Killer Cell Immunoglobulin-like Receptors Gene Profiles Research Articles

O-034 Specific KIR gene profiles and recurrent implantation failure

Abstract Study question Is there a link between killer cell immunoglobulin-like receptors (KIRs) genes, haplotypes, or genotypes and recurrent implantation failure (RIF)? Summary answer The KIRAA1 genotype significantly increases the risk of RIF. The presence of the full-length receptor KIR2DS4norm in KIRAA haplotype patients is indicative of RIF development. What is known already KIRs are expressed by a subset of uterine natural killer cells (uNK cells). The KIRs family consists of 16 genes with high polymorphism that are divided into two main haplotypes: KIRAA and KIRBx. The KIRAA haplotype consists mostly of inhibitory KIRs and only one activating receptor, KIR2DS4, whose function is uncertain, whereas the Bx haplotype has a diverse gene composition, with a focus on activating receptor genes. The primary difference is in the balance of KIRs, which can activate or inhibit uNKcells’ ability to produce components required for embryo-implantation, and hence they are thought to being implicated in RIF. Study design, size, duration A three-year observational cohort research was conducted at a private infertility centre. A total of 82 patients were genotyped for activating or inhibiting KIR genes. The study included 60 ovarian normo-responders under the age of 40, with 28 women with repeated implantation failure serving as the study group and 32 as controls. Participants/materials, setting, methods DNA was extracted from blood samples of all participants, including RIF patients and controls. The 16 KIR genes were investigated utilizing PCR with Sequence-Specific Primer (SSP) technique. Individual KIR gene profiles, KIRAA and KIRBx haplotypes, and their unique genotypes were detected by software analyses of the collected data based on the reaction pattern when compared to patterns associated with described KIR gene sequences. All data were statistically analysed with the Fisher Exact Test. Main results and the role of chance The frequencies of the two main haplotypes, KIR AA and KIR Bx, were 28% and 72%, respectively. Patients with more inhibitory KIR genes (haplotype KIR AA) had a higher rate of RIF (60% vs 40% in controls; P = 0.2) than those with KIR Bx phenotypes (37.5% RIF vs 62.5% controls; p = 0.026). Further analysis of KIR AA revealed two genotypes: KIR AA 1 (31.82%) and KIR AA195 (68.18%). The KIR2DS4 locus in the full-length receptor (KIR2DS4-norm) was only expressed in KIR AA1. The distribution of RIF occurrences in the two different genotypes demonstrates a significant increase in the number of RIF in the possessors of KIR AA1 (75% vs 15%, p = 0.01), with no significant difference between the two groups in the KIR AA195. Limitations, reasons for caution The study encompasses small samples but the association strength was noticeably high, which confers the findings more confidence. Wider implications of the findings These findings imply that women with a high proportion of inhibited KIR genes (haplotype KIR AA) and KIR2DS4norm are more likely to develop RIF. Trial registration number NA

Clinical and histopathological changes in different KIR gene profiles in chronic HCV Romanian patients.

Hepatitis C virus (HCV)-infected individuals may have a faster progression of liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development when influenced by host, viral and environmental factors. Hepatitis C virus disease progression is also associated with genetic variants of specific killer cell immunoglobulin-like receptors (KIRs) and genes of the major histocompatibility complex (MHC). The aim of the present study was to correlate clinical, virologic and biochemical parameters and to evaluate the possible influence of KIR genes and their HLA class I ligands in patients infected with hepatitis C virus. The present study analysed a total of 127 chronic HCV-infected patients for various biochemical and genetics factors that can influence disease progression and prognosis. Liver function parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), direct bilirubin (DB), alpha-fetoprotein (AFP), HCV RNA levels and fibrosis indices were analysed using well-established biochemical methods. At the same time, KIR and HLA genotyping was performed using a polymerase chain reaction sequence-specific primer technique. Analysis of HLA class I and HLA ligands revealed that HLA-C*12:02 and HLA-A3 and HLA-A11 were positively associated with the F3-F4 fibrosis group (p=.026; OR=8.717, CI=1.040-73.077; respectively, p=.047; OR=2.187; 95% CI=1.066-4.486). KIR2DL2-positive patients had high median levels of AST after treatment and direct bilirubin levels when compared to KIR2DL2-negative patients (p=.013, respectively, p=.028). KIR2DL2/KIR2DL2-C1C1 genotype was associated with increased AST, ALT and GGT levels. A higher GGT level was also observed in KIR2DS2-C1-positive patients when compared to KIR2DS2-C1-negative patients. The present research demonstrates several links between specific clinical, virologic and biochemical parameters and the expression of KIR genes and their HLA ligands in HCV-infected patients. These connections should be taken into account when considering disease development and treatment.

KIRs gene content diversity in Iranians with urothelial bladder cancer.

Natural killer cells (NK) are the first arm of the innate immune system in defense against tumor and infection. 16 distinct Killer-cell immunoglobulin-like receptors (KIRs) are involved in orchestrating NK cell function. The KIR family contains 14 genes and 2 pseudogenes. Six of these receptors are activating (aKIR) and the remaining receptors are inhibitory KIRs (iKIR), that interact with MHC-I molecules; producing signals which stop NK cell function. In the current study, we have investigated the genomic diversity of KIRs and determining the A and B haplotypes as well as Bx subsets in 119 patients with bladder cancer and 200 healthy controls to find out if there is an association between KIR system and susceptibility to bladder cancer. Polymerase chain reaction with sequence specific primers (SSP-PCR) typing system was used to determine the KIR gene profile. The results implicated decreased frequency of inhibitory KIR2DL2 and activating KIR2DS2 while increased frequency of CxT4 genotypes in patients compared with healthy controls. Among Bx subsets, the CxT4 gene cluster is more frequent in bladder cancer patients compared to controls. Our results provide a conclusion that KIR2S2 and KIR2L2 may play a protective role against bladder cancer development while the CxT4 gene cluster may underlie susceptibility to bladder cancer in Iranian population.

Killer cell immunoglobulin-like receptor and human leukocyte antigen gene profiles in a cohort of HIV-infected Mexican Mestizos.

Killer cell immunoglobulin-like receptors (KIRs) represent the most polymorphic genes responsible for natural killer cell function, while human leukocyte antigen (HLA) class I molecules define and restrict cytotoxic T lymphocyte responses. Specific KIR, HLA, or KIR-HLA combinations have been implicated in the outcome of human immunodeficiency virus (HIV) disease. The remarkable polymorphism of KIR and HLA genes warrants descriptive gene frequency studies in different populations, as well as their impact on HIV disease progression in different immunogenetic contexts. We report KIR and HLA class I gene profiles of 511 unrelated HIV-infected Mexican Mestizo individuals from 18 states for whom genetic ancestry proportions were assessed. KIR and HLA gene profiles were compared between individuals from the north and central-south regions of the country and between individuals with higher European (EUR) or Amerindian (AMI) genetic ancestry component. A total of 65 KIR genotypes were observed, 11 harboring novel KIR gene combinations. A total of 164 HLA alleles were observed: 43 HLA-A, 87 HLA-B, and 34 HLA-C. Differences in the distribution of 12 HLA alleles were observed between individuals with higher AMI or EUR ancestry components (p<0.05, q<0.2). After correcting for genetic ancestry, only individual HLA alleles were associated with HIV disease progression, including a novel association with A*02:06, an Amerindian HLA allele associated with lower CD4+ T cell counts. No KIR effects were significant. Our results highlight the advantages of considering a detailed genetic stratification within populations when studying genetic profiles that could be implicated in disease-association studies.

Profile of killer cell immunoglobulin-like receptor and its human leucocyte antigen ligands in dengue-infected patients from Western India.

Killer cell immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells (NKs). Qualitative and quantitative differences in the type and the number of KIRs expressed on NK cells affect its activation which would influence the outcome of the disease. In this study, 114 hospitalized cases of dengue [82 dengue fever (DF) and 32 dengue haemorrhagic fever (DHF) cases] and 104 healthy controls (HC) without no known history of hospitalization for dengue-like illness were investigated for their KIR gene profile to find out the association of KIR genes with dengue disease severity. KIR gene profile was investigated using duplex sequence-specific priming polymerase chain reaction-based typing system. The results revealed a higher frequency of KIR3DL1 gene [P=0.0225; odds ratio (OR) 4.1 95% confidence interval (CI) 1.1-14.8] and lower frequency of KIR3DS1/3DS1 genotype [P=0.0225; OR 0.24 95% CI (0.068-0.88)] in DF cases compared to HC. Immunoglobulin-like receptor gene frequencies were not different between DHF and DF or HC. The results suggest that KIR3DL1/KIR3DS1 locus might be associated with the risk of developing DF.

Predominance of B haplotype associated KIR genes in Tamil Speaking Dravidians

Killer cell immunoglobulin like receptors (KIRs) are a group of activating (aKIRs) and inhibitory receptors (iKIRs) expressed on subsets of lymphoid cells. Their interaction with HLA class I molecules modulate the innate and adaptive immune response against infections and malignancies. KIR haplotypes varies in gene content and also at allelic level, thereby, distinguishing individuals and populations. Hence, the present study is aimed to determine the KIR gene diversity in Piramalai Kallar (PK) population of South India. The PK population shows diverged KIR gene frequencies and novel haplotypes than other South Indian populations. 52 different KIR gene profiles were identified and 18 of them were new in this population. In phylogenetic analysis the study population is positioned between African and Iranian population in the clade, which supports the South African ancestry of Indian population.

Killer cell immunoglobulin-like receptor (KIR) locus profiles in the Tunisian population

Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activatory receptors that are expressed by most natural killer (NK) cells. The KIR gene family is polymorphic: genomic diversity is achieved through differences in gene content and allelic polymorphism. The number of KIR loci has been reported to vary among individuals, resulting in different KIR haplotypes. In this study we report the genotypic structure of KIRs in 267 unrelated and healthy Tunisian subjects by polymerase chain reaction-sequence-specific primer (PCR-SSP) method.All 16 KIR genes were observed in the population with different frequencies; framework genes KIR3DP1 and KIR3DL2 and the nonframework genes KIR2DL1 and KIR2DP1 were present in all individuals. A total of 26 different KIR gene profiles and 54 subgenotypes were observed in the tested population samples. Genotype 1, with a frequency of 36.6%, is the most commonly observed in the Tunisian population.Our results showed that the Tunisian population possesses the previously reported general features of the Caucasian as well as African populations, with some additional interesting differences.Such knowledge of the KIR gene distribution in populations is very useful in the study of associations with diseases and in selection of donors for haploidentical bone marrow transplantation.

KIR gene content does not contribute to susceptibility to Graves' disease.

Killer cell immunoglobulin-like receptors (KIR) are expressed on NK cells and a subset of T cells. The variable KIR receptors along with their ligands, HLA class I, influence risk for autoimmune and malignant diseases. To investigate the KIR gene profiles in relation to susceptibility to Graves' disease in patients with ophthalmopathy. KIR genes profiles were analyzed in 90 patients presenting Graves' disease with ophthalmopathy representing upper eyelid retraction, swelling, redness, conjunctivitis, and bulging eyes and were compared with the KIR gene profiles of 112 healthy controls. The presence and absence of 11 variable KIR genes were characterized using a gene-specific PCR typing system. There was no significant difference in the distribution of KIR gene profiles between patients and controls. Our data show that none of the KIR genotypes contribute in susceptibility to Graves' disease; although the role of HLA ligand remains to be characterized.

Study of the KIR gene profiles and analysis of the phylogenetic relationships of Rajbanshi population of West Bengal, India

The natural killer (NK) cells have distinct receptors called killer cell immunoglobulin-like receptors (KIR) which are responsible for regulating NK cell responses to infections and malignancy. The extensive variations in the number and type of KIR genes can be used as a tool to understand the differentiation of populations and also for tracing genetic background. In this study, we have aimed to analyze the KIR gene polymorphism in the Rajbanshi population of West Bengal, India. To our knowledge this is the first report on the KIR gene polymorphism in the Rajbanshis, a population widely distributed in the Terai and Dooars region of West Bengal, India. Herein, we have studied the gene distribution of 14 KIR genes (KIR3DL1-3DL3, KIR 2DL1-2DL5, 2DS1-2DS5 and 3DS1) and two pseudogenes (KIR3DP1 and 2DP1). The gene frequencies and genotypic frequencies were calculated, based on which statistical analyses were performed. The presence of a considerable number of genotypic profiles suggests substantial diversity in the KIR gene pool of the Rajbanshis in the region studied. Apart from the framework genes (KIR2DL4, 3DL2, 3DL3 and 3DP1) present in all the individuals, the gene frequencies of other KIR genes varied between 0.84 and 0.15. Moreover the KIR polymorphisms of the Rajbanshis were also compared with that of available published data of the populations of other ethnicities. Though the Rajbanshi population showed a tendency to cluster with other Indian population based on KIR gene frequencies, the influence of Tibeto-Burman Lineage on their KIR genotypic profiles cannot be overlooked. Furthermore, evidences from previously published data on Y chromosome haplogroup diversity study on Rajbanshis support the view. Our results will not only help to understand the genetic background of the Rajbanshi population, but also in tracing the population migration events in the North-Eastern part of India and in illustrating the extensive genetic admixture amongst the different linguistic groups of the country and also in KIR-related disease researches.

The distribution of genetic diversity of KIR genes in the Chinese Mongolian population

Killer cell immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and as such regulate their response against infection and malignancy. KIR genes are variable in gene content and type, which results in different KIR haplotypes, and can be used to discriminate individuals and populations from different regions or ethnic groups. In the present study, we represent the first report on the KIR gene frequency and content diversities of 14 KIR genes (KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) and 2 pseudogenes (KIR3DP1 and 2DP1) in the Chinese Mongolian population. The 16 detected KIR genes were all observed. All the individuals were typed positive for the four framework genes KIR3DL3, 3DL2, 2DL4 and the pseudogene KIR3DP1, as well as for the pseudogene KIR2DP1. The observed carrier gene frequencies (OF) of the other KIR genes ranged from 16% at the KIR2DL2 locus to 93% at the KIR3DL1 locus. Over all, 48 different gene profiles were found in the study population and the most commonly observed KIR gene profile with a frequency of 14% consisted of KIR2DL4, 3DL2, 3DL3, 2DP1, 3DP1, 2DL1, 2DL3 and 3DL1 which belongs to the AA genotype. Principal component analysis (PCA) and the dendrogram illustrated the genetic distances between our study population and previously published populations from other ethnic groups or regions. The results of the present study show that the KIR gene family is highly polymorphic and can be a valuable tool for enriching the Chinese ethnical gene information resources, for anthropological studies, as well as for KIR gene related disease research.

Diversity distributions of killer cell immunoglobulin-like receptor genes and their ligands in the Chinese Shaanxi Han population

In the present study, 17 killer cell immunoglobulin-like receptors (KIR) genes and KIR ligands (human leukocyte antigen [HLA] –A and -B) were detected by using a polymerase chain reaction–sequence-specific primer (PCR-SSP) method in 104 unrelated healthy Han individuals living in Shaanxi province, China. The observed carrier frequencies of the 12 KIR genes ranged from 0.14 to 0.96. KIR2DL4, 3DL2, 3DL3, 2DP1 and 3DP1 were found to be present in every individual. A total of 51 different KIR gene profiles were identified, in which 11 gene profiles exclusively belonged to the study population. Neighbor-joining phylogenetic tree between the studing population and its neighboring ethnic groups was constructed using the observed carrier frequencies of 13 KIR loci. The phylogenetic tree shows that the Shaanxi Han population, Han populations in different regions, Yi, Japanese, and Koreans were in the same cluster. KIR/HLA relationships show that KIR3DS1 −/3DL1 +/Bw4 + was the most common association in the population. In conclusion, the present study findings reveal the high polymorphism of KIRs in the Shaanxi Han population, demonstrate the KIR/HLA association in the study population, and enrich the KIR and HLA gene resources. The obtained KIR data will further the understanding of genetic relationships among populations in different geographic areas, and assist in answering questions regarding KIR/HLA relationships.

Diversity of killer cell immunoglobulin-like receptor genes in Southern Turkey

Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activating receptors expressed by natural killer (NK) cells and regulate NK cells' activity. KIR genes are highly polymorphic markers, characterized by a wide diversity, and can therefore be considered as good population genetic markers. The aim of this study was to determine KIR gene frequencies, ratios of haplotypes and genotypes in Southern Turkey and also to compare the data with other worldwide populations studied previously. The study group consisted of 200 non-related individuals from Southern Turkey. The percentage of each KIR gene in the population group was determined by direct counting. Differences between populations in the distribution of each KIR gene and genotype profile were estimated by two-tailed Fisher Exact test. The most frequent non-framework KIR genes detected in Southern Turkey population were: KIR 2DL1 (97%), KIR 3DL1 (91%), KIR 2DS4 (92%) and the pseudogene 2DP1 (96%). Fourty different genotypes were found in 200 subjects and AA1 genotype was the most frequent (27%). Among 40 different genotypes, ten of these were described for the first time in this study and were added to the database ( http://www.allelefrequencies.net ) numerized as genotype ID from 400 to 409. Gene frequencies and found genotypes demonstrated similarity of Southern Turkey's KIR repertoire with the KIR repertoires of Middle East and European population. High variability seen in KIR genome in this region is thought to be formed as a result of migration and settlement of different civilizations in this region and heterogenity formed in time.

Role of human leukocyte antigen, killer-cell immunoglobulin-like receptors, and cytokine gene polymorphisms in leptospirosis

Leptospirosis is an emerging zoonotic disease caused by pathogenic species of the genus Leptospira. It has a broad range of clinical presentations in humans. Although progress has been made in the characterization of the host immune system factors that may affect disease progression and outcome, to date few reports have addressed the role of genetic polymorphisms in the susceptibility to leptospirosis. In this work a group of patients with a history of leptospiral infection and a control group were compared for polymorphisms in the human leukocyte antigen (HLA), in killer-cell immunoglobulin-like receptors (KIR), and in cytokine genes. Alleles in the HLA-A and -B loci were associated with susceptibility, as were the class I haplotype A*01-B*08-Cw*07 and the 8.1 ancestral haplotype (A*01-B*08-Cw*07-DRB1*03-DQB1*02). Single nucleotide polymorphisms in the interleukin (IL)-4 and IL-4Rα genes also had significantly higher frequencies in the patient group. No association was reported between KIR gene profile and leptospirosis. This work highlights the importance of using genetic polymorphisms to better understand the mechanisms involved in the immune response to leptospirosis.

Distinct diversity of KIR genes in three southern Indian populations: comparison with world populations revealed a link between KIR gene content and pre-historic human migrations

By interacting with polymorphic HLA class I molecules, the killer cell immunoglobulin-like receptors (KIR) influence the innate and adaptive immune response to infection. The KIR family varies in gene content and sequence polymorphism, thereby, distinguishing individuals and populations. To investigate KIR diversity in the earliest settlers of India, we have characterized the KIR gene content in three Dravidian-speaking populations (Mollukurumba, Kanikar, and Paravar) from the state of Tamil Nadu, southern India. The activating KIR genes and putative group-B KIR haplotypes were frequent in Paravar and Kanikar, a scenario analogous to those seen previously in other populations of Indian origin, indicating that predominance of group-B KIR haplotypes is the characteristic feature of Indian populations. In contrast, the KIR gene profile of Mollukurumba was more related to Caucasian type. It is not clear whether a local-specific selection or a recent admixture from Iran is responsible for such discrete profile in Mollukurumba. Each southern Indian population had distinct KIR genotype profile. Comparative analyses with world populations revealed that group-B KIR haplotypes were frequent in the natives of India, Australia, and America, the populations associated with those involved in extensive prehistoric human migrations. Whether or not natural selection has acted to enrich group-B KIR haplotypes in these migratory descendants is an issue that requires objective testing.