HLA-G Locus Research Articles

Особливості функціонування імунологічної толерантності під час вагітності (огляд літератури)

Pregnancy is a special state in a woman’s life, which can definitely be considered an «immunological paradox», because the growth of a genetically «alien» fetus takes place in a woman’s body. Despite the direct contact between cells of fetal origin (syncytiotrophoblast) and cells of the maternal immune system, which are in excess in the decidual membrane of the uterus, rejection of the semi-allogeneic fetus does not occur. A state of permanent natural immunological tolerance, during which the body does not respond to certain antigens expressed by trophoblast cells, while maintaining the ability to respond immunologically to other immunogens is the opposite phenomenon of the immune response, it is acquired by the body during its development and is not genetically determined. Purpose - to analyze the phasing of immunological changes in the mother’s body, which are aimed at the development and preservation of pregnancy, to specify their role in the correct flow of placental waves, prevention of the development of placental dysfunction and obstetric complications associated with it. A review of modern medical literature on the processes of immunological changes during trophoblast invasion and placentation in early pregnancy is given. For a more detailed understanding, the influence of each link of the immune response in the process of developing immune tolerance was analyzed. It has been established that for the development of a normal pregnancy there is a genetically programmed immune mechanism that ensures a decrease in the local and systemic immune response to the semi-alien implanted blastocyst, embryo and fetus. This is achieved through the step-by-step course of three phases of immunological shifts: the unfolded immune conflict; suppression of the immune response and intense immune conflict. The physiological course of gestation and the development of the placenta, in which the balance between the processes of neoangiogenesis and apoptosis is maintained, is ensured by adequate expression of HLA-G locus molecules by trophoblast cells, inhibition of Th1-type cytotoxic reactions against placenta cells by the mother's body. Analyzed changes in the cytokine balance, which shifts towards immunosuppressive cytokines, which suppress cellular immune reactions and stimulate the production of blocking antibodies, the quantitative composition of which can be considered decisive when carrying a genetically foreign fetus. Consequently, a relative secondary cellular immunodeficiency is formed, which is mainly due to a deficiency of circulating T-helper/inducers, a decrease in the CD4/CD8 immunoregulatory index and suppression of the functional activity of the T-cell immune system. It has been proven that impaired immunological tolerance, trophoblast invasion and vascular remodelling processes controlled by the maternal immune system at the local and systemic levels lead to early reproductive losses, premature birth, placental dysfunction, and are associated with fetal growth retardation syndrome, pre-eclampsia and other complications. No conflict of interests was declared by the authors.

The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis.

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH).Method and materialsWe analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy).ResultsAnalysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D’ = 0.92 vs D’ = 0.50 respectively; P = 1.3x10-8). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 – 17.4) U/mL vs 21.3 (16.5 – 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 – 44.8) U/mL vs 8.8 (6.1 – 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies.ConclusionThis study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1.

Association of the HLA-G locus genetic polymorphism and the susceptibility to contract systemic lupus erythematosus expressed in some clinical manifestations

Association of the HLA-G locus genetic polymorphism and the susceptibility to contract systemic lupus erythematosus expressed in some clinical manifestations

HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives.

The non-classical HLA-G is a well-known immune-modulatory molecule. In physiological condition, HLA-G surface expression is restricted to the maternal–fetal interface and to immune-privileged adult tissues, whereas soluble forms of HLA-G are detectable in various body fluids. HLA-G can be de novo expressed in pathological conditions including tumors, chronic infections, or after allogeneic transplantation. HLA-G exerts positive effects modulating innate and adaptive immune responses and promoting tolerance, or detrimental effects inducing immune escape mechanisms. HLA-G locus, in contrast to classical HLA class I gene, is highly polymorphic in the non-coding 3′ untranslated region (UTR) and in the 5′ upstream regulatory region (5′ URR). Variability in these regions influences HLA-G expression by modifying mRNA stability or allowing posttranscriptional regulation in the case of 3′ UTR or by sensing the microenvironment and responding to specific stimuli in the case of HLA-G promoter regions (5′ URR). The influence of genetic variations on the expression of HLA-G makes it an attractive biomarker to monitor disease predisposition and progression, or response to therapy. Here, we summarize the current knowledge, efforts, and obstacles to generate a general consensus on the correlation between HLA-G genetic variability, protein expression, and disease predisposition. Moreover, we discuss perspectives for future investigation on HLA-G genotype/expression in association with disease predisposition and progression.

HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study

Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present.Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population.One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark.Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pc = 1 × 10−3; OR:3.5, 95%CI: 1.8–6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect.These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.

A pilot study on Hla-G locus control region haplotypes and cervical intraepithelial neoplasias

Human papillomavirus (HPV) can induce cervical intraepithelial neoplasias (CIN) grades 1, 2 and 3. Untreated, these lesions may progress to cervical cancer (CC) which is the third most common cancer in women worldwide. HLA-G plays an immunotolerant role in the immune response. The aim of this study was to characterize the configuration of SNPs located at the distal promoter of HLA-G in patients with CIN2 and CIN3 and control women. The study sample was composed of 207 women as follows: 73 diagnosed with CIN2 lesions, 56 with CIN3 and 78 healthy control women. Genotyping was performed by sequence base typing. Eleven haplotype configurations subdivided in two main haplogroups (H1dist and H2dist), were characterized and compared between patients and controls. The haplotypes H1.1Dist (GAGAACGC) and H2.1Dist (AGGTACAC) were more frequent in Euro-Descendants as well as in Brazilian Mixed. Nevertheless, the haplotype H2.1Dist standed out as a susceptibility haplotype in Brazilian Mixed patients while the H1.1Dist presented a protector effect in this same ethnic group. Whether such LCR haplotype configurations can impact on HLA-G gene expression levels in women who developed cervical intraepithelial neoplasia is still unknown and it is of utmost importance that more investigation on this field be pursued.

Hypoxia inducible factor-1 mediates the expression of the immune checkpoint HLA-G in glioma cells through hypoxia response element located in exon 2.

HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G. We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2′deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G. Both treatments enhanced the amount of HLA-G mRNA and protein in HLA-G negative U251MG glioma cells. Electrophoretic Mobility Shift Assays and luciferase reporter gene assays revealed that HLA-G upregulation depends on Hypoxia Inducible Factor-1 (HIF-1) and a hypoxia responsive element (HRE) located in exon 2. A polymorphic HRE at −966 bp in the 5′UT region may modulate the magnitude of the response mediated by the exon 2 HRE. We suggest that therapeutic strategies should take into account that HLA-G expression in response to hypoxic tumor environment is dependent on HLA-G gene polymorphism and DNA methylation state at the HLA-G locus.

A distant trophoblast-specific enhancer controls HLA-G expression at the maternal–fetal interface

HLA-G, a nonclassical HLA molecule uniquely expressed in the placenta, is a central component of fetus-induced immune tolerance during pregnancy. The tissue-specific expression of HLA-G, however, remains poorly understood. Here, systematic interrogation of the HLA-G locus using massively parallel reporter assay (MPRA) uncovered a previously unidentified cis-regulatory element 12 kb upstream of HLA-G with enhancer activity, Enhancer L Strikingly, clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9-mediated deletion of this enhancer resulted in ablation of HLA-G expression in JEG3 cells and in primary human trophoblasts isolated from placenta. RNA-seq analysis demonstrated that Enhancer L specifically controls HLA-G expression. Moreover, DNase-seq and chromatin conformation capture (3C) defined Enhancer L as a cell type-specific enhancer that loops into the HLA-G promoter. Interestingly, MPRA-based saturation mutagenesis of Enhancer L identified motifs for transcription factors of the CEBP and GATA families essential for placentation. These factors associate with Enhancer L and regulate HLA-G expression. Our findings identify long-range chromatin looping mediated by core trophoblast transcription factors as the mechanism controlling tissue-specific HLA-G expression at the maternal-fetal interface. More broadly, these results establish the combination of MPRA and CRISPR/Cas9 deletion as a powerful strategy to investigate human immune gene regulation.

Long-range chromatin interactions control trophoblast-restricted HLA-G expression during pregnancy (IRM6P.657)

Abstract Human pregnancy poses an immunological paradox: at the fetal-maternal interface, semi-allogeneic fetal extravillous trophoblasts (EVT) invade the uterine mucosa without being rejected by the maternal immune system. HLA-G is a nonclassical MHC class I molecule specifically expressed on the surface of EVT and is believed to be a key to fetus-induced immune tolerance. However, the EVT-specific expression of HLA-G is still poorly understood. A novel enhancer more than 10 kb upstream of HLA-G, Enhancer L, was discovered via dissection of the HLA-G locus using a Massively Parallel Reporter Assay (MPRA). DNase I Hypersensitive Site (DHS) mapping, Chromosome Conformation Capture (3C) and reporter gene assays established Enhancer L as a cell type-specific enhancer that loops into the HLA-G classical promoter. Strikingly, deletion of Enhancer L using a CRISPR/Cas9 dual guide approach results in complete ablation of HLA-G expression. Saturation mutagenesis of Enhancer L revealed the existence of motifs for transcription factors paramount in trophoblast development. Two of them, GATA2 and CEBPB, associate with Enhancer L and the HLA-G classical promoter, and are absolutely required for HLA-G expression. Interestingly, progesterone upregulates HLA-G, as well as GATA2, via a nonclassical membrane progesterone receptor complex in trophoblasts. These findings shed light on the mechanism by which HLA-G is specifically expressed in invasive trophoblasts during pregnancy.

HLA-G expression levels influence the tolerogenic activity of human DC-10.

Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule with known immune-modulatory functions. Our group identified a subset of human dendritic cells, named DC-10, that induce adaptive interleukin-10-producing T regulatory type 1 (Tr1) cells via the interleukin-10-dependent HLA-G/ILT4 pathway. In this study we aimed at defining the role of HLA-G in DC-10-mediated Tr1 cell differentiation. We analyzed phenotype, functions, and genetic variations in the 3' untranslated region of the HLA-G locus of in vitro-differentiated DC-10 from 67 healthy donors. We showed that HLA-G expression on DC-10 is donor-dependent. Functional studies demonstrated that DC-10, independently of HLA-G expression, secrete interleukin-10 and negligible levels of interleukin-12. Interestingly, DC-10 with high HLA-G promote allo-specific anergic T cells that contain a significantly higher frequency of Tr1 cells, defined as interleukin-10-producing (P=0.0121) or CD49b(+)LAG-3(+) (P=0.0031) T cells, compared to DC-10 with low HLA-G. We found that the HLA-G expression on DC-10 is genetically imprinted, being associated with specific variations in the 3' untranslated region of the gene, and it may be finely tuned by microRNA-mediated post-transcriptional regulation. These data highlight the important role of HLA-G in boosting DC-10 tolerogenic activity and confirm that interleukin-10 production by DC-10 is necessary but not sufficient to promote Tr1 cells at high frequency. These new insights into the role of HLA-G in DC-10-mediated induction of Tr1 cells provide additional information for clinical use in Tr1- or DC-10-based cell therapy approaches.

Association of HLA-G 14bp INS/DEL Polymorphism with brain morphology in Schizophrenia

Background Multiple lines of evidence have implicated dysregulated immune processes in the pathogenesis of schizophrenia. Being an important immuno-modulatory molecule, Human Leukocyte Antigen (HLA)-G plays a pivotal role in successful pregnancy. Altered expression of HLA-G due to environmental and genetic variations not only lead to pregnancy complications but also a range of immunopathologies, some of which are being considered to confer risk for schizophrenia. One of the polymorphic marker, 14bp insertion/deletion (INDEL) located within the 3 UTR region of the HLA-G locus in Chr.6p21.3 is associated with HLA-G expression and function. The current study is aimed at analysing the role of 14bp polymorphism and the impact of feto-maternal compatibility/incompatibility at this locus on the risk of schizophrenia. In addition, the effect of 14bp INDEL on brain structure alterations in schizophrenia patients was also investigated.

141-P: IMPACT OF HLA-G EXON 8- INDEL POLYMORPHISM AND SOLUBLE LEVELS ON TYPE 1 DIABETES

Aim Type 1 Diabetes (T1D) association with HLA-DRB1∗03 /∗04 is reported worldwide, however not all DR3 or DR4 haplotypes predispose equally. HLA-G, a nonclassical class I molecule having immunomodulatory potential is implicated in the pathogenesis of autoimmune diseases, infections, cancers and transplantation. A 14bp INDEL in the 3’-UTR of the HLA-G exon 8 influences the mRNA stability and soluble HLA-G (sHLA-G) levels. Studies on Psoriasis, SLE and RA reported differential ability of 14bp genotypes to counteract inflammation and a potential role of sHLA-G was suggested. Induction of HLA-G expression on dendritic cells from diabetic subjects mediated the inhibition of autologous T cell activation, indicating role in diabetes pathogenesis. Conditional analysis among 2400 T1D affected families, revealed novel association around the HLA-G locus. Presently, we aimed to investigate the role of 14bp INDEL polymorphism in T1D patients from North India. Methods 78 T1D cases and 70 ethnically matched healthy controls (HCs) were tested by PCR-SSP /sequencing. Results The +14bp allele (53% vs 47%) and Genotype +/+14 bp (31% vs 20.5%) were observed more frequently in T1D cohort than in HCs. The study cohort was sub grouped on basis of HLA-DRB1∗03 presence or absence. Among the DR3+ve group, the 14bp +/+ genotype was more common in patients (28% vs 9%) and 14bp-/- was more frequent in the DR3+ve HCs (55% vs 28%). In the DR3-ve cohort, higher number of T1D cases carried the +/+ genotype (43% vs 22%, P=0.04). The 14bp genotypes may lead to variability in the sHLA-G levels in T1D patients which might modulate the autoreactive T cells. Further, the regulation of HLA-G gene expression is also influenced by the G/C SNP at +3142 (of 3’UTR), a putative miRNA binding site. Conclusions Preliminary findings indicate role of 14bpINDEL polymorphism in diabetes pathogenesis. Investigations on sHLA-G levels and +3142 G/C SNP polymorphism is currently ongoing and results will be correlated with above findings and presented.

Frequency of null allele of HLA-G Locus in East Azarbayjan patients with recurrent miscarriage

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The HLA-G low expressor genotype is associated with protection against bipolar disorder

Implication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc=0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc=0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed.

89-P

Aim The clinical behavior of the human urinary bladder papillary transitional cell carcinoma (TCC) probably results from a complex interaction between carcinogenic insults and host resistance during the patient’s life. While the main recognized risk factor is smoking, little information exists about the susceptibility to TCC development. The human leukocyte antigen E (HLA-E) molecule plays an important role both as a modulator of natural killer (NK) cell activity by interacting with CD94-NKG2A receptor in the innate immunity pathway and as an antigen-presenting molecule triggering a specific immune response, thus it may influence tumor immune surveillance. The aim of this study was to explore a possible influence of five HLA-E variation sites, one in exon 2 at position 424 (rs1059510), three at exon 3 in the positions 756 (rs1264457), 887 (rs41560815) and 906 (rs41562314) and one in exon 4 at the position 1691 (rs17875370), on the susceptibility to urinary bladder TCC development and progression in Brazilian subjects. Methods These variation sites were evaluated by means of direct sequencing of PCR products using an ABI3100 Genetic Analyzer. On this bases, 105 healthy donors and 73 patients with historical of TCC, both from Ribeirao Preto City, Southeast Brazil, were evaluated for the variation sites described above. Results Only two of the five variation sites evaluated were polymorphic in an admixed population such as Brazilians, i.e., positions +424 and +756. Considering these, the allele and genotype distributions in patients and controls were very similar and no significant difference was detected, even when patients were compared as a whole or stratified into high and low grade tumor patients. Conclusions In conclusion, although previous associations have been described evolving neighboring genes such as HLA-A and HLA-G, the HLA-G locus seems to be not associated with TCC susceptibility and/or progression to aggressive tumors.

New evidence for balancing selection at the HLA-G locus in South Amerindians

HLA-G is a non-classical HLA (Human Leukocyte Antigen) molecule characterized by limited tissue distribution under normal physiological conditions and low variability at both DNA and protein levels. Several studies suggest that HLA-G could play a role, as an immunoregulatory molecule, in situations as diverse as transplantation, cancer, viral infections and inflammatory diseases. A total of 237 individuals from 21 South American tribes speaking nine different linguistic families were studied in relation to the 14 bp insertion/deletion polymorphism at the HLA-G gene. A consistent (seven in nine) excess of heterozygosity in samples classified by language was obtained. Our data supply evidences for balancing selection acting at the HLA-G 14 bp INDEL region. Enhanced fetal survival in a pathogen-rich environment may account for these findings.

A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution

HLA-G molecule plays an important role on immune response regulation and has been implicated on the inhibition of T and natural killer cell cytolytic function and inhibition of allogeneic T-cell proliferation. Due to its immune-modulator properties, the HLA-G gene expression has been associated with the outcome of allograft and of autoimmune, infectious, and malignant disorders. Several lines of evidence indicate that HLA-G polymorphisms at the 5'-upstream regulatory region (5' URR) and 3'-untranslated region (3' UTR) may influence the HLA-G expression levels. Because Brazilians represent one of the most heterogeneous populations in the world with the widest HLA-G coding region variability already detected among the studied populations, a high level of variability and haplotype diversity would be expected in Brazilians. On this basis, the 5' URR, coding, and 3' UTR variability were evaluated in a Brazilian series consisting of 100 healthy bone marrow donors, as well as the linkage disequilibrium pattern along the gene and the extended haplotypes encompassing several gene segment variations. The HLA-G locus seems to present six different HLA-G lineages showing functional variations mainly in nucleotides of the regulatory regions. Differences were observed at the 5' URR in positions that either coincide with or are close to transcription factor-binding sites and at the 3' UTR mainly in positions that have already been reported to influence HLA-G mRNA availability. We report several lines of evidence for balancing selection acting on the regulatory regions, which may indicate that these HLA-G lineages may be related to the differential HLA-G expression profiles.

HLA-G gene polymorphisms in spontaneous miscarriage

OBJECTIVE: The HLA-G is supposed to be important modulator of the immune rejection to the semiallogenic embryo. Certain HLA-G gene polymorphisms can affect genetic and amino acid sequence and superficial protein expression, which may be associated to recurrent miscarriage. The aim of this study was to analyze the presence of polymorphisms in certain regions of the HLA-G locus in the foetal trophoblast of spontaneous unexplained miscarriages compared to abortions with abnormal karyotype.

Study of the structure and impact of human leukocyte antigen (HLA)-G-A, HLA-G-B, and HLA-G-DRB1 haplotypes in families with recurrent miscarriage

A 14-base pair (bp) long insertion (ins) /deletion (del) polymorphism in exon 8 in the 3′-untranslated region of the human leukocyte antigen (HLA)-G gene is suggested to affect transcription of the gene. Carriage of the G14bp ins is associated with low levels of soluble HLA-G and increases the risk of recurrent miscarriage (RM). Due to existence of strong linkage disequilibrium (LD) in the HLA region, the primary susceptibility genes for RM in the HLA-G region have not yet been identified. HLA-A, -B, -DRB1, and -G14bp polymorphisms were investigated in 29 Caucasian families with two or more siblings suffering unexplained RM. Strong positive LD was detected between the G14bp ins and HLA-A*01, -A*11, -A*31, -B*08, and DRB1*03, whereas strong negative LD was found between G14bp ins and HLA-A*02, -A*03, and -A*24. The frequency of haplotypes with HLA-G14bp ins inherited from the mother was significantly increased in probands with RM ( p = 0.05). The increased compatibility between probands and their mothers for maternal G14 ins positive haplotypes suggests that maternal-fetal compatibility for chromosomal segments adjacent to HLA-G locus is a risk factor for female offspring to experience RM in their later reproductive life.

HLA-G*0105N and HLA-G 14 bp dimorphisms in exon 8 in four distinct populations in mainland China

In this study, we investigated human leukocyte antigen (HLA)-G*0105N and the 14 bp deletion/insertion polymorphism in exon 8 of the HLA-G gene in 600 individuals from two southern Chinese Han populations (Hunan Han and Guangdong Han) and two northern Chinese populations (Inner Mongolia Han and Inner Mongolia Mongol), we also studied the linkage disequilibrium (LD) between HLA-G and HLA-A locus in these four populations. Our data showed that (1) the allele and haplotype frequencies of HLA-G and HLA-A loci did not differ significantly between the two southern Chinese Han populations, and showed remarkable homogeneity in the two northern Chinese populations; (2) HLA-G*0105N had significantly higher frequencies in the two northern Chinese populations with a frequency of 10.1% in the Inner Mongolia Han population, HLA-G 14 bp deletion/insertion frequency did not differ significantly between the southern and northern Chinese populations; (3) Ewens-Watterson homozygosity statistics at HLA-G*0105N, HLA-G 14 bp deletion/insertion polymorphism and HLA-A were consistent with neutral expectations for all populations; (4) HLA-G*0105N allele harbored the HLA-G 14 bp insertion in exon 8 and was linked to HLA-A*30, five HLA-G*0105N homozygotes were detected in the four populations; (5) haplotypes HLA-A*30-HLA-G*0105N and HLA-A*02-HLA-G 14 bp deletion were in significant LD across four populations, other LD patterns were more population-specific. Our data suggest that HLA-A*30-HLA-G*0105N-HLA-G 14 bp insertion is a conserved haplotype, the ethnic and/or geographic difference in HLA-G*0105N and HLA-G 14 bp distribution could largely be attributable to demographic factors other than selection. The LD patterns uncovered will facilitate the understanding of HLA-G role in associations previously described between HLA-A subregion and diseases.