Genetic Variation in Intercellular Adhesion Molecule-1 (ICAM-1): candidate gene in susceptibility to malaria in the Indian population
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SUBMITTER: Gupta A
PROVIDER: S-EPMC4043398 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:Plasmodium falciparum is responsible for malaria-related morbidity and mortality. PfEMP1 (P. falciparum erythrocyte membrane protein 1) mediates infected erythrocytes adhesion to various surface vascular receptors, including intercellular adhesion molecule-1 (ICAM-1), associating this interaction with severe malaria in several studies. Genetic variation in host ICAM-1 plays a significant role in determining susceptibility to malaria infection via clinical phenotypes such as the ICAM-1Kilifi variant which has been reported to be associated with susceptibility in populations. Our genomic and structural analysis of single nucleotide polymorphisms (SNPs) in ICAM-1 revealed 9 unique mutations each in its distinct A-type and BC-type PfEMP1 DBLβ-interacting regions. These mutations are noted in only a few field isolates and mainly in the African/African American population. The ICAM-1Kilifi variant lies in a flexible loop proximal to the DBLβ-interacting region. This analysis will assist in establishing functional correlations of reported global mutations via experimental and clinical studies and in the tailored design of population-specific genetic surveillance studies. Understanding host polymorphism as an evolutionary force in diverse populations can help to predict predisposition to disease severity and will contribute towards laying the framework for designing population-specific personalized medicines for severe malaria.
| S-EPMC10720214 | biostudies-literature
Project description:BackgroundIntercellular adhesion molecule-1 (ICAM-1) Lys469Glu (K469E) polymorphism and Gly 241Arg (G241R) polymorphism might play important roles in cancer development and progression. However, the results of previous studies are inconsistent. The aim of this study was to evaluate the association between ICAM-1 K469E and G241R polymorphisms and the risk of cancer by meta-analysis.MethodsA comprehensive literature search (last search updated in November 2013) was conducted to identify case-control studies that investigated the association between ICAM-1 K469E and G241R polymorphisms and cancer risk.ResultsA total of 18 case-control studies for ICAM-1 polymorphisms were included in the meta-analysis, including 4,844 cancer cases and 5,618 healthy controls. For K469E polymorphism, no significant association was found between K469E polymorphism and cancer risk. However, subgroup analysis by ethnicity revealed one genetic comparison (GG vs. AA) presented the relationship with cancer risk in Asian subgroup, and two genetic models (GG+GA vs. AA and GA vs. AA) in European subgroup, respectively. For G241R polymorphism, G241R polymorphism was significantly association with cancer risk in overall analysis. The subgroup analysis by ethnicity showed that G241R polymorphism was significantly associated with cancer risk in European subgroup.ConclusionICAM-1 G241R polymorphism might be associated with cancer risk, especially in European populations, but the results doesn't support ICAM-1 K469E polymorphism as a risk factor for cancer.
| S-EPMC4537618 | biostudies-literature
Project description:BACKGROUND Many epidemiology studies have indicated that polymorphisms in ICAM-1 are associated with a variety of cancers, but published data are contradictory and inconclusive. Therefore, we conducted the current meta-analysis to elaborate the effects of ICAM-1 polymorphisms (rs5491, rs3093030, rs281432, and rs1799969) on cancer susceptibility. MATERIAL AND METHODS We conducted a comprehensive literature search in PubMed, Web of Science, and Google Scholar. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between ICAM-1 polymorphisms and cancer susceptibility. RESULTS We enrolled 14 published case-control studies including 4608 cancer cases and 4913 controls. We found an increased susceptibility of cancer in polymorphism rs1799969 (C vs. T: OR=1.662, 95%CI=1.288-2.143, p=0141; CT vs. TT: OR=1.860, 95%CI=1.398-2.474, p=0.507; CC+CT vs. TT: OR=1.812, 95%CI=1.373-2.391, p=0.284) of ICAM-1 among the overall population. However, no association between polymorphisms rs5491, rs3093030, or rs281432 of ICAM-1 and cancer susceptibility was identified. In the stratification analysis by ethnicity, we identified an increased susceptibility for Asians in rs3093030 polymorphism (CC vs. TC+TT: OR=1.728, 95% CI=1.234-2.421, p=0.787). CONCLUSIONS Our results suggest that the ICAM-1 polymorphism rs1799969 is significantly associated with increased susceptibility to overall cancer. Further studies (preferably prospective) are warranted to validate these relationships.
| S-EPMC4763808 | biostudies-literature
Project description:Many epidemiological studies have confirmed that ICAM-1 gene single-nucleotide polymorphisms (SNPs) are associated with susceptibility of various cancers, but there are relatively few studies on the relationship between ICAM-1 gene polymorphisms and the risk of cervical cancer. Therefore, we aimed to explore the potential role of ICAM-1 gene polymorphisms and the combined effect of SNPs in the pathogenesis of cervical cancer in Han women in northern China. This case-control group includes 488 cases of cervical cancer, 684 cases of cervical precancerous lesions, and 510 healthy females. Multiplex polymerase chain reaction (PCR) combined with the next-generation sequencing method was used for the determination of gene polymorphisms (rs5498, rs3093030, and rs281432). In our study, we divide cervical cancer into two subgroups: cervical squamous cell carcinoma (CSCC) group and cervical adenocarcinoma (CAC) group. We analyzed the alleles and genotypes of all research subjects using multivariate logistic regression analysis combined with 10,000 permutation tests. In addition, we also analyzed the distribution of haplotypes of the three SNPs in cervical cancer and cervical precancerous lesions. We found that the T allele and the dominant model of rs3093030 were associated with the susceptibility of cervical cancer (p = 0.042, p = 0.040, respectively). However, the significance disappeared after the Bonferroni correction for multiple testing (p > 0.05). For rs5498, its mutant gene G, the codominant model, and the dominant model could reduce the risk of CAC (p = 0.009, p = 0.028, p = 0.011, respectively). Significant differences remained after Bonferroni correction (p < 0.05, all). In addition, the frequency of haplotype "CTG" was significantly lower in the CAC group than in the controls. In conclusion, the study suggested that ICAM-1 gene polymorphisms may have a potential role in the pathogenesis of cervical cancer in the northern Chinese Han population.
| S-EPMC8353393 | biostudies-literature
Project description:The interaction between integrin lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) is critical in immunological and inflammatory reactions but, like other adhesive interactions, is of low affinity. Here, multiple rational design methods were used to engineer ICAM-1 mutants with enhanced affinity for LFA-1. Five amino acid substitutions 1) enhance the hydrophobicity and packing of residues surrounding Glu-34 of ICAM-1, which coordinates to a Mg2+ in the LFA-1 I domain, and 2) alter associations at the edges of the binding interface. The affinity of the most improved ICAM-1 mutant for intermediate- and high-affinity LFA-1 I domains was increased by 19-fold and 22-fold, respectively, relative to wild type. Moreover, potency was similarly enhanced for inhibition of LFA-1-dependent ligand binding and cell adhesion. Thus, rational design can be used to engineer novel adhesion molecules with high monomeric affinity; furthermore, the ICAM-1 mutant holds promise for targeting LFA-1-ICAM-1 interaction for biological studies and therapeutic purposes.
| S-EPMC1455478 | biostudies-literature
Project description:Background and purposePaeoniflorin (PF) has ameliorative effects on learning and memory impairment and cerebral ischaemia in rats and has protective effects against the degeneration of dopaminergic neurons in substantia nigra. The neuroprotective effects of PF are most probably derived from its anti-inflammatory property. Abnormally high levels of intercellular adhesion molecule-1 (ICAM-1) have been found to be associated with a wide range of inflammatory and immune responses. Here we studied whether PF regulates the levels of ICAM-1 elevated in LPS-activated differentiated human monocytic U937 cells and TNF-α-stimulated human umbilical vein endothelial cells (HUVECs).Experimental approachmRNA levels were evaluated by RT-PCR. Protein levels were evaluated by Western blot analysis. An immunofluorescence technique was used to estimate NF-κB translocation, and NF-κB binding to nuclear DNA was determined by EMSA.Key resultsPF inhibited ICAM-1 expression elevated in LPS-induced U937 cells and TNF-α-stimulated HUVECs. Although previous reports showed that PF's action is mediated by activating adenosine A₁ receptors, application of a selective adenosine A₁ receptor antagonist did not change the inhibitory effect of PF in our experiments. To elucidate the underlying mechanisms of the effect of PF, we studied its effect on signalling pathways upstream of ICAM-1 expression. PF suppressed the activation of the NF-κB pathway, which regulates the expression of ICAM-1. The TLR4 and MAPK pathways were shown not to be involved in the effects of PF in these cells.Conclusions and implicationsPF inhibits ICAM-1 expression in LPS-treated U937 cells and TNF-α-stimulated HUVECs by suppressing the activation of the NF-κB pathway.
| S-EPMC3188904 | biostudies-literature
Project description:Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The anti-diabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of anti-apoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.
| S-EPMC8789909 | biostudies-literature
Project description:Simple Summary Intercellular adhesion molecule 1 (ICAM-1) is a protein produced by cells in blood vessel walls, as well as many other cell types. It localizes to the surface of these cells to allow them to communicate with adjacent cells. The production of ICAM-1 is induced by inflammation, such as occurs during infection, when one of its main functions is to direct white blood cells to the site of the infection. However, in autoimmune diseases and certain types of infection, ICAM-1 can be involved in directing cells to damage healthy tissue. ICAM-1 can also promote or protect against cancer, depending on the type of cancer and the cell populations that are producing it. In this review article, the ICAM1 gene and ICAM-1 protein are introduced, and their regulation is summarized. The roles of ICAM-1 in the immune system and a spectrum of diseases, as well as therapeutics that target ICAM-1, are discussed. Abstract Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein in the immunoglobulin superfamily expressed on the surface of multiple cell populations and upregulated by inflammatory stimuli. It mediates cellular adhesive interactions by binding to the β2 integrins macrophage antigen 1 and leukocyte function-associated antigen 1, as well as other ligands. It has important roles in the immune system, including in leukocyte adhesion to the endothelium and transendothelial migration, and at the immunological synapse formed between lymphocytes and antigen-presenting cells. ICAM-1 has also been implicated in the pathophysiology of diverse diseases from cardiovascular diseases to autoimmune disorders, certain infections, and cancer. In this review, we summarize the current understanding of the structure and regulation of the ICAM1 gene and the ICAM-1 protein. We discuss the roles of ICAM-1 in the normal immune system and a selection of diseases to highlight the breadth and often double-edged nature of its functions. Finally, we discuss current therapeutics and opportunities for advancements.
| S-EPMC10215618 | biostudies-literature
Project description:The immunoglobulin (Ig) superfamily is one of the largest families in the vertebrate genome, found most frequently in cell surface molecules. Intercellular adhesion molecule-1 (ICAM-1) contains five extracellular Ig superfamily domains (D1-D5) of which the first domain, D1, is the binding site for the integrin lymphocyte function-associated antigen-1 (LFA-1) and human rhinovirus. Despite the modular nature of many Ig superfamily domains with respect to domain folding and ligand recognition, D1 does not fold on its own due to the loss of its interaction with the second domain. The goal of this study was to engineer ICAM-1 D1 by introducing mutations that would stabilize the Ig superfamily domain fold while retaining its ability to bind to LFA-1 and rhinovirus. First, with a directed evolution approach, we isolated mutations in D1 that showed binding to conformation-specific antibodies and the ligand binding domain of LFA-1 called the inserted, or I, domain. Then, with a rational design approach we introduced mutations that contributed to the stability of ICAM-1 D1 in solution. The mutations that restored native folding of D1 in isolation were those that would convert hydrogen bond networks in buried regions into hydrophobic contacts. Notably, for most mutations, identical or similar types of substitutions were found in ICAM-1 molecules of different species and other ICAM family members. The systematic approach demonstrated in this study to engineer a single Ig superfamily fold in ICAM-1 can be broadly applicable to the engineering of modular Ig superfamily domains in other cell surface molecules.
| S-EPMC2871458 | biostudies-literature
Project description:Many human inherited disorders cause protein N-glycosylation defects, but there are few cellular markers to test gene complementation for such defects. Plasma membrane glycoproteins are potential biomarkers because they may be reduced or even absent in plasma membranes of glycosylation-deficient cells. We combined stable isotope labeling by amino acids in cell culture (SILAC) with linear ion trap mass spectrometry (LTQ Orbitrap(TM)) to identify and quantify membrane proteins from wild-type CHO and glycosylation-deficient CHO (Lec9) cells. We identified 165 underrepresented proteins from 1447 unique quantified proteins, including 18 N-glycosylated plasma membrane proteins. Using various methods, we found that intercellular cell adhesion molecule 1 (ICAM-1) was reduced in Lec9 cells and in fibroblasts from 31 congenital disorder of glycosylation (CDG) patients compared with normal controls. Mannose supplementation of phosphomannose isomerase-deficient CDG-Ib (MPI-CDG) cells and complementation with PMM2 in PMM2-deficient CDG-Ia (PMM2-CDG) cells partially corrected hypoglycosylation based on increased ICAM-1 presence on the plasma membrane. These data indicate that ICAM-1 could be a useful hypoglycosylation biomarker to assess gene complementation of CDG-I patient cells and to monitor improved glycosylation in response to therapeutic drugs.
| S-EPMC3365753 | biostudies-literature