibility complex molecule, was reported to be upregulated in patients diagnosed with HF, suggesting a tentative to regulate the inflammatory condition. We evaluated soluble (s)HLA-G plasmatic levels in patients with stable chronic heart failure at baseline visit and after 6 and 12 months. The 14 bp Insertion/Deletion polymorphisms of the HLA-G gene was also analyzed. We showed that in HF subjects, sHLA-G levels were higher in NYHA class II and III subjects (mild-severe symptoms) (6.11 ± 1.15 ng/ml; 8.25 ± 2.27 ng/ml, respectively) in comparison with NYHA class I subjects (no symptoms) (2.35 ± 0.43 ng/ml) (I vs II: p = 0.0156; I vs III: p = 0.0122). Moreover, the exposure to chemicals seems to affect sHLA-G levels, with higher sHLA-G levels in exposed patients (3.36 ± 5.12 ng/ml) in comparison with unexposed subjects (2.01 ± 2.84 ng/ml). The HLA-G 3′UTR 14 bp INS/DEL polymorphism correlated with sHLA-G, with the 14 bp INS/INS genotype associated with higher sHLA-G levels during the 12 months follow-up in unexposed subjects (p = 0.008). In conclusion, these results support a correlation between sHLA-G levels, genetics and HF disease in presence of work chemical exposition.

Human leukocyte antigen-G polymorphisms in periodontitis

Objective: This study evaluated human leucocyte antigen-G gene polymorphisms in patients with periodontitis and healthy controls.Material and methods: The insertion/deletion polymorphism of 14 bp and a single nucleotide polymorphism (SNP) C > G on the position +3142 of the 3′ untranslated region of the gene were analyzed in chronic periodontitis (n = 62), aggressive periodontitis (n = 24) patients and healthy individuals (n = 47).Results: Considering the 14 bp insertion/deletion, a significant deviation from Hardy-Weinberg expectations in the chronic periodontitis group was observed, but not in the other groups. No significant deviations were observed in patients and control groups considering the +3142 C > G SNP. A significant increased frequency of homozygotes for the 14 bp deletion allele was observed in the chronic periodontitis group as compared to controls. This group also presented a higher frequency of the deletion allele, which was marginally not significant. Concerning this polymorphism, no significant differences were observed between the aggressive periodontitis and healthy control groups. In addition, no significant differences were seen amongst patients and controls when considering the +3142 C > G frequencies.Conclusion: No differences were found amongst patients and controls when considering the +3142 C > G SNP haplotypes frequencies, but a significant increased frequency of homozygotes for the 14 bp deletion allele was observed in chronic periodontitis patients compared to healthy controls, suggesting a susceptibility role of this polymorphism in the pathogenesis of this condition.

Association of human leukocyte antigen-G 14 bp polymorphism with recurrent pregnancy loss in European countries: a meta-analysis of literature studies

To study the controversial association between human leukocyte antigen-G (HLA-G) 14bp polymorphism and recurrent pregnancy loss (RPL). We performed a meta-analysis of studies in the literature that enrolled only women of European countries who experienced RPL spontaneously or after undergoing IVF. Systematic meta-analysis of articles published before January 2019 pertaining the association of HLA-G genotype and RPL. The search was performed in electronic databases (PubMed, Web of Science, Scopus, EMBASE), without any language or publication year restriction. Academic hospitals and private clinics. Women who experienced RPL spontaneously or after undergoing IVF. Genotyping of 14bp polymorphism (insertion/insertion, insertion/deletion, deletion/deletion) in exon 8 of the HLA-G gene. Meta-analyses of the association between HLA-G 14bp polymorphism in homozygosis (insertion/insertion) and heterozygosis (insertion/deletion) in women with RPL compared with pregnant controls with at least one live birth and no history of RPL. Ten studies were analyzed comprising 1,091 women with RPL and 808 controls without RPL. Women with RPL showed significantly higher prevalence of HLA-G 14bp insertion/insertion genotype compared with women without RPL (19.8% vs. 14.1%; odds ratio = 1.562; 95% confidence interval, 1.203-2.027), and this result was also confirmed when separately analyzing women with RPL during a spontaneous pregnancy (odds ratio, 1.562; 95% confidence interval, 1.203-2.027) and those undergoing IVF (odds ratio, 1.990; 95% confidence interval, 0.978-4.051). Women of European countries with the HLA-G 14bp insertion/insertion genotype have a significantly higher prevalence of RPL.

Molecular Analysis of HLA-G in Women with High-Risk Pregnancy and Their Partners with Regard to Possible Complications.

The understanding of the molecular and biochemical characteristics of the human leukocyte antigen-G (HLA-G) is important because of the diverse influence of this antigen’s polymorphisms on the course of a pregnancy. The aim of our study was to assess how the variation of the HLA-G allele and the HLA-G 14-bp ins/del polymorphism influence predisposition to a complicated pregnancy. The clinical material consisted of parental pairs with complicated pregnancies (210 women; 190 men). The control group included parental pairs without complications during pregnancy (89 women; 86 men). The study involved isolation of genome DNA from peripheral blood leukocytes, sequencing, and analysis of the 14-bp ins/del polymorphism in the 3′-untranslated region (3′-UTR) of the HLA-G gene based on polymerase chain reaction (PCR). The most common HLA-G allele in the group of women with complicated pregnancies was the HLA-G 10101 allele. There were no statistically significant differences in the frequencies of the 14-bp ins/del polymorphism in the 3′UTR of the HLA-G gene between the groups. Our results suggest that the risk of complications in pregnancy is influenced by the HLA-G 10101, HLA-G 10108, and HLA-G 10106 alleles and is not influenced by the 14-bp ins/del polymorphism in the 3′UTR of the HLA-G gene.

Human leucocyte antigen-G 14-bp InDel polymorphism and oral squamous cell carcinoma risk in Chinese Han population: A case-control study.

Human leucocyte antigen-G (HLA-G) is a nonclassical HLA class I molecule involved in tumour immune escape. The purpose of this study was to investigate the association between the 14-bp insertion/deletion (InDel) polymorphism in the 3' untranslated region (3'-UTR) of HLA-G gene and oral squamous cell carcinoma (OSCC) risk in Chinese Han population (216 cases and 193 healthy controls), and furthermore, to evaluate serum soluble HLA-G (sHLA-G) levels in the OSCC patients. Our results demonstrated that the Ins allele was significantly less frequent in the OSCC patients than that in the healthy controls (odds ratio [OR]=0.75; 95% confidence interval [CI]: 0.57-0.99; p=0.040). Distribution of the 14-bp genotypes in the OSCC patients and the healthy controls revealed that the Ins/Ins genotype was associated with decreased OSCC risk in both the codominant model (Ins/Ins versus Del/Del; OR=0.57; 95% CI=0.33-0.99; p=0.044) and the log-additive model (OR=0.76; 95% CI: 0.58-0.99; p=0.044). The serum sHLA-G level was significantly higher in the OSCC patients than those in the healthy controls (p<0.001). Receiver operating characteristic (ROC) curve revealed the valuable diagnostic value of sHLA-G for OSCC detection, with an area under the ROC curve (AUC) of 0.891 (95% CI: 0.856-0.925, p<0.001). The OSCC patients with Ins/Ins genotype had lower serum sHLA-G levels than those with Ins/Del and Del/Del genotypes (p=0.015). Furthermore, serum sHLA-G levels were significantly increased with the increasing TNM stages of the OSCC patients (p=0.017). Our findings revealed that the HLA-G 14-bp InDel polymorphism might be a genetic risk factor for OSCC susceptibility, and the serum sHLA-G may act as a promising biomarker for noninvasive diagnosis of OSCC.

Association between HLA-G 14bp Gene Polymorphism and Serum sHLA-G Protein Concentrations in Preeclamptic Patients and Normal Pregnant Women

ABSTRACTBackground: Preeclampsia (PE) is a multisystem syndrome that is a primary source of fetal–maternal morbidity and mortality. Human leukocyte antigen-G (HLA-G) is a nonclassical Major histocompatibility complex (MHC) class-Ib molecule expressed on the extravillous trophoblast and seems to have immunomodulatory functions during pregnancy. The purpose of our study was to investigate whether HLA-G may be a vital marker in the modulation of the pregnancy.Methods: In this case-control study, a number of 150 healthy pregnant women and 150 patients with PE had been genotyped for the 14 base-pair (bp) insertion/deletion polymorphism in exon 8 of the HLA-G gene, and the serum level of soluble HLA-G (sHLA-G) protein was measured using the enzyme-linked immunosorbent assay.Results: Data showed that the PE syndrome was not related to the HLA-G 14 bp genotype. But, the serum level of sHLA-G in PE patients was significantly lower than that in healthy pregnant women in the third trimester (11.74 and 24.48 U/ml, respectively, p < 0.001). However, no significant association was observed between the HLA-G 14 bp genotype and serum sHLA-G level.Conclusion: Our results demonstrate that measurement of sHLA-G protein level may be helpful as a primary diagnosis for the pathogenesis of PE. Overall, this study suggests that the association between HLA-G 14 bp polymorphism and serum sHLA-G level in different ethnic populations of PE should be taken into consideration.

Influence of correlation between HLA-G polymorphism and Interleukin-6 (IL6) gene expression on the risk of schizophrenia

Converging evidence suggests important implications of immuno-inflammatory pathway in the risk and progression of schizophrenia. Prenatal infection resulting in maternal immune activation and developmental neuroinflammation reportedly increases the risk of schizophrenia in the offspring by generating pro-inflammatory cytokines including IL-6. However, it is not known how prenatal infection can induce immuno-inflammatory responses despite the presence of immuno-inhibitory Human Leukocyte Antigen-G (HLA-G) molecules. To address this, the present study was aimed at examining the correlation between 14 bp Insertion/Deletion (INDEL) polymorphism of HLA-G and IL-6 gene expression in schizophrenia patients. The 14 bp INDEL polymorphism was studied by PCR amplification/direct sequencing and IL-6 gene expression was quantified by using real-time RT-PCR in 56 schizophrenia patients and 99 healthy controls.We observed significantly low IL6 gene expression in the peripheral mononuclear cells (PBMCs) of schizophrenia patients (t = 3.8, p = .004) compared to the controls. In addition, schizophrenia patients carrying Del/Del genotype of HLA-G 14 bp INDEL exhibited significantly lower IL6 gene expression (t = 3.1; p = .004) than the Del/Ins as well as Ins/Ins carriers. Our findings suggest that presence of “high-expressor” HLA-G 14 bp Del/Del genotype in schizophrenia patients could attenuate IL-6 mediated inflammation in schizophrenia. Based on these findings it can be assumed that HLA-G and cytokine interactions might play an important role in the immunological underpinnings of schizophrenia.