KIR2DS1 Research Articles

KIR and HLA-C: Immunogenetic regulation of human birth weight

Pregnancies resulting in very small or very large babies are at higher risk of obstetric complications with increased morbidity for both mother and baby. Using data from the Medical Birth Registry of Norway we have shown how human birth weight is still subject to stabilizing selection. Particular combinations of maternal/fetal immune genes have been implicated in pregnancies resulting in a low birth weight baby (<5th birth weight centile). More specifically, an inhibitory maternal KIRAA genotype with a paternally derived fetal HLA-C2 ligand. At the other end of the birth weight spectrum the presence of an activating maternal KIR2DS1 gene is associated with increased birth weight in linear or logistic regression analyses of all pregnancies >5th centile (p=0.005, OR=2.65). Thus, inhibitory maternal KIR combined with fetal HLA-C2 is more frequently associated with low birth weight, whereas activating maternal KIR with fetal HLA-C2 ligand is associated with increasing birth weight. Our findings using the MoBa cohort have replicated the association of KIR and HLA-C seen in poor placentation, and confirm the importance of maternal/fetal immune gene interactions in determining the outcome of pregnancy.

Novel insights in the genomic organization and hotspots of recombination in the human KIR locus through analysis of intergenic regions.

The Killer Immunoglobulin-like Receptor (KIR) proteins constitute a family of highly homologous surface receptors involved in the regulation of the innate cytotoxicity of natural killer (NK) cells. Within the human genome, 17 KIR genes are present, many of which show large variation across the population owing to the high number of allelic variants and copy number variation (CNV). KIR genotyping and CNV determination were used to map the KIR locus in a large cohort of >400 Caucasian individuals. Gene order and structure was determined by sequence-specific polymerase chain reaction of the intergenic regions. In this way, we could show that KIR3DL1 and KIR2DS4 gene variants are linked and that--contrary to current views--the gene KIR2DS5 is only present in the telomeric half of the KIR locus. Our study revealed novel insights in the highly organized distribution of KIR genes. Novel recombination hotspots were identified that contribute to the diversity of KIR gene distribution in the Caucasian population. Next-generation sequencing of the KIR intergenic regions allowed for a detailed single-nucleotide polymorphism analysis, which demonstrated several gene-specific as well as haplotype-specific nucleotides for a more accurate genotyping of this notoriously complex gene cluster.

KIR genotype distribution among patients with multiple myeloma: Higher prevalence of KIR 2DS4 and KIR 2DS5 genes

IntroductionNatural killer (NK) cells possess an antitumor activity against multiple myeloma cells proven by the susceptibility of plasmocytes to NK lysis. In the early stage of MM, the killing of MM cells is mediated by natural cytotoxicity receptors (NRC) and NKG2D-dependent pathway, while in the late stage, NK cells lose their killing potential against MM cells due to the high expression of HLA class I molecules on MM cells. AimThe aim of this paper is to study KIR expression of NK cells in MM patients and in healthy controls, to check for any association between KIR genotypes and MM. MethodsKIR genotype was analyzed in 120 healthy Lebanese individuals and 34 MM patients using the KIR Genotyping SSP kit. ResultsKIR 2DS4*001/002 and KIR 2DS5 were found to be significantly more prevalent among MM patients as compared to controls. For MM patients, the AA, AB, and BB genotype frequencies were, respectively, 38.23%, 47.06% and 14.71% with an A:B ratio of 1.62:1. As for the healthy controls, the AA, AB, and BB genotype frequencies were, respectively, 39.17%, 50%, and 10.83% with an A:B ratio of 1.80:1. ConclusionThe interesting observation of the significant presence of KIR2DS4 and KIR2DS5 genes more among multiple myeloma patients than controls is worth further clinical, translational as well as survival research studies in these cases.

Presence of the full-length KIR2DS4 gene reduces the chance of rheumatoid arthritis patients to respond to methotrexate treatment.

BackgroundKIR genes coding for natural killer cell immunoglobulin-like receptors, KIR, influence the effector and regulatory function of NK cells as well as some subpopulations of T lymphocytes (e.g. CD4+CD28-KIR+) depending on presence of ligands (particularly HLA-C molecules). KIR-KIR ligand interaction may lead to the development of autoimmune disorders, including rheumatoid arthritis (RA). However, their role in the response of RA patients to methotrexate therapy is not known.MethodsKIR genes and KIR-ligand (HLA-C C1/C2 allomorphs) genotyping was performed using the PCR-SSP method in 312 RA patients (179 classified as good responders and 133 as poor responders using DAS28 criteria). Thus, we evaluated the association of KIR genes and HLA-C allomorphs with the response to methotrexate (MTX) treatment.ResultsWe observed that patients possessing the full-length KIR2DS4 (KIR2DS4f) gene had a lower chance of responding in comparison to KIR2DS4f-negative cases. This phenomenon was observed both in erosive disease (ED) and rheumatoid factor (RF) positive and in ED- and RF-negative patients. Interestingly, the observed effect of the KIR2DS4f gene was strongest in individuals possessing medium values (20-33 mm/h) of the erythrocyte sedimentation rate (ESR). Patients with high ESR values had low probability and, in contrast, patients with low ESR had a high probability of MTX response, and the presence of KIR2DS4f did not affect their outcome. Additionally, we show that the KIR2DS4f effect did not depend on the presence of either C1 or C2 allomorphs.ConclusionOur results suggest that the response of RA patients with medium ESR values to MTX treatment may be dependent on the full-length KIR2DS4 gene.

Associations of killer cell immunoglobulin like receptors with rheumatoid arthritis among North Indian population

IntroductionRheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease of unknown etiology. Killer cell immunoglobulin-like receptors (KIR) expressed on surface of natural killer cells and CD28 null T-cells which are present in synovial membrane of RA. The present study has evaluated associations of KIR genes with RA among North Indian population from Uttar Pradesh. Materials and methodsKIR genotypes were determined in 100 RA cases and 100 healthy controls using sequence specific primer polymerase chain reaction (PCR-SSP) method. ResultsRA cases positive for KIR3DS1 (OR=1.17, p-value=0.0498) and KIR2DS2 (OR=2.21, p-value=0.0120) showed risk associations. While, KIR2DL2 (OR=0.40, p-value=0.0026), KIR2DL3 (OR=0.44, p-value=0.0283) and KIR3DL1 (OR=0.32, p-value=0.0012) showed protective associations. Increased incidence of BB genotype (45%) was revealed among cases. Risk association was noted against telomeric region (OR=2.12, p=0.0120) genes for RA. Pair-wise linkage disequilibrium (LD) analysis among RA cases revealed KIR2DS1-2DL1 (D′=0.83, r2=0.36), KIR3DL1-3DS1 (D′=1, r2=0.58) and KIR2DL1-2DL2 (D′=1, r2=0.61) to be in significant LD. KIR3DS1 and KIR2DS3 genes showed significant risk associations among RA patients with extra-articular manifestations (OR=5.14, p-value=0.0018; OR=3.79, p-value=0.0106) and in limited range of motion in affected joints (OR=14.91, p-value=0.0001; OR=2.95, p-value=0.0126). ConclusionThe KIR activating genes have risk association with RA in the present study.

KIR2DS4 promotes HIV-1 pathogenesis: new evidence from analyses of immunogenetic data and natural killer cell function.

Background KIR2DS4 gene variants encode full-length and truncated protein products, with only the former serving as membrane-bound receptors to activate natural killer (NK) cells. We have previously shown that full-length KIR2DS4 was associated with relatively high viral load and accelerated heterosexual HIV-1 transmission. Our objective here was to provide confirmatory data and to offer new insights about the potential mechanisms.Methodology/Principal FindingsMixed models for repeated (longitudinal) outcome measurements on 207 HIV-1 seropositive American youth revealed an association of full-length KIR2DS4 with relatively high viral load and low CD4+ T-cell count (p<0.01 for both). Depending on KIR2DS4 expression (presence or absence) on cell surface, NK cells from 43 individuals with untreated, chronic HIV-1 infection often differed in functional properties, including degranulation and secretion of IFN-γ and MIP-1β. In particular, polyfunctional NK cells were enriched in the KIR2DS4-positive subset.Conclusions/SignificanceFull-length KIR2DS4 promotes HIV-1 pathogenesis during chronic infection, probably through the maintenance of an excessively pro-inflammatory state.

Genetic variations in the KIR gene family may contribute to susceptibility to ankylosing spondylitis: a meta-analysis.

The present meta-analysis of relevant case-control studies was conducted to investigate the possible relationships between genetic variations in the killer cell immunoglobulin-like receptor (KIR) gene clusters of the human KIR gene family and susceptibility to ankylosing spondylitis (AS). The following electronic databases were searched for relevant articles without language restrictions: the Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, the Chinese Biomedical Database (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases, covering all papers published until 2013. STATA statistical software was adopted in this meta-analysis as well. We also calculated the crude odds ratios (OR) and its 95% confidence intervals (95 % CI). Seven case-control studies with 1,004 patients diagnosed with AS and 2,138 healthy cases were implicated in our meta-analysis, and 15 genes in the KIR gene family were also evaluated. The results of our meta-analysis show statistical significance between the genetic variations in the KIR2DL1, KIR2DS4, KIR2DS5 and KIR3DS1 genes and an increased susceptibility to AS (KIR2DL1: OR 7.82, 95% CI 3.87-15.81, P< 0.001; KIR2DS4: OR 1.91, 95% CI 1.16-3.13, P = 0.010; KIR2DS5: OR1.51, 95% CI 1.14-2.01, P = 0.004; KIR3DS1: OR 1.58, 95% CI 1.34-1.86, P< 0.001; respectively). However, we failed to found positive correlations between other genes and susceptibility to AS (all P >0.05). The current meta-analysis provides reliable evidence that genetic variations in the KIR gene family may contribute to susceptibility to AS, especially for the KIR2DL1, KIR2DS4, KIR2DS5 and KIR3DS1 genes.

Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.

Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are ≤ 5th birth weight centile, specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 1316) were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal-activating KIR2DS1 gene was associated with increased birth weight in linear or logistic regression analyses of all pregnancies >5th centile (p = 0.005, n = 1316). Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p = 0.005, odds ratio = 2.65). Thus, maternal KIR are more frequently inhibitory with small babies but activating with big babies. At both extremes of birth weight, the KIR associations occur when their HLA-C2 ligand is paternally inherited by a fetus. We conclude that the two polymorphic immune gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birth weight between two extremes with a clear role for paternal HLA.

1039-LBP: Influence of IL28B (rs12979860) polimorphisms and KIR genes in spontaneous clearance of hepatitis C virus in a multi-ethnic population from Rio de Janeiro (Brazil)

Aim IL-28B (rs12979860) SNP and KIR genes were investigated as candidates for susceptibility to persistent HCV infection or HCV clearance in a sample of Rio de Janeiro (Brazil) population. Methods The PCR-rSSO was employed to identify KIR genes and pseudogenes and 207 chronic hepatitis C (CHC) patients and 45 spontaneously recovered (SR) individuals. Also, IL28B (rs12979860) single nucleotide polymorphism was typed by real-time PCR. Results The carrier frequency (CF) of the following KIR genes was higher in SR compared to CHC: KIR2DL2 (73.3% vs. 46.4%; p = 0.001, OR = 0.33), KIR2DS1 (48.9% vs. 28.0%, p = 0.006, OR = 0.4), KIR3DS1 (46.7% vs. 26.1%, p = 0.006, OR = 0.4). In addition, rs12979860 CC genotype was more frequent in SR (62.2%) than CHC (27.5%; p = 0.0001, OR = 0.2) and this effect was influenced by the presence of some specific genes – KIR2DL2 (44.4% vs. 13.0%, p = 0.0001, OR = 0.2), KIR3DS1 (20.0% vs. 8.2%, p = 0.01, OR = 0.4) and KIR2DS1 (24.4% vs. 8.7%, p = 0.003, OR = 0.3) as well as the absence of some other genes – KIR3DS1 (42.2% vs. 19.3%, p = 0.001, OR = 0.3), KIR2DS1 (37.8% vs. 18.8%, p = 0.005, OR = 0.4) and KIR2DS5 (37.8% vs. 17.9%, p = 0.003, OR = 0.4). Multivariate analysis revealed that IL-28B CC genotype ( p = 0.0001, OR = 5.0, 95%CI = 2.3–11.2), KIR2DL2 ( p = 0.0008, OR = 7.8, 95%CI = 2.3–27.0) and KIR2DS1 ( p = 0.004, OR = 4.5, 95%CI = 1.6–13.3) genes were associated with spontaneous recovery. Conclusions IL28B rs12979860 CC genotype associated with diverse KIR genes strongly enhances spontaneous resolution of HCV infection. These findings support a role for natural killer (NK) cell activation in clearance of HCV, partially mediated by IL28B effect among individuals of Rio de Janeiro (Brazil) population.

The role of KIR2DS1 in multiple sclerosis - KIR in Portuguese MS patients

Killer Immunoglobulin-like Receptor (KIR) genes may influence both resistance and susceptibility to different autoimmune diseases, but their role in the pathogenesis of Multiple Sclerosis (MS) is still unclear. We investigated the influence of KIR genes on MS susceptibility in 447 MS Portuguese patients, and also whether genetic interactions between specific KIR genes and their HLA class I ligands could contribute to the pathogenesis of MS. We observed a negative association between the activating KIR2DS1 gene and MS (adjusted OR=0.450, p=0.030) independently from the presence of HLA-DRB1*15 allele. The activating KIR2DS1 receptor seems to confer protection against MS most probably through modulation of autoreactive T cells by Natural Killer cells.

Role of KIR genes and genotypes in susceptibility to or protection against hepatitis B virus infection in a Turkish cohort

BackgroundKiller cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activating receptors expressed by natural killer (NK) cells and regulate NK cell activity in the innate response against viral infections. The aim of this study was to determine the possibility of KIR genes and genotypes as a candidate for susceptibility to or protection against chronic hepatitis B virus (HBV) infection or spontaneous remission of the infection in a Turkish cohort.Material/MethodsThe present study was carried out on 37 patients with chronic HBV infection, 36 patients in spontaneous remission of HBV infection, and 85 healthy subjects. Sequence-specific oligonucleotide probes analysis was used to investigate 16 KIR genes. All data were statistically analyzed by the Fisher exact test.ResultsThe rate of inhibitory KIR2DL3 (p=0.0) and 3DS1 (p=0.0) were higher in the healthy group than the group composed of chronic HBV patients and patients with spontaneous remission. There were no statistically significant differences between the rate of AA and Bx genotypes of chronic HBV patients and patients with spontaneous remission and the control group (p>0.05).ConclusionsOur results suggest that KIR2DL3 and KIR3DS1 genes could be protector genes for HBV infection and they could be important immuno-genetic markers in determining antiviral immunity in the Turkish population.

Influence of KIR genes and their HLA ligands in susceptibility to dengue in a population from southern Brazil

Killer cell immunoglobulin-like receptors (KIR) form a group of regulatory molecules that specifically recognise human leukocyte antigen (HLA) class I molecules, modulating the cytolytic activity of natural killer cells. The purpose of this study was to investigate the influence of KIR genes and their class I HLA ligands in susceptibility to dengue fever in a population from southern Brazil through a case-control study. One hundred four subjects with confirmed diagnoses of dengue participated in this study, along with a control group of 172 individuals from the same geographic area. HLA and KIR genotyping was performed by polymerase chain reaction with sequence-specific oligonucleotide probes (PCR-SSOP) and with sequence-specific primer (PCR-SSP) techniques, respectively. Data analysis showed significant differences for the KIR2DS1 (54.8% vs 40.7%, P = 0.03), KIR2DS5 (50.0% vs 36.0%, P = 0.03) and KIR2DL5 (76.0% vs 56.4%, P = 0.001) genes. With regard to KIR-ligand pairs, positive associations with dengue were observed in KIR3DS1-Bw4 (45.2% vs 29.7%, P = 0.01), KIR3DL1-Bw4 (80.7% vs 65.1%, P < 0.001), KIR2DL1-C2 (75.0% vs 62.2%, P = 0.03) and KIR2DS1-C2 (40.4% vs 25.6%, P = 0.01) interactions, and a negative association in KIR2DL3-C1/C1 (18.2% vs 33.1%, P = 0.01). Furthermore, the analysis of KIR haplogroups showed a possible protective factor against dengue fever in individuals with the AA genotype. Taken together, these results suggest the existence of genetic predisposition to dengue fever in the population from southern Brazil.

Rituximab response in follicular lymphoma: contributions from KIR 2DS1 and HLA-C

Meeting abstracts Immunotherapeutic response in cancer patients, specifically those attributed to antibody-dependent cellular cytotoxicity (ADCC), may be variable dependent upon an individual's genotype. A recent Eastern Cooperative Oncology Group (ECOG) Phase III clinical trial, E4402, sought to

91-P: KIR GENOTYPE DISTRIBUTION AMONG PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: IS THERE A ROLE FOR KIR 2DS4 AND KIR 2DS5 GENES?

Aim Study KIR expression of NK cells in CLL patients and in healthy controls, to check for any association between KIR genotypes and CLL. Methods KIR genotype was analysed for 120 healthy Lebanese patients and 56 CLL patients. using the KIR Genotyping SSP kit. Results KIR genotypic profile distribution among the 56 Lebanese patients with CLL is shown in Table 1 .[figure1] Table 2 shows the distribution of different KIR genotypes among the 120 healthy Lebanese controls. The content of KIR genes ranged from 6 to 15 and, as per Table 4, the AA, AB, and BB genotypes frequencies were, respectively, 42.5%, 50%, and 7.5% with an A:B ratio of 2.08:1. Table 3 shows the distribution of different KIR genes among the 120 controls and the 56 CLL patients.[figure2] KIR 2DL4 , KIR 3DL2, and KIR 3DL3 were present in all individuals. KIR 2DS4 ∗ 001/002 and KIR 2DS5 were found to be significantly (with a p-value of 0.02 and 0.04, respectively) more prevalent among CLL patients as compared to controls. Conclusions The interesting observation of the significant presence of KIR 2DS4 and KIR 2DS5 genes more among Chronic Lymphocytic Leukemia than controls is worth further clinical and translational research in the future as well as correlation with outcome of bone marrow transplantation in these cases.

90-P: KIR GENOTYPE DISTRIBUTION AMONG PATIENTS WITH MULTIPLE MYELOMA: HIGHER PREVALENCE OF KIR 2DS4 AND KIR 2DS5 GENES

Aim Study KIR expression of NK cells in MM patients and in healthy controls, to check for any association between KIR genotypes and MM. Methods KIR genotype was analysed for 120 healthy Lebanese patients and 34 MM patients. using the KIR Genotyping SSP kit. Results The content of KIR genes ranged from 7 to 15 and as per Table 4, the AA, AB, and BB genotypes frequencies were, respectively, 38.24%, 47.06% and 14.71% with an A:B ratio of 1.62:1. [figure1]Table 2 shows the distribution of different KIR genotypes among the 120 healthy Lebanese controls. The content of KIR genes ranged from 6 to 15 and, as per Table 4, the AA, AB, and BB genotypes frequencies were, respectively, 42.5%, 50%, and 7.5% with an A:B ratio of 2.08:1.[figure2]Fig. 2 shows the distribution of different KIR genes among the 120 controls and the 34 MM patients. KIR 3DL2 KIR 3DL3, and KIR 3DP1∗003 were present in all individuals. KIR 2DS4∗001/002 and KIR 2DS5 were found to be significantly (with a p-value of 0.04 and 0.007, respectively) more prevalent among MM patients as compared to controls. Conclusions The interesting observation of the significant presence of KIR 2DS4 and KIR 2DS5 genes more among Multiple Myeloma than controls is worth further clinical and translational research in the future as well as correlation with outcome of bone marrow transplantation in these cases.

98-P: KIR mRNA EXPRESSION IN PBMC AND ENRICHED NK CELLS ASSAYED BY QUANTITATIVE REAL-TIME PCR

To develop assays to quantify the mRNA transcribed from KIR genes utilizing a quantitative real-time PCR (qPCR) method. To study the KIR mRNA expression patterns in PBMC and enriched NK cells among healthy volunteers. PBMCs were obtained from freshly drawn whole blood (maximum 48 hours) from 14 healthy volunteers using a Ficoll method. NK cell enrichment from PBMC was performed by negative selection using a magnetic bead kit. mRNA extraction and cDNA synthesis was followed by EvaGreen based qPCR. Relative KIR mRNA expression was quantified by 2-ΔΔCt algorithm with GAPDH as reference. qPCR with a Cq ⩽ 38.0 was considered positive. 10 mRNA expression assays for the 9 KIR genes 2DL1, 2DL5A, 2DL5B, 2DS1, 2DS2, 2DS3, 2DS4 (2DS4-full length and 2DS4-truncated), 2DS5 and 3DS1 have been developed and validated. Among the 14 individuals, KIR mRNAs were detected in all samples carrying respective KIR genes and were negative for KIR gene negative samples. The mRNA expression varied among individuals. In PBMC, the relative quantification (RQ) of cDNA showed the largest variation for 2DL1 (14-fold, n = 14) and the smallest for 3DS1 (1.8-fold, n = 3) among volunteers who were positive for the respective genes. 2DL5B cDNA was not detected, as expected for this gene. More KIR cDNA was detected in the enriched NK cell fraction when compared to PBMC, with the largest difference observed for 2DL1 (NK : PBMC ratio, mean ± SD: 37.8 ± 25.0, n = 14). Development of qPCR assays with high specificity and easy applicability will be useful, because all known 15 KIR genes share > 90% identity at the genomic level. We established 10 assays for the mRNA expression of 9 KIR genes. KIR mRNA expression varied among healthy individuals carrying the same KIR genotype. Because NK cells are the predominant, but not the only source of KIR mRNA, analyzing PBMC and NK cells will allow establishing an overall and NK cell specific KIR mRNA expression signature from an individual.

Variation in Both IL28B and KIR2DS3 Genes Influence Pegylated Interferon and Ribavirin Hepatitis C Treatment Outcome in HIV-1 Co-Infection

Pegylated-IFN and ribavirin remains the current treatment for chronic HCV infection in patients co-infected with HIV-1, but this regimen has low efficacy rates, particularly for HCV genotype 1/4 infection, has severe side effects and is extremely costly. Therefore, accurate prediction of treatment response is urgently required. We have recently shown that the NK cell gene, KIR2DS3 and a SNP associated with the IL28B gene synergise to increase the risk of chronic infection in primary HCV mono-infected patients. Identification of SNPs associated with the IL28B gene has also proven very powerful for predicting patient response to treatment. Patients co-infected with HIV-1 are of particular concern given they respond less well to HCV treatment, have more side effects and suffer a more rapid liver disease progression. In this study, we examined both IL28B and KIR2DS3 for their ability to predict treatment response in a cohort of HIV-1/HCV co-infected patients attending two treatment centres in Europe. We found that variation in both host genetic risk factors, IL28B and KIR2DS3, was strongly associated with sustained virological response (SVR) to treatment in our co-infected cohort (n = 149). The majority of patients who achieved a rapid virological response (RVR) achieved a SVR. However, it is currently impossible to predict treatment outcome in patients who fail to achieve an RVR. In our cohort, the presence of host genetic risk factors, IL28B-T and KIR2DS3 alleles, resulted in increased odds of treatment failure in these RVR negative patients (n = 88). Our data suggests that testing for host genetic factors will improve predicting treatment responsiveness in the clinical management of co-infected patients, and provides further evidence of the importance of the innate immune system in the immune response to HCV.

AB0001 Prevalence of kir b haplotype in irish rheumatoid arthritis patients

BackgroundKiller cell immunoglobulin like receptors (KIR) expressed on NK and T cell subsets interact with HLA ligands to influence the reactivity of these cells. The KIR/HLA genotype of an individual...

Association of KIR genotype with susceptibility to HLA-B27-positive ankylosing spondylitis

Objective Recent studies have explored the role of killer cell immunoglobulin-like receptors (KIRs) in chronic autoimmune diseases. The purpose of this study was to demonstrate whether KIR genes contribute to the pathogenesis of ankylosing spondylitis (AS) in Chinese populations.Methods Sixteen KIR genes were genotyped from 60 unrelated patients with AS and 60 HLA-B27-positive matched healthy controls by PCR-SSP. The frequencies of the KIR alleles and genotypes in the AS and control groups were assessed by the χ2 test.Results Our results showed that the frequency of the activator receptor KIR3DS1 gene in the AS group was significantly increased compared to the controls (χ2 = 5.263, P = 0.006, OR = 3.059, 95 % CI = 1.357–6.896). Moreover, the frequency of the KIR3DL1/3DS1 genotype was greater in the AS group than in the control group (P = 0.039, OR = 3.059, 95 % CI = 1.357–6.896). In contrast, the frequency of the no KIR3DL1/no 3DS1 genotype was lower in patients with AS compared with the controls (P = 0.032, OR = 0.110, 95 % CI = 0.013–0.911).Conclusion KIR3DS1, in addition to HLA-B27, may play an important independent role in the pathogenesis of AS in the Chinese population.

Abstract 1353: KIR copy-number variation and cutaneous melanoma risk.

Abstract Prevention of cutaneous malignant melanoma requires the identification and clearance of abnormal, pre-cancerous cells by the immune system. Central to this immune surveillance is the interplay between KIR receptors present on natural killer cells and their HLA ligands expressed on target cells. Like HLA, the KIR genes are highly polymorphic. They encode both activating receptors (that trigger NK-cell mediated killing), and inhibitory receptors (important in NK cell education and self-tolerance). Many of the KIR genes occur as copy number variants, and we hypothesize that inter- individual variability in KIR copy number is associated with melanoma risk. A random sample of cases and controls within the large, population-based Minnesota Skin Health Study were selected for examination (84 cases and 87 controls). Using Luminex technology and genomic DNA isolated from subject buccal cells we tested for the presence or absence of specific KIR genes (KIR3DL1, KIR2DS1, KIR2DL2, KIR2DL3, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4 {truncating allele}, KIR2DS5, KIR2DS1). In addition to investigating each gene as a melanoma risk factor, we created an integrated locus score for 2DL2/DL3 and 3DL1/DS1, reflecting the typical mutual exclusivity of these genes at their respective loci. Results: Homozygous deletion of the activating KIR gene 2DS1 was associated with both an increasing number of nevi (p&amp;lt;0.04), and increased melanoma risk (OR 2.2, 95% CI 1.2 - 4.3). Similarly, at the shared 3DL1/3DS1 locus, absence of the activating KIR3DS1 gene was significantly associated with increased melanoma risk (OR 2.0, 95% CI 1.0 - 3.3), and a borderline significant increase in the number of nevi (p&amp;lt;0.07). In contrast, at the KIR2DL2/2DL3 locus, which encodes two inhibitory KIR alleles, our data suggest that a lack of diversity at this locus may be more important than the presence or absence of either gene; individuals homozygous for either 2DL2 or 2DL3 were at increased risk for both nevi (p&amp;lt;0.03), and melanoma (OR 1.8, 95% CI 1.0 - 3.4) relative to those who had both 2DL2 and 2DL3. These novel analyses at the complex KIR locus indicate that absence of certain activating KIR receptors, and balance in diversity of KIR inhibitory receptors are important determinants of cutaneous melanoma risk. Citation Format: Heather H. Nelson, Karin Vineretsky, DeAnn Lazovich. KIR copy-number variation and cutaneous melanoma risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2013-1353