Prevalence of risk alleles in the lysyl oxidase-like 1 gene in pseudoexfoliation glaucoma patients in India

Purpose: The purpose of this study was to genotype two previously identified SNPs (rs1048661:R141L, and rs3825942:G153D) in the lysyl oxidase?like 1 (LOXL1) gene and determine their association with pseudoexfoliation glaucoma (XFG) in patients from Pune, India. Methods: All subjects underwent detailed phenotyping, and DNA extraction was performed on blood samples by using standardized techniques. Exon 1 of the LOXL1 gene containing the SNPs (rs3825942:G153D; rs1048661:R141L) were Sanger sequenced, and the results were analyzed using sequence analysis software SeqScape 2.1.1. Results: Data were analyzed from 71 patients with XFG and 81 disease?negative, age?matched controls. There was a strong association between the G allele of rs3825942 and XFG with an odds ratio of 10.2 (CI: 3.92–26.6; P < 0.001). The G allele of rs1048661 also showed an increase in risk relative to the T allele (OR = 1.49; CI: 0.88–2.51; P = 0.13), but this was not significant. Haplotype combination frequencies were estimated for rs1048661 and rs3825942; the GG haplotype was associated with a significant increase in risk (OR = 3.91; CI: 2.27–6.73; P < 0.001). Both the GA and TG haplotypes were associated with decreased XFG risk, although the latter was not significant (GA: OR = 0.08; CI: 0.03–0.21; P < 0.001; TG: OR = 0.67; CI: 0.40–1.13; P = 0.13). Conclusion: The risk G allele in rs3852942 (G153D) is strongly associated with the development of XFG in the Western Indian population. Genetic screening strategies to identify LOXL1 risk alleles in the population can assist in case definition and early diagnosis, targeting precious resources to high?risk patients.

The Dual Role of LOXL4 in Pathogenesis and Development of Human Malignant Tumors / 中国生物化学与分子生物学报

Lysyl oxidase like 4 (LOXL4) is one member of the LOX protein family and is a secreted copper-dependent amine oxidase involved in the assembly and maintenance of extracellular matrix (ECM). LOXL4 is up-regulated in human liver cancer, gastric cancer, breast cancer, cervical cancer, head and neck squamous cell carcinoma, esophageal carcinoma and colorectal cancer, but down-regulated in human bladder and lung cancer. It also inhibits tumor growth in bladder and lung cancer, suggesting that L0XL4 has a dual role of promoting or inhibiting tumors in different types of human malignant tumors. L0XL4 in tumor cell exosomes promotes cell matrix adhesion and cell migration by activating the FAK/Src pathway, which is dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. Exosome-mediated L0XL4 can also promote tumor cell proliferation and immune escape by activating the PI3K/Akt signaling pathway. L0XL4 can be transported to macrophages via exosomes in tumor cells, where it further activates the immunosuppression function of cells and the expression of programmed death ligand 1 (PD-L1) via STAT1- and STAT3-mediated signaling pathways. It then will trigger the immunosuppressive function of macrophages and promote the immune escape of tumor cells. In addition, LOXL4 can also exert the tumor suppressive function by activating p53 and inhibiting the Ras/ERK pathway. This paper mainly reviews the structure and the function of LOXL4, and the relationship between LOXL4 and the pathogenesis and development of human malignant tumors. We then further explore the application of LOXL4 in the study of malignant tumors, laying a theoretical foundation for its future utilization in the clinical diagnosis and treatment, and screening of prognostic markers of human malignant tumors.

Lox Family and Their Role in Tumour Formation: An Overview

@#The lysyl oxidase family has five family members which are; Lysyl Oxidase (LOX), Lysyl Oxidase Like-1 (LOXL1), Lysyl Oxidase Like-2 (LOXL2), Lysyl Oxidase Like-3 (LOXL3), and Lysyl Oxidase Like-4 (LOXL4). These are amine oxidases which are copper (Cu) dependent. The main function of these secreted enzymes is covalently crosslinking extracellular collagens and elastins, making the extracellular matrix (ECM) stable. Association with LOX family enzymes has been found in various diseases including tumours, suggesting that it may be involved in the pathogenesis of the lesions. To add to the complexity, some of the LOX family members have been linked with tumour suppression while the other members were associated with tumour promotion, progression and metastasis. Thus, this review will explore further insight into the role of LOX family in tumour formation.

Exfoliation syndrome associated with LOXL1 gene polymorphisms in a Black patient from Latin America: a case report / Síndrome de esfoliação associada a polimorfismos do gene LOXL1 em paciente negro da América Latina: relato de caso

ABSTRACT A 89-year-old Black female with a 6-year history of advanced open-angle glaucoma was referred to the Glaucoma Service of the Ophthalmology Department - Federal University of São Paulo (UNIFESP). Best-corrected visual acuity was 20/400 in the right eye and 20/60 in the left eye. Pseudoexfoliation material was observed at the iris border, angle, and the anterior lens surface. Anterior biomicroscopy revealed exfoliation material forming an evident peripheral zone and a central disc separated by a clear intermediate zone on the anterior lens surface OU. Gonioscopy showed an open-angle Sampaolesis's line and whitish material deposits OU. Fundus examination revealed a cup-to-disc ratio of 1.0 OU with peripapillary atrophy. Genetic analysis for single nucleo­tide polymorphisms of the lysyl oxidase-like 1 gene linked to exfoliation syndrome identified two such single nucleotide polymorphisms, rs1048661 and rs216524.

RESUMO Uma mulher negra de 89 anos com um histórico de seis anos de glaucoma avançado de ângulo aberto avançado foi encaminhada ao Serviço de Glaucoma do Departamento de Oftalmologia da Universidade Federal de São Paulo (UNIFESP). A acuidade visual melhor corrigida era 20/400 no olho direito e 20/60 no olho esquerdo. Material pseudo-exfoliativo foi observado na borda iriana, ângulo e superfície anterior do cristalino. A biomicroscopia de segmento anterior demonstrou material exfoliativo formando uma zona periférica evidente e um disco central separado por uma zona intermediária livre na cápsula anterior do cristalino. A gonioscopia mostrou uma linha de Sampaolesi de ângulo aberto e depósitos esbranquiçados. O exame de fundo de olho revelou disco óptico com escavação total em ambos os olhos com atrofia peripapilar. A análise genética para polimorfismos de nucleotídeo único do gene semelhante à lysyl oxidase-like 1 ligado à síndrome de esfoliação identificou dois desses polimorfismos de nucleotídeo único, rs1048661 e rs216524.

Comparison of LOXL-2 Expression between Active Systematic Scleroderma and Active Mixed Connective Tissue Disease / 中国医科大学学报

Objective To investigate the expression of lysyl oxidase like protein?2(LOXL?2)in the sera of patients with active systemic scleroder?ma(SSc)and mixed connective tissue disease(MCTD). Methods An enzyme?linked immunosorbent assay was adopted to measure LOXL?2 in the serum of 20 patients with active SSc,20 patients with active MCTD,and 20 healthy controls. The measurements among different groups was com?pared,and correlations between LOXL?2 levels and clinical manifestations of SSc and MCTD were examined. Results The levels of LOXL?2 ex?pression in MCTD and SSc groups were significantly higher than those in control group(P<0.05 for all groups). LOXL?2 expression is also related to the presence of skin lesions in SSc(r=0.982 P=0.001). Conclusion High serum level of LOXL?2 in these patients with active SSc and active MCTD suggests that LOXL?2 may be involved in the process of fibrosis and the resulting vasculitis in multiple organs.

Association between single nucleotide polymorphisms at LOXL1 promoter and Uygur patients with exfoliation syndrome / 中华实验眼科杂志

Background Exfoliation syndrome (XFS) is a systemic disease with abnormal accumulation of extracellular matrix.Researches showed that the single nucleotide polymorphisms (SNPs) of lysyl oxidase-like 1 (LOXL1) gene is associated with the pathogenesis of XFS in global population.However,the results are varied among different ethnicity and regions.Objective This study aimed to assess the association between LOXL1 gene polymorphisms and XFS in Uygur population.Methods One-hundred and fifty-two Uygur XFS patients without relativeness were enrolled from January to August in 2014,and 228 ethnicity-and gender-matched normal controls were recruited at the same period from the same region.Each individual underwent comprehensive eye examinations and 5 ml peripheral blood was collected.Genomic DNA was extracted from peripheral blood.PCR-ligase detection response (LDR) was used to determine the allele and genotype frequencies of the six SNPs rs12914489,rs4886467,rs4558370,rs4461027,rs4886761 and rs16958477 in the promoter region of LOXL1 gene.The distribution frequency between the patients and normal controls was compared by x2 test.Logistic regression analysis was used for age adjustment.This study was approved by Ethic Committe of Xinjiang Medical University,and informed consent was obtained from the subjects.Results rs12914489 site in the normal control group diverged from Hardy-Weinberg equilibrium (HWE) (P =0.033),and the rs4886467,rs4558370,rs4461027,rs4886761 and rs16958477 sites followed HWE.The frequencies of G allele and GG genotype of rs4886467 in the XFS group were lower than those in the control group (both at P =0.00) and were protective factors of XFS (OR =0.54,95 ％ CI:0.40-0.74,P =0.000;OR=0.51,95％ CI:0.33-0.78,P=0.001);the frequencies of T allele and TT genotype of rs4558370 in the XFS group were significantly higher than those in the control group (both at P=0.00) and were the risk factors of XFS (OR=1.96,95％ CI:1.23-3.11,P =0.004;OR =2.18,95％ CI:1.31-3.64,P =0.002);the frequencies of C allele and CC genotype of rs4461027 in the XFS group were significantly higher than those in the control group (both at P=0.00) and were the risk factors of XFS (OR=2.25,95％ CI:1.67-3.04,P=0.000;OR=3.06,95％ CI:1.89-4.96,P=0.000);the frequencies of T allele and TT genotype of rs4886761 in the XFS group were significantly higher than those in the control group (both at P=0.00) and were the risk factors of XFS (OR=2.44,95％ CI:1.79-3.33,P =0.000;OR =3.02,95％ CI:1.63-5.60,P =0.000);the frequencies of C allele and CC genotype of rs16958477 in the XFS group were significantly higher than those in the control group (both at P=0.00) and were the risk factors of XFS (OR =2.00,95 ％ CI:1.47-2.71,P =0.000;OR =2.37,95 ％ CI:1.31-4.27,P =0.004).Conclusions The SNPs of promoter region of LOXL1 gene are associated with hereditary susceptibility of XFS individually in Uygur population.The SNPs of rs4886467 locus are protective factor,while the SNPs of rs4558370,rs4461027,rs4886761 and rs16958477 locus are risk factors for pathogenesis of XFS.

The expression and significance of lysyl oxidase like-2 in pulmonary fibrosis mice / 中华风湿病学杂志

Objective To assess whether lysyl oxidase like-2 (LOXL2) has a predictive or prognostic value in pulmonary fibrosis mice,and identify the relationship between LOXL2 and transforming growth factor (TGF)-β 1.Methods Male C57BL/6 mice (n=50) were randomly divided into the experimental group (n=40) and controls (n=10).Each mouse in the experimental group was induced by injecting bleomycin into trachea and mice were sacrificed on day 3,7,14 and 28,respectively.The concentrations of LOXL2,TGF-β 1 of the serum and lung homogenates were measured by enzyme-linked immunosorbent assay.One-factor analysis of variance (ANOVA) and nonparametric rank sum test was used for the comparisons between the two groups.Associations between these factors were analyzed by Spearman's test.Results ① The levels of serum and lung homogenates LOXL2 in the experimental group were obviously increased as compared to those in the controls [serum:(56±48) vs (25±23),P＜0.05;lung homogenates:(61±32) vs (22±16),P＜0.05].And in the experimental group,a positive correlation was found between the level of LOXL2 and the radiological index,the pathological score of inflammation and fibrosis.(Serum:r=0.435,0.533,0.335,P＜0.05;lung homogenates:0.675,0.736,0.526,P＜0.05).② The levels of lung homogenates TGF-β 1 in the experimental group were obviously increased as compared to those in the controls [(302±197) vs (64±16),P＜0.05].A positive correlation was found between the level of lung homogenates LOXL2 and the level of lung homogenates TGF-β1 (r=0.520,P＜0.05).Conclusion LOXL2 participates in the pathological process of bleomycin induced pulmonary fibrosis in mice.It predicts pulmonary fibrosis in the preclinical stage and is associated with increased risk for disease progression.The elevated levels of LOXL2 and TGF-β 1 may have some relationship.They both are involved in the disease progression of pulmonary fibrosis.

Lisil-oxidasa (LOX) y proteinas tipo LOX: rol de amino-oxidasas, propiedades moleculares y cataliticas / Lysyl oxidase (LOX) and LOX-like proteins: role of amino-oxidases, molecular and catalytic properties / Lisil-oxidase (LOX) e proteinas tipo LOX: papel da amino-oxidases, propriedades moleculares e catalíticas

Las amino-oxidasas pertenecen a dos grupos de proteinas: flavoenzimas y quinoenzimas. La lisil-oxidasa (LOX) es una quinoenzima que contiene cobre y lisil-tirosil-quinona como cofactor. Los niveles de LOX aumentan en muchas enfermedades fibroticas y en algunos tumores promoviendo metastasis, mientras que la expresion de la enzima esta disminuida en enfermedades que involucran un deterioro en el metabolismo del cobre. Se discute el rol de LOX como amino-oxidasa en la catalisis de la desaminacion oxidativa de residuos de lisina en los precursores del colageno y de elastina, y la participacion de los restantes miembros de esta familia genica: LOXL1, LOXL2, LOXL3 y LOXL4, asi como sus propiedades moleculares. Se analizan su biosintesis, sus propiedades cataliticas y mecanismo de reaccion, cofactores e inhibidores y la expresion y respuesta a diversos efectores celulares.

Amino-oxidases belong to two groups of proteins: flavoenzymes and quinoenzymes. Lysyl oxidase (LOX) is a copper-containing quinoenzime, having lysyl-tyrosyl-quinone as cofactor. LOX levels are increased in many fibrotic diseases, and in some tumors promoting metastasis, while the enzyme expression is decreased in diseases that involve deterioration in copper metabolism. The role of LOX as amino oxidase in catalyzing the oxidative deamination of lysine residues in precursors of collagen and elastin is discussed, as well as the participation of other members of this gene family: LOXL1, LOXL2, LOXL3, and LOXL4, and their molecular properties. The biosynthesis, catalytic properties and reaction mechanism, cofactors and inhibitors, and the expression and response to various cellular effectors are analyzed.

As amina oxidases pertencem a dois grupos de proteínas: flavoenzimas e quinoenzimas. A lisil-oxidase (LOX) é uma quinoenzima contendo cobre e lisil-tirosil-quinona como cofator. Os níveis da enzima LOX aumentam em muitas doenças fibróticas e em alguns tumores promovendo metástase, enquanto que a expressão da enzima está reduzida em doenças que envolvem a deterioração no metabolismo do cobre. Discute-se o papel de LOX como amina oxidase na catálise a desaminação oxidativa de resíduos de lisina de precursores de colágeno e de elastina, e a participação dos outros membros desta família gênica: LOXL1, LOXL2, LOXL3 e LOXL4, bem como as suas propriedades moleculares. A sua biossíntese, as suas propriedades catalíticas e mecanismo de reação, cofatores e inibidores e a expressão e resposta a diversos efetores celulares são analisados.

Correlation between lysyl oxidase-like protein 2 and neoplasms and its mechanism / 国际肿瘤学杂志

Lysyl oxidase-like protein 2 (LOXL2) is one of the lysyl oxidases (LOX) families.At present,most of scholars consider that LOXL2 is a neoplasm metastasis gene,whereas some others belleve that LOXL2 is a neoplasm suppressor gene.Studies found that LOXL2 gene combined with other oncogenes promotes neoplasm invasion,metastasis and indicates a poor prognosis.Related researches provide new ideas for judging tumor metastasis and prognosis and looking for new targets for cancer therapy.