Human Leukocyte antigen-G Gene Polymorphisms 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.

Association of Human Leukocyte Antigen-G Gene Polymorphisms with Rheumatoid Arthritis: Relationship with Disease Activity, Severity and Treatment Response

Association of Human Leukocyte Antigen-G Gene Polymorphisms with Rheumatoid Arthritis: Relationship with Disease Activity, Severity and Treatment Response

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).

Analysis of HLA-G gene polymorphisms in Slovak women with pre-eclampsia

To identify possible association between the selected HLA-G gene polymorphisms and risk of pre-eclampsia. Pre-eclampsia is a serious multisystem disorder that affects women during pregnancy. Despite many research studies, the pathology of pre-eclampsia is not fully understood. Human leukocyte antigen G (HLA-G) belongs to the molecules that induce fetal acceptance by the maternal immune system. HLA-G expression was found to be impaired in the women suffering from pre-eclampsia suggesting its involvement in the development of pre-eclampsia. 123 women with pre-eclampsia and 102 women with normotensive pregnancy were included in the study. HLA-G gene polymorphisms affecting its expression was determined, namely the HLA-G 14 bp insertion/deletion polymorphism in the 3'UTR and HLA-G 1597ΔC polymorphism tagging the HLA-G*01:05N null allele. Genotyping was performed by PCR and PCR-RFLP. No statistically significant differences in either allele or genotype frequencies between pre-eclampsia cases and control group have been observed (p > 0.05). Genetic predisposition of HLA-G to pre-eclampsia in Slovak women was examined for the first time. No association between analysed HLA-G gene polymorphisms and susceptibility to pre-eclampsia was observed. Further investigations are needed to determine the role of immunosuppressive molecule HLA-G in pre-eclampsia development (Tab. 5, Fig. 2, Ref. 37).

Upregulation of Soluble HLA-G in Chronic Left Ventricular Systolic Dysfunction.

Left ventricular systolic dysfunction (LVSD) defined by ejection fraction (EF) <40% is common, serious but treatable, and correct diagnosis is the cornerstone of effective treatment. Biomarkers may help to diagnose LVSD and give insight into the pathophysiology. The immune system is activated in LVSD, and the immunomodulatory molecule human leukocyte antigen-G (HLA-G) may be involved. The primary aim was to measure soluble HLA-G (sHLA-G) in the blood in different stages of LVSD (<30% and 30–40%), in the midrange EF 40–50%, and in preserved EF ≥ 50% and to validate sHLA-G as a LVSD biomarker. The secondary aim was to examine associations between HLA-G gene polymorphisms influencing expression levels and LVSD. The 260 study participants were ≥75 years old, many with risk factors for heart disease or with known heart disease. Soluble HLA-G was significantly and uniformly higher in the groups with EF < 50% (<30, 30–40, and 40–50%) compared to EF > 50% (p < 0.0001). N-terminal fragment-pro-B-type natriuretic peptide (NT-proBNP) and uric acid values were inversely related to EF. According to Receiver Operating Characteristic (ROC) curves NT-proBNP outperformed both sHLA-G and uric acid as biomarkers of LVSD. Soluble HLA-G in blood plasma was elevated in LVSD regardless of EF. A novel finding was that a combined 14 bp ins-del/+3142 SNP HLA-G haplotype was associated with EF < 40%.

Associations between HLA-G gene polymorphisms and the susceptibility to high risk HPV type 18 infection

Objective To investigate the associations between single nucleotide polymorphisms in the gene encoding human leukocyte antigen-G (HLA-G) and the genetic susceptibility to high risk human papillomavirus (HPV) type 18 infection in the subjects from Taizhou, Zhejiang province. Methods The genetic polymorphisms of HLA-G gene (14 bp In/Del and + 3142C/G) in cervical samples collected from HPV 18-positive and healthy women were analyzed by PCR and gene sequencing technology. Statistical analysis was performed by using SPSS version 16.0. Chi-squared test was used to analyze the differences with HLA-G gene allele and genotype frequencies between healthy subjects and patients. Results Compared with healthy subjects, women with oncogenic HPV18 infection showed lower frequencies of -14 bp allele, -14 bp/-14 bp genotype and -14 bp/+ 3142C haplotype (P<0.05). Moreover, lower frequencies of + 3142C/C genotype were detected in HPV18-infected women with pathologically normal cervix (6.3% vs 21.1%, OR=0.25, P<0.05) and higher percentages of + 3142G/G genotype were detected in women with CIN2/3 stage HPV18 infection as compared with those of the control group (68.8% vs 35.1%, OR=4.06, P<0.05). Conclusion The HLA-G gene 3' UTR polymorphisms were closely associated with HPV18 infection and cervical intraepithelial neoplasia. Key words: HLA-G gene polymorphism; Linkage disequilibrium; Human papillomavirus; Cervical intraepithelial neoplasia

HLA-G gene polymorphisms associated with susceptibility to rheumatoid arthritis disease and its severity in Brazilian patients.

We analyzed the possible association between human leukocyte antigen-G (HLA-G) genetic variants, supposed to regulate HLA-G expression, and the susceptibility to develop rheumatoid arthritis (RA) as well as its clinical manifestations. The 5'upstream regulatory region (5'URR) and 3'untranslated region (3'UTR) regions of the HLA-G gene were screened in 127 RA patients and 128 controls: 10 5'URR and 3 3'UTR HLA-G polymorphisms as well as two haplotypes were associated with risk for RA development, while a polymorphism in the 5'URR showed an association with the degree of disease activity. These findings, although the number of cases analyzed is limited and the P-values are modest, indicate a possible association between HLA-G gene polymorphisms and susceptibility to develop RA disease and its severity.

Analysis of HLA-G gene polymorphism and protein expression in invasive breast ductal carcinoma

The human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule predominantly expressed in trophoblastic placental cells to protect the fetus during pregnancy. However, evidence has shown that this molecule may be implicated in the immune escape mechanism of tumor cells. Thus, the aim of this study was to evaluate the frequency of 14-bp insertion/deletion HLA-G polymorphism, as well as the expression of this molecule in patients with invasive breast ductal carcinoma (IDC). A significant association between the expression of HLA-G and the presence of metastasis in lymph nodes (p=0.01) was observed and the expression of HLA-G was significantly higher in patients with shorter survival time (p=0.03). The analysis suggests that the polymorphism observed in patients with IDC may be inducing a higher expression of the HLA-G molecule, which may possibly contribute to shorter survival time and a worse clinical prognosis for such patients.

Impact of HLA-G analysis in prevention, diagnosis and treatment of pathological conditions.

Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions.

AB0010 Hla-g 14-bp insertion/deletion polymorphism modulates MTX therapeutic effect in a cohort of patients with rheumatoid arthritis

BackgroundIn recent years, a convincing body of scientific evidence has indicated that the expression of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, plays a...

A fast and easy real‐time PCR genotyping method for the HLA‐G 14‐bp insertion/deletion polymorphism in the 3′ untranslated region

Human leukocyte antigen-G (HLA-G) is a non-classical HLA class Ib molecule shown to exhibit immunomodulatory function in a wide range of immune-based disorders. A number of functional HLA-G gene polymorphisms have been identified, including a 14-bp insertion/deletion polymorphism in exon 8 of the 3' untranslated region of the HLA-G gene, which has been associated with HLA-G mRNA stability. Moreover, studies show that homozygosity for the 14-bp insertion/deletion polymorphism is associated with lower HLA-G mRNA and protein levels and unique alternative splicing patterns. Here, we introduce a quick and reliable method to screen for the HLA-G 14-bp insertion/deletion polymorphism using an optimized real-time polymerase chain reaction protocol. The genotyping assay has been validated by comparison with conventional methods. As results can be obtained within a few hours, the assay will have a potential for clinical use.

Relationship between HLA-G gene polymorphism and the susceptibility of esophageal cancer in Kazakh and Han nationality in Xinjiang

Objective: To explore the association between polymorphism of the human leukocyte antigen G (HLA-G) and susceptibility of esophageal carcinoma (EC) in Kazakh and Han nationality in Xinjiang.Methods: The 14 bp deletion/insertion (rs16375) and 0105N (rs41557518) of HLA-G genotyping were determined by PCR and PCR-RFLP, respectively in 239 patients and 467 controls.Results: There was a 2.69-fold (Pc = 0.04, 95% CI: 1.30–5.55) increased risk of developing EC in individuals with the −14 bp/−14 bp genotype (rs16375) compared with those carrying +14 bp/+14 bp genotype in Kazakh after Bonferroni correction, there was no association of 0105N (rs41557518) both in Kazak and Han population. And there was a 2.82-fold (Pc = 0.04, 95% CI: 1.32–6.04) increased risk of developing EC in individuals with −14 bp/−14 bp and C/C genotypes compared with those who had +14 bp/+14 bp and C/C genotypes in Kazakh.Conclusions: The study demonstrates that EC is associated with polymorphism of HLA-G14 bp in Chinese Kazak population. The 14 bp deletion/insertion of HLA-G gene may play a role in EC susceptibility of Kazakh.

Association of HLA-G Haplotype Risk Model with Overall Survival In Acute Myeloid Leukemia Patients

AbstractAbstract 2169 Introduction:The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and exerts multiple immunosuppressive functions. Thus, HLA-G expression in tumor cells favors tumor immune escape and tumor progression. The HLA-G gene polymorphism is extremely restricted in comparison to the classical HLA antigens. However, specific HLA-G polymorphisms in exons 3, 4, 5, 7 and parts of the 3′UTR encode for different haplotypes/alleles. Because of the prognostic role of HLA-G in cancer, especially in B-CLL, we investigated here the role of the HLA-G haplotypes in acute myeloid leukemia (AML). Methods:Genotyping was performed on the basis of examining exons 3, 4, 5, 7 and parts of the 3′UTR by pyrosequencing in 166 patients with AML. In total, we found 17 different haplotypes in the cohort. Results:The haplotype distributions between 166 AML patients and 190 healthy controls were significantly different in two alleles, arguing that these two haplotypes of HLA-G on the one hand increases (*01:06, p=0.042) and on the other hand decreases (*01:01:12 variante, p=0.0014) the susceptibility for AML. Next a risk model was generated for overall survival (OS) adapted to specific haplotypes/alleles of the HLA-G gene. The favorable group (A) consisted of the alleles *01:06 and *01:01:20 variant at codon 57 G (12 patients), the intermediate group (B) of *01:01:20, *01:04:10, *01:01:30 and *01:01:41 variant at codon 57 A (113 patients) and the unfavorable group (C) of the remaining 11 alleles (41 patients). The OS for patients in group C was significantly (p=0.02) shorter (median OS 613 days) than for those in group B (median OS 961 days) and A (median OS not reached). Multivariate analysis shows a trend that the risk HLA-G model (Hazard ratio (HR) 1.4, p=0.084) was an independent predictor next to the established prognostic factors cytogenetics (HR 2.1, p=0.001), age (HR 1.8, p=0.009), leucocytes (HR 1.6, p=0.026), ECOG stage (HR 1.5, p=0.006) and platelets (HR 2.1, p=0.015). Moreover, the new risk model was able to further subdivide patients with intermediate cytogenetic risk profile (median OS: group A not reached; group B 987 days; group C 624 days; p=0.10). Conclusion:Our study is the first study demonstrating that the combination of different alleles of the HLA-G gene is associated with the overall survival in AML patients. This fact emphasizes the extensive role of this gene by the tumor escape mechanism and could be responsible for progress in other cancers. Disclosures:No relevant conflicts of interest to declare.

HLA-G and its role in implantation (review)

Human leukocyte antigen G (HLA-G) is thought to play a key role in implantation by modulating cytokine secretion to control trophopblastic cell invasion and to maintain a local immunotolerance. The literature is reviewed to provide a description of the genetic background, properties of the protein, and the function of HLA-G. Data are presented on potential clinical applications of HLA-G including the use of evaluation of HLA-G gene polymorphisms in the diagnosis of patients experiencing recurrent pregnancy loss and evaluation and testing of soluble HLA-G (sHLA-G) in embryo culture media for the selection of embryos for transfer after in vitro fertilization (IVF). The literature supports a central role of HLA-G for successful implantation. Of couples experiencing recurrent pregnancy loss, 32% demonstrated the -1725G HLA-G polymorphism. Our data showed that when embryos were selected for transfer after IVF based on culture media concentrations of sHLA-G > or = 2 U/ml and good morphologic grade, a 65% pregnancy rate compared with a 0% pregnancy rate in those with <2 U/ml sHLA-G. HLA-G is important for successful implantation in human beings. The HLA-G -725 promoter polymorphism is a risk factor for recurrent miscarriage. Measurement of sHLA-G in embryo culture media can help select embryos for transfer after IVF allowing fewer embryos to be transferred in an attempt to lower multiple gestation rates.