Alternative titles; symbols
HGNC Approved Gene Symbol: SELE
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38): 1:169,722,640-169,734,079 (from NCBI)
Endothelial leukocyte adhesion molecule-1 is expressed by cytokine-stimulated endothelial cells. It is thought to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. It exhibits structural features homologous to those of LYAM1 (153240), including the presence of lectin- and EGF-like domains followed by short consensus repeat (SCR) domains that contain 6 conserved cysteine residues. These proteins are part of the selectin family of cell adhesion molecules (Watson et al., 1990; Collins et al., 1991).
Collins et al. (1991) established that the ELAM gene is present in single copy in the human genome and contains 14 exons spanning about 13 kb of DNA. The positions of exon-intron boundaries correlated with the putative functional subdivisions of the protein.
Watson et al. (1990) found that the ELAM1 gene is in the same 300-kb segment as the GRMP (173610) and LYAM1 genes on chromosome 1.
By analysis of human-mouse hybrid cell lines, Collins et al. (1991) assigned the ELAM gene to the 1q12-qter region. LYAM1 and GRMP have been localized to 1q, as have also the structurally related complement binding proteins, e.g., C4BPA (120830), suggesting that these genes may share a common evolutionary history.
The glaucomas are a group of optic neuropathies comprising the leading cause of irreversible blindness worldwide. Elevated intraocular pressure due to a reduction in normal aqueous outflow is a major causal risk factor. Wang et al. (2001) found that ELAM1, the earliest marker for the atherosclerotic plaque in the vasculature, was consistently present on trabecular meshwork cells in the outflow pathways of eyes with glaucomas of diverse etiology. They determined expression of ELAM1 to be controlled by activation of an interleukin-1 (see 147760) autocrine feedback loop through transcription factor NK-kappa-B (see 164011), and activity of this signaling pathway was shown to protect trabecular meshwork cells against oxidative stress. Wang et al. (2001) concluded that their findings characterized a protective stress response specific to the eye's aqueous outflow pathways and provided the first known diagnostic indicator of glaucomatous trabecular meshwork cells. They further indicated that common mechanisms contribute to the pathophysiology of the glaucomas and vascular diseases.
Using affinity chromatography, pull-down assays, and mass spectrometric analysis on adenocarcinoma cell lines, Gout et al. (2006) showed that SELE bound death receptor-3 (DR3, or TNFRSF25; 603366) on the cancer cells. Western blot analysis revealed that the SELE-binding protein was recognized by anti-DR3 antibodies. Anti-DR3 or knockdown of DR3 by small interfering RNA decreased adhesion of colon cancer cells to SELE and to SELE-expressing endothelial cells. Moreover, DR3 inhibition and knockdown impaired transendothelial migration of adenocarcinoma cells and blocked p38 (MAPK14; 600289) and ERK (see MAPK1; 176948) activation by SELE. DR3 was expressed as high molecular mass isoforms in primary human colon carcinomas, but not in normal colon tissue. SELE activation of DR3 failed to induce apoptosis in colon cancer cells, except when ERK was inhibited. Gout et al. (2006) concluded that SELE activation of DR3 on colon cancer cells triggers activation of p38 and ERK and confers migration and survival advantages. They proposed that activation of DR3 by SELE acts as a switch that regulates metastasis by allowing colon cancer cells to escape apoptosis.
Iida and Nakamura (2003) constructed a high-resolution SNP map in the 55-kb region of chromosome 1q24-q25 corresponding to the SELE and SELL genes.
Blood soluble E-selectin (sE-selectin) levels have been related to various conditions such as type 2 diabetes (125853). Qi et al. (2010) performed a genomewide association study among women of European ancestry from the Nurses' Health Study, and identified genomewide-significant associations between a cluster of markers at the ABO locus (110300) on chromosome 9q34 and plasma sE-selectin concentration. The strongest association was with rs651007, which explained approximately 9.71% of the variation in sE-selectin concentrations. rs651007 was also nominally associated with soluble intracellular cell adhesion molecule-1 (sICAM1; 147840) and TNFR2 (TNFRSF1B; 191191) levels, independent of sE-selectin. The genetic-inferred ABO blood group genotypes were also associated with sE-selectin concentrations. The genetic-inferred blood group B was associated with a decreased risk of type 2 diabetes compared with blood group O, adjusting for sE-selectin, sICAM1, TNFR2, and other covariates. The authors concluded that the genetic variants at the ABO locus affect plasma sE-selectin levels and diabetes risk, and that the genetic associations with diabetes risk were independent of sE-selectin levels.
Role in Leukocyte Recruitment
Neutrophil accumulation at sites of inflammation is mediated by specific groups of cell adhesion molecules including the CD18 integrins (600065) on leukocytes and the selectins (P-selectin (173610) and E-selectin on the endothelium and L-selectin (153240) on the leukocytes). This is supported by studies of patients with leukocyte adhesion deficiency syndromes whose leukocytes are genetically deficient in the expression of CD18 or selectin carbohydrate ligands (e.g., leukocyte adhesion deficiency type II; 266265). However, inherited deficiency or dysfunction of endothelial cell adhesion molecules involved in leukocyte recruitment had not been described. DeLisser et al. (1999) described a child with recurrent infections and clinical evidence of impaired pus formation reminiscent of a leukocyte adhesion deficiency syndrome, but whose neutrophils were functionally normal and expressed normal levels of CD18, L-selectin, and sialyl-Lewis x. In contrast, immunohistochemical staining of inflamed tissue from the patient showed the absence of E-selectin from the endothelium, although E-selectin mRNA was present. However, E-selectin protein was expressed, as significantly elevated levels of circulating soluble E-selectin were detected, the molecular size of which was consistent with a proteolytically cleaved form of E-selectin. Gene sequencing failed to show evidence of a secreted mutant variant. These findings were thought to represent the first description of a potentially inherited dysfunction of an endothelial cell adhesion molecule involved in leukocyte recruitment and provided additional evidence in the human of the importance of endothelial selectins in the inflammatory response.
S128R Polymorphism
Since adhesion molecules such as members of the selectin family participate in the interaction between leukocytes and the endothelium and appear to be involved in the pathogenesis of atherosclerosis, Wenzel et al. (1994) sought DNA polymorphisms in the ELAM1 gene, which appears to be expressed only in activated endothelium. They identified an A-to-C transversion at cDNA nucleotide 561, resulting in an amino acid exchange from serine to arginine at codon 128 (S128R) in the epidermal growth factor-like domain. They found a significantly higher frequency of the mutation in 97 patients aged 50 years or less with angiographically proven severe atherosclerosis (arginine allele frequency, 0.155) compared with an unselected population (arginine allele frequency, 0.088), as well as in 40 patients aged 40 years or less (arginine allele frequency, 0.21).
Zheng et al. (2001) examined whether a polymorphism in the SELE gene, due to a G-to-T mutation (98G-T) in the untranslated region of exon 2, was related to premature coronary artery disease (CAD). Both lipid and nonlipid risk factors, including the S128R substitution studied by Wenzel et al. (1994), were also assessed. The frequency of the 98G-T mutation was found to be significantly increased among male patients under 45 years of age and female patients under 55 years of age. After controlling for other CAD risk factors by multiple logistic analysis, the 98G-T mutation was still a significant predictor of premature CAD.
Rao et al. (2002) found that CHO cell monolayers expressing SELE with the S128R polymorphism recruited significantly greater numbers of Th2 and Th0, but not Th1, memory T cells than monolayers expressing wildtype SELE. They proposed that the S128R polymorphism extends the range of lymphocytes recruited by SELE, possibly providing a mechanism for the increased susceptibility to vascular inflammatory disease associated with S128R.
Associations Pending Confirmation
Accumulation of leukocytes within the glomerulus and interstitium of the kidney is considered to be a key pathogenetic mechanism in various types of glomerulonephritis. The selectins represent one group of adhesion molecules involved in these interactions. Evidence from various sources suggests an involvement of E-selectin, L-selectin, and perhaps P-selectin, as reviewed by Takei et al. (2002). The genes for these 3 forms of selectin are clustered on 1q24-q25. Takei et al. (2002) found that 2 SNPs in the E-selectin gene and 6 SNPs in the L-selectin gene are significantly associated with IgA nephropathy (IGAN; 161950) in Japanese patients. All 8 SNPs were in almost complete linkage disequilibrium.
By genomewide linkage and candidate gene-based association studies, Chang et al. (2007) demonstrated that a replicated linkage peak for blood pressure regulation on human chromosome 1q23-q32, homologous to mouse and rat quantitative trait loci (QTLs) for blood pressure, contains at least 3 genes associated with blood pressures level in multiple samples: ATP1B1 (182330), RGS5 (603276), and SELE. Individual variants in these 3 genes accounted for 2- to 5-mm Hg differences in mean systolic blood pressure, and the cumulative effect reached 8 to 10 mm Hg. Because the associated alleles in these genes are relatively common (frequency more than 5%), these 3 genes are important contributors to elevated blood pressure in the population at large. Chang et al. (2007) viewed the probable relationship between each of these genes and blood pressure regulation.
Forlow et al. (2002) stated that mice lacking both Selp (173610) and Sele kept under specific pathogen-free barrier conditions have high circulating neutrophil counts and develop hypercellular cervical lymph nodes containing numerous plasma cells, severe ulcerative dermatitis, conjunctivitis, and lung pathology, eventually leading to premature death. They hypothesized that the pathology in Selp and Sele double-knockout mice might be due to dysfunctional lymphocyte activity and, to test this hypothesis, they crossed Selp and Sele double-knockout mice with mice deficient in Rag1 (179615), which lack mature T and B lymphocytes. The triple-knockout mice had high circulating neutrophil counts and plasma Gcsf (CSF3; 138970), but none developed the conjunctivitis or dermatitis observed in Selp and Sele double-knockout mice. Histopathologic analysis revealed fewer lung anomalies and smaller cervical lymph nodes, which contained few mononuclear cells and no plasma cells, in triple-knockout mice compared with Selp and Sele double-knockout mice. Forlow et al. (2002) concluded that the severe disease phenotype, but not the elevated neutrophil counts, in Selp and Sele double-knockout mice depends on lymphocyte function.
Using fluorescence intravital microscopy (IVM) with homing assays, Hidalgo et al. (2002) examined the repopulation of bone marrow of sublethally irradiated nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice, which have multiple defects in innate and adaptive immunologic functions, with human CD34 (142230)-positive hematopoietic progenitor cells obtained either from cord blood or from adult bone marrow or peripheral blood. Human hematopoietic progenitor cells rolled and arrested in NOD/SCID bone marrow microvessels, and the rolling capacity of neonatal cord blood cells was much lower than that of adult cells. Rolling and retention were nearly abolished in NOD/SCID Selp -/- Sele -/- mice and in NOD/SCID Sele -/- mice. Flow cytometric and IVM analyses suggested that the neonatal defect resulted from expression of a nonfunctional form of SELPLG (600738) on cord blood CD34-positive cells that were unable to bind Selp. This subset of cells was enriched in CD34-positive/CD38 (107270)-low/negative progenitors. Hidalgo et al. (2002) proposed that manipulation of expression of selectins and their ligands may improve homing of cord blood CD34-positive cells to bone marrow.
Bevilacqua et al. (1991) suggested that the homologous proteins involved in cell-cell adhesion be referred to as selectins to reflect the involvement of carbohydrate recognition in their functions. Individual members of the family would be designated by a prefix capital letter, as is done for the cadherins (e.g., 114020). Letters would be chosen based on the tissue of original discovery and would not imply cell-type specificity. ELAM1 was termed E-selectin.
This variant, formerly titled IgA NEPHROPATHY, SUSCEPTIBILITY TO, has been reclassified based on the findings of Maxwell and Wang (2006).
In a case-control association study using selectin SNPs to identify regions containing loci responsible for phenotypes of IgA nephropathy (IGAN; 161950), Takei et al. (2002) found an association between a 1402C-T transition in exon 9 of the SELE gene, resulting in substitution of tyr for his at codon 468 (H468Y), and IGAN in Japanese subjects. Overall, Takei et al. (2002) found that 2 SNPs in SELE and 6 SNPs in the SELL (153240) were associated with IGAN in Japanese patients; all 8 SNPs were in almost complete linkage disequilibrium.
Maxwell and Wang (2006) included the selectin variants reported by Takei et al. (2002) in a table of genetic associations with IgA nephropathy, noting that although plausible, these genetic associations had not generally been observed in more than 1 study and could not be proved to contribute to IgA nephropathy causation or progression.
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DeLisser, H. M., Christofidou-Solomidou, M., Sun, J., Nakada, M. T., Sullivan, K. E. Loss of endothelial surface expression of E-selectin in a patient with recurrent infections. Blood 94: 884-894, 1999. [PubMed: 10419878]
Forlow, S. B., White, E. J., Thomas, K. L., Bagby, G. J., Foley, P. L., Ley, K. T cell requirement for development of chronic ulcerative dermatitis in E- and P-selectin-deficient mice. J. Immun. 169: 4797-4804, 2002. Note: Erratum: J. Immun. 170: 643 only, 2003. [PubMed: 12391189] [Full Text: https://doi.org/10.4049/jimmunol.169.9.4797]
Gout, S., Morin, C., Houle, F., Huot, J. Death receptor-3, a new E-selectin counter-receptor that confers migration and survival advantages to colon carcinoma cells by triggering p38 and ERK MAPK activation. Cancer Res. 66: 9117-9124, 2006. [PubMed: 16982754] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-4605]
Hidalgo, A., Weiss, L. A., Frenette, P. S. Functional selectin ligands mediating human CD34+ cell interactions with bone marrow endothelium are enhanced postnatally. J. Clin. Invest. 110: 559-569, 2002. [PubMed: 12189250] [Full Text: https://doi.org/10.1172/JCI14047]
Iida, A., Nakamura, Y. High-resolution SNP map in the 55-kb region containing the selectin gene family on chromosome 1q24-q25. J. Hum. Genet. 48: 150-154, 2003. [PubMed: 12624727] [Full Text: https://doi.org/10.1007/s100380300023]
Maxwell, P. H., Wang, Y. Genetic studies of IgA nephropathy. Nephron Exp. Nephrol. 102: e76-e80, 2006. Note: Electronic Article. [PubMed: 16282702] [Full Text: https://doi.org/10.1159/000089685]
Qi, L., Cornelis, M. C., Kraft, P., Jensen, M., van Dam, R. M., Sun, Q., Girman, C. J., Laurie, C. C., Mirel, D. B., Hunter, D. J., Rimm, E., Hu, F. B. Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes. Hum. Molec. Genet. 19: 1856-1862, 2010. [PubMed: 20147318] [Full Text: https://doi.org/10.1093/hmg/ddq057]
Rao, R. M., Haskard, D. O., Landis, R. C. Enhanced recruitment of Th2 and CLA-negative lymphocytes by the S128R polymorphism of E-selectin. J. Immun. 169: 5860-5865, 2002. [PubMed: 12421968] [Full Text: https://doi.org/10.4049/jimmunol.169.10.5860]
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Zheng, F., Chevalier, J. A., Zhang, L. Q., Virgil, D., Ye, S. Q., Kwiterovich, P. O. An HphI polymorphism in the E-selectin gene is associated with premature coronary artery disease. Clin. Genet. 59: 58-64, 2001. [PubMed: 11168027] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.590110.x]