Alternative titles; symbols
HGNC Approved Gene Symbol: OLR1
Cytogenetic location: 12p13.2 Genomic coordinates (GRCh38): 12:10,158,301-10,176,266 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.2 | {Myocardial infarction, susceptibility to} | 608446 | 3 |
The OLR1 gene encodes a cell-surface endocytosis receptor for oxidized low density lipoprotein (OxLDL). LDL is oxidized in vascular endothelial cells to a highly injurious product that results in endothelial cell injury, which is implicated in the development of atherosclerosis. Vascular endothelial cells also internalize and degrade OxLDL though the OLR1 receptor (Mehta and Li, 1998).
Sawamura et al. (1997) isolated a bovine aortic endothelial cell cDNA encoding a 270-amino acid OxLDL receptor protein, which they termed LOX1. Sawamura et al. (1997) cloned a human LOX1 cDNA from a lung cDNA library. The deduced 273-amino acid protein shares 72% sequence identity with the bovine protein and has a structure similar to that of several lectin-like killer cell receptors such as CD94 (KLRD1; 602894) and NKR-P1 (KLRB1; 602890). Northern blot analysis detected a 2.8-kb LOX1 mRNA in various tissues, with highest expression in placenta. Immunofluorescence studies showed that bovine LOX1 is expressed on the cell surface. Cells stably expressing human LOX1 showed uptake of labeled OxLDL.
Yamanaka et al. (1998) determined that LOX1 is expressed in vascular-rich organs but not in lymphocytes.
Yamanaka et al. (1998) determined that the LOX1 gene spans approximately 15 kb and contains 6 exons.
Aoyama et al. (1999) determined the detailed structure of the LOX1 gene. The first 3 exons corresponded to the different functional domains of the protein, cytoplasmic, transmembrane, and neck domains, and the last 3 exons encoded the carbohydrate-recognition domain common to other C-type lectin genes.
By fluorescence in situ hybridization, Yamanaka et al. (1998) mapped the LOX1 gene to 12p13-p12. They noted that several genes encoding natural killer cell receptors are clustered in the same region.
By fluorescence in situ hybridization, Aoyama et al. (1999) refined the LOX1 gene location to 12p13.2-p12.3.
Mehta and Li (1998) detected LOX1 mRNA in cultures of human coronary artery endothelial cells (HCAEC), and binding assays indicated a significant number of high-affinity binding sites on the cells. Incubation of the cells with LDL had no effect on LOX1 expression, but incubation with OxLDL resulted in a dose-dependent increase in LOX1 mRNA and protein expression; however, very high concentrations of OxLDL caused a decrease in OxLDL expression, perhaps indicating toxic effects on endothelial cells.
Scavenger receptors on the surface of macrophages play a role in the uptake of modified lipoproteins such as OxLDL, resulting in foam cell formation, a pathogenic change found in atherosclerosis. By RT-PCR, immunohistochemistry, flow cytometry, and Western blot analysis, Yoshida et al. (1998) demonstrated that LOX1 is expressed on the plasma membrane of differentiated macrophages, but not on monocytes. Western blot analysis identified a 40-kD protein which specifically recognized moderately oxidized LDL, but not fully oxidized LDL or native LDL. The findings indicated that the LOX1 protein acts as a macrophage scavenger receptor (see e.g., MSR1, 153622).
In rat cultured vascular endothelial cells, Nagase et al. (1998) found that LOX1 gene expression was upregulated 9-fold by shear stress, 21-fold by lipopolysaccharide, and 4-fold by tumor necrosis factor-alpha (TNFA; 191160). LOX1 was also expressed in macrophages, but not in vascular smooth muscle cells. The findings suggested a role for LOX1 in the pathophysiology of atherosclerotic cardiovascular disease.
Heat shock proteins (HSPs) are molecular chaperones that control protein folding and prevent aggregation of proteins. They complex with peptides and bind to dendritic cells (DCs) and macrophages before being internalized in a receptor-dependent manner. HSPs then colocalize with MHC class I molecules to initiate protective and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Using flow cytometric and Western blot analyses with binding inhibition assays, Delneste et al. (2002) found that HSP70 (140550) bound LOX1, but not other scavenger receptors tested, on both DCs and macrophages to gain access to the MHC class I pathway to initiate CTL responses.
Honjo et al. (2004) examined choroidal neovascular membranes from patients with exudative age-related macular degeneration (ARMD; see 153800) for expression of LOX1. LOX1 expression was detected in all choroidal neovascular membranes, regardless of structure, whereas there was no evidence of LOX1 within the posterior segments of normal eyes. Honjo et al. (2004) concluded that their findings suggested that LOX1 plays an active role in the pathogenesis of choroidal neovascularization, especially in ARMD.
Alzheimer Disease
Because OLR1 is abundantly expressed in brain and maps close to the A2M gene (103950), which had been implicated in a form of Alzheimer disease (AD5; 602096) mapping to chromosome 12p, Luedecking-Zimmer et al. (2002) studied OLR1 as a candidate gene for AD5. In more than 800 late-onset Alzheimer disease cases and more than 700 controls, they studied intragenic polymorphisms that showed significant association with Alzheimer disease after stratification by APOE*4. Luedecking-Zimmer et al. (2002) concluded that genetic variation in the OLR1 gene may modify the risk of Alzheimer disease in an APOE*4-dependent fashion.
Lambert et al. (2003) presented evidence that genetic variation in the OLR1 gene might modify the risk of Alzheimer disease. They described an association of a 3-prime UTR +1073C-T polymorphism of OLR1 with AD in French sporadic and American familial cases. The age- and sex-adjusted odds ratio between the CC/CT genotypes versus the TT genotypes was 1.56 in the French sample and 1.92 in the American sample. In studies of OLR1 expression in lymphocytes from AD cases compared with controls, they found the OLR1 expression significantly lower in AD cases bearing the CC and CT genotypes.
Contrary to the findings of Luedecking-Zimmer et al. (2002) and Lambert et al. (2003), Bertram et al. (2004) found no evidence favoring a genetic involvement of the 3-prime UTR +1073C-T polymorphism of the OLR1 gene in Alzheimer disease. Their study involved a large sample of 437 multiplex AD families. They also observed no linkage disequilibrium between this SNP and polymorphisms in the A2M gene.
Cardiovascular Disease
In 2 independent studies, Tatsuguchi et al. (2003) and Mango et al. (2003) reported an association between polymorphisms in the OLR1 gene (601602.0002; 601602.0003) and myocardial infarction (608446).
Tatsuguchi et al. (2003) identified a single nucleotide polymorphism in the LOX1 gene, a 501G-C transversion, resulting in a lys167-to-asn (K167N) substitution. In 102 patients with a history of myocardial infarction (608446), the authors found a significantly higher frequency (38.2%) of the 501G-C polymorphism compared to 102 controls (17.6%). The odds ratio for the risk of MI associated with the 501G-C change was 2.89.
Mango et al. (2003) identified a polymorphism in the 3-prime UTR of the LOX1 gene, a C-to-T change 188 nucleotides from the stop codon (3-prime UTR +188C-T), that was significantly associated with myocardial infarction (608446) in a group of 150 patients. Genotypes with the T allele were found in 91.3% of patients compared to 73.8% of controls, yielding an odds ratio of 3.74.
In a study of 589 white and 122 black women who underwent angiography for suspected ischemia, Chen et al. (2003) found that the frequency of the 3-prime UTR T allele was significantly higher in whites than in blacks (p less than 0.0001). Among white women, the frequency of the T allele was 67.9%, 75.0%, and 79.2% in individuals with less than 20%, 20 to 49%, and greater than 49% stenosis, respectively (chi square trend = 6.23, p = 0.013). The T-allele carriers had significantly higher IgG anti-oxLDL levels than those with the CC genotype (p = 0.032); and electrophoretic mobility shift assay data indicated that the 3-prime UTR binds regulatory proteins and that the C allele has a higher affinity for binding than the T allele.
Aoyama, T., Sawamura, T., Furutani, Y., Matsuoka, R., Yoshida, M. C., Fujiwara, H., Masaki, T. Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. Biochem. J. 339: 177-184, 1999. [PubMed: 10085242]
Bertram, L., Parkinson, M., Mullin, K., Menon, R., Blacker, D., Tanzi, R. E. No association between a previously reported ORL1 3-prime UTR polymorphism and Alzheimer's disease in a large family sample. J. Med. Genet. 41: 286-288, 2004. [PubMed: 15060104] [Full Text: https://doi.org/10.1136/jmg.2003.016980]
Chen, Q., Reis, S. E., Kammerer, C., Craig, W. Y., LaPierre, S. E., Zimmer, E. L., McNamara, D. M., Pauly, D. F., Sharaf, B., Holubkov, R., Merz, C. N. B., Sopko, G., Bontempo, F., Kamboh, M. I. Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease. Circulation 107: 3146-3151, 2003. [PubMed: 12810610] [Full Text: https://doi.org/10.1161/01.CIR.0000074207.85796.36]
Delneste, Y., Magistrelli, G., Gauchat, J.-F., Haeuw, J.-F., Aubry, J.-P., Nakamura, K., Kawakami-Honda, N., Goetsch, L., Sawamura, T., Bonnefoy, J.-Y., Jeannin, P. Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 17: 353-362, 2002. [PubMed: 12354387] [Full Text: https://doi.org/10.1016/s1074-7613(02)00388-6]
Honjo, M., Sawamura, T., Hinagata, J., Nakamura, K., Sanada, N., Tanihara, H., Honda, Y., Kiryu, J. Expression of LOX-1, an oxidized low-density lipoprotein receptor, in choroidal neovascularization. Arch. Ophthal. 122: 1873-1876, 2004. [PubMed: 15596594] [Full Text: https://doi.org/10.1001/archopht.122.12.1873]
Lambert, J.-C., Luedecking-Zimmer, E., Merrot, S., Hayes, A., Thaker, U., Desai, P., Houzet, A., Hermant, X., Cottel, D., Pritchard, A., Iwatsubo, T., Pasquier, F., Frigard, B., Conneally, P. M., Chartier-Harlin, M.-C., DeKosky, S. T., Lendon, C., Mann, D., Kamboh, M. I., Amouyel, P. Association of 3-prime-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. J. Med. Genet. 40: 424-430, 2003. [PubMed: 12807963] [Full Text: https://doi.org/10.1136/jmg.40.6.424]
Luedecking-Zimmer, E., DeKosky, S. T., Chen, Q., Barmada, M. M., Kamboh, M. I. Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. Hum. Genet. 111: 443-451, 2002. [PubMed: 12384789] [Full Text: https://doi.org/10.1007/s00439-002-0802-7]
Mango, R., Clementi, F., Borgiani, P., Forleo, G. B., Federici, M., Contino, G., Giardina, E., Garza, L., Fahdi, I. E., Lauro, R., Mehta, J. L., Novelli, G., Romeo, F. Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. (Letter) J. Med. Genet. 40: 933-936, 2003. [PubMed: 14684693] [Full Text: https://doi.org/10.1136/jmg.40.12.933]
Mehta, J. L., Li, D. Y. Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells. Biochem. Biophys. Res. Commun. 248: 511-514, 1998. [PubMed: 9703956] [Full Text: https://doi.org/10.1006/bbrc.1998.9004]
Nagase, M., Abe, J., Takahashi, K., Ando, J., Hirose, S., Fujita, T. Genomic organization and regulation of expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1) gene. J. Biol. Chem. 273: 33702-33707, 1998. [PubMed: 9837956] [Full Text: https://doi.org/10.1074/jbc.273.50.33702]
Sawamura, T., Kume, N., Aoyama, T., Moriwaki, H., Hoshikawa, H., Aiba, Y., Tanaka, T., Miwa, S., Katsura, Y., Kita, T., Masaki, T. An endothelial receptor for oxidized low-density lipoprotein. Nature 386: 73-77, 1997. [PubMed: 9052782] [Full Text: https://doi.org/10.1038/386073a0]
Tatsuguchi, M., Furutani, M., Hinagata, J., Tanaka, T., Furutani, Y., Imamura, S., Kawana, M., Masaki, T., Kasanuki, H., Sawamura, T., Matsuoka, R. Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction. Biochem. Biophys. Res. Commun. 303: 247-250, 2003. [PubMed: 12646194] [Full Text: https://doi.org/10.1016/s0006-291x(03)00326-7]
Yamanaka, S., Zhang, X.-Y., Miura, K., Kim, S., Iwao, H. The human gene encoding the lectin-type oxidized LDL receptor (OLR1) is a novel member of the natural killer gene complex with a unique expression profile. Genomics 54: 191-199, 1998. [PubMed: 9828121] [Full Text: https://doi.org/10.1006/geno.1998.5561]
Yoshida, H., Kondratenko, N., Green, S., Steinberg, D., Quehenberger, O. Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential as a scavenger receptor. Biochem. J. 334: 9-13, 1998. [PubMed: 9693095] [Full Text: https://doi.org/10.1042/bj3340009]