Intercellular adhesion molecule-1 K469E polymorphism: study of association with multiple sclerosis

Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).     

细胞间黏附分子-1基因K469E多态性与广西壮族人群缺血性脑卒中的遗传易感性

目的探讨细胞间黏附分子-1(intercellular adhesion molecule-1, ICAM-1)基因多态性与广西地区壮族人群缺血性脑卒中(ischemic stroke,IS)的关系.方法采用聚合酶链反应-限制性片段长度多态性和DNA序列测定法检测205例IS及210名对照者 ICAM-1基因第6外显子K469E多态性,同时采用酶联免疫吸附试验检测IS和对照者血清ICAM-1水平. 结果 IS组ICAM-1血清水平显著高于对照组(P<0.01), ICAM-1基因K469E基因型频率和等位基因频率在IS组和对照组比较差异有统计学意义(P<0.05),等位基因频率的相对风险分析发现,E等位基因携带者患IS的风险是K等位基因的1.424倍(OR=1.424,95%CI1.071～1.894),携带E等位基因的IS患者ICAM-1血清水平显著高于不携带者[(501.24±139.56)ng/ml vs(475.17±118.35)ng/ml, P<0.01]. 结论 ICAM-1基因K469E多态性与IS的发病具有相关性,E等位基因可能是广西地区壮族人群IS发病的遗传易感基因,携带E等位基因的个体可能通过促进 ICAM-1的高度表达进而增加IS的发病风险.     

细胞间黏附分子-1基因K469E多态性与冠心病关系的研究

目的：探讨细胞间黏附分子-1（ICAM-1）基因K469E多态性在冠心病及正常人群中的分布，初步分析其基因型及血清水平与冠心病的关系。方法：采用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）技术和DNA序列测定法，检测了225例冠心病患者和230例对照者的ICAM-1基因K469E多态性，并用酶联免疫吸附试验检测了ICAM-1的血清水平。结果：冠心病组血清ICAM-1水平显著高于对照组（P〈0．01），ICAM-1基因型及等位基因的分布频率在冠心病组和对照组间比较差异具有显著性（P〈0．05），K等位基因携带者患冠心病的相对风险度是E等位基因的1．430倍（与对照组相比），而患心肌梗死的相对风险度是1．816倍（与心绞痛组相比）。结论：ICAM-1基因K469E多态性与冠心病的发生、发展及该疾病的严重程度密切相关，其中K等位基因可能是冠心病发病的遗传易感基因。     

Intercellular adhesion molecule-1 (ICAM-1) K469E polymorphism: no association with type 1 diabetes among Finns

The intercellular adhesion molecule-1 (ICAM-1) has an important role in the process of lymphocyte migration and activation, and is supposed to be involved in the pathogenesis of type 1 diabetes. We studied A/G (K469E) polymorphism of the ICAM-1 gene in 218 type 1 diabetes patients and 212 controls from Finland and found no association. We then studied transmission of the ICAM-1 alleles in 102 Finnish families using a transmission disequilibrium test (TDT). Alleles A and G were transmitted to the affected offspring in 50% each. Stratification by the HLA-DQB1-DQA1 genotypes, sex and age at onset did not reveal association. Our data demonstrate that in the Finnish population K469E polymorphism of the ICAM-1 gene is not associated with type 1 diabetes.     

The intercellular adhesion molecule-1 (ICAM-1) gene polymorphism K469E in end-stage renal disease patients with cardiovascular disease

The intercellular adhesion molecule-1 (ICAM-1) mediates interaction of activated endothelial cells with leukocytes. It plays an important role in the pathogenesis of atherosclerosis. A functionally important polymorphism of the ICAM-1 gene, K469E, has been described. We investigated whether this polymorphism influences the risk of CVD in end-stage renal disease (ESRD) patients. The groups of 1016 ESRD patients and 824 healthy individuals were genotyped by PCR and allele specific oligonucleotide technique. The T allele of the K469E polymorphism was significantly more frequent in ESRD CVD+ patients than CVD- and controls (OR 2.26, 95% CI 1.87-2.72 and 1.82, 95% CI 1.55-2.11, respectively). The TT genotype was also more frequent in CVD+ patients (OR 9.90, 95% CI 6.17-15.88 vs. CVD- subgroup). When patients were stratified according to clinical outcome of CVD, there was a tendency towards higher frequencies of the T allele and TT genotype in patients with myocardial infarction (OR for T allele 1, 57, 95% CI 1.12-2.18 vs. patients without MI). In the multivariate regression analysis the carrier status of T allele of K469E was an independent risk factor of susceptibility to CVD. Our data suggest that the ICAM-1 K469E polymorphism is associated with CVD in ESRD patients.     

Absence of association between an intercellular adhesion molecule 1 gene E469K polymorphism and Alzheimer's disease in Finnish patients

Increased expression of intercellular adhesion molecule 1 (ICAM1), a protein known to contribute to inflammatory responses, has been detected in the brain tissue of patients with Alzheimer's disease (AD) and animals modelled to mimic AD or Parkinson's disease (PD). ICAM1 may, thus, be implicated in the pathogenesis of these disorders. Our purpose was to investigate whether genetic variants of the ICAM1 gene have a role in causing susceptibility to AD and/or PD. We genotyped the E469K polymorphism of ICAM1 in 196 AD, 52 PD and 202 control patients of Finnish origin. The distributions of the genotype and allele frequencies of the polymorphism did not differ significantly between the AD, PD or the control patients. We therefore conclude that the E469K polymorphism of ICAM1 is not a risk factor for AD or PD.     

细胞间黏附分子-1基因K469E多态性与类风湿性关节炎的关系

目的 探讨细胞间黏附分子-1(intercelluhr adhesion molecul-1,ICAM-1)基因K469E多态性与类风湿性关节炎(rheumatoid arthritis,RA)的关系.方法 对275例类风湿性关节炎患者和254名体检健康者作为对照组进行研究.采用聚合酶链反应-限制性片段长度多态性方法分析ICAM-1基因K469E的多态性.结果 RA组K469E位点KK、KE和EE基因型频率为0.535、0.411和0.054;健康对照组K469E位点KK、KE和EE基因型频率为0.512、0.437和0.051.RA组K469E基因型频率与健康对照组相比差异无统计学意义(x2=0.371,P=0.831).RA组K等位基因频率(0.74)与健康对照组(0.73)相比差异无统计学意义(x2=0.127,P=0.721,OR=1.051,95%CI为0.800～1.381),在RA组中KK+KE基因型频率与对照组相比,差异无统计学意义(P=0.863,OR=0.935,95%CI为0.436～2.005).结论 ICAM-1基因K469E多态性分布与RA的易感性无明显相关性.

Abstract：

Objective To investigate the association of the intercellular adhesion molecule-1 gene (ICAM-1)K469E polymorphism and rheumatoid arthritis (RA). Methods Two hundred and seventy five patients with RA and 254 healthy individuals were collected and enrolled in the study. The K469E polymorphism of ICAM-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results The genotype frequencies of KK, KE and EE of K469E polymorphism were 0. 535,0.411 and 0. 054 respectively in the RA patients, and 0. 512,0. 437 and 0. 051 respectively in the healthy individuals, and there was no significant difference between the two groups (x2 =0. 371,P=0. 831). The frequencies of the K469 allele were 0. 74 and 0. 73 in the RA patients and the controls respectively (x2 = 0. 127, P = 0. 721, OR = 1.051,95 % CI: 0. 800-1. 381 ). No significant difference was observed in KK+KE genotype frequencies between the two groups (P=0. 863), with an odds ratio of 0. 935 (95% CI: 0. 436-2.005). Conclusion The K469E polymorphism of the ICAM-1 gene was not associated with the susceptibility of rheumatoid arthritis.     

Intercellular adhesion molecule 1 K469E gene polymorphism is associated with presence of skin lesions in Tunisian Behçet's disease patients

Abstract
Intercellular adhesion molecule 1 ( ICAM1 ) gene polymorphisms have been implicated in the susceptibility to inflammatory diseases. The expression of both soluble and tissue ICAM1 were increased in Behçet's disease (BD) but the contribution of ICAM1 gene polymorphisms to this disease remains unknown. We sought to establish the association of ICAM1 gene K469E polymorphism in exon 6 with susceptibility for BD. One hundred and thirty-five Tunisian patients who satisfied the International Study Group criteria for BD and 157 healthy blood donor controls from the same geographic area were genotyped by polymerase chain reaction method for the K469E ICAM1 gene polymorphisms in exon 6. There were no significant differences in the distribution of the K469E allele or genotype frequencies between the BD patients and healthy controls in the ICA1 gene. Among patients, significant association was found between the presence of skin lesions and the studied polymorphism in the distribution of the K469E allele ( P = 0.004; odds ratio = 1.26; 95% confidence interval = 2.13–3.62) and genotype frequencies ( P = 0.0028;χ² = 11.75). Our findings suggest that K469E ICAM1 gene polymorphism was associated with Tunisian BD patients with skin lesions.     

细胞间黏附分子1基因K469E多态性与冠状动脉粥样硬化性心脏病的关联研究

目的研究中国汉族人群中细胞间黏附分子1（intercellular adhesion moleculel，ICAM1）基因K469E多态性与冠状动脉粥样硬化性心脏病（简称冠心病）的关联。方法采用聚合酶链反应．限制性片段长度多态性方法检测了173例冠心病患者和141名对照的ICAM1基因K469E基因型和等位基因的分布。结果基因型频率符合Hardy-Weinberg平衡。冠心病组的KK基因型的频率显著高于对照组（64．2％比48．9％，P〈0．01），同样，冠心病组K等位基因的频率显著高于对照组（79．2％比69．9％，P〈0．01）。经Logistic回归分析排除年龄，性别，和冠心病其它危险因素的影响后，KK纯合子患冠心病的危险性是KE和EE基因型的2．35倍（95％CI：1．03-5．36，P〈0．05）。结论ICAM1基因K469E多态性与中国汉族人冠心病的危险性相关，其中K等位基因可能是冠心病的遗传危险因素。     

Intercellular adhesion molecule-1 gene polymorphisms in Beh?et's disease.

Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms have been implicated in the susceptibility to inflammatory diseases, including multiple sclerosis and inflammatory bowel disease. The expression of both soluble and tissue ICAM-1 is increased in Beh?et's disease (BD) but the contribution of ICAM-1 gene polymorphisms to this disease remains unknown. Associations with BD have been reported for genes within the MHC, including HLA-B51, TNF and MICA, but the role of non-MHC genes in BD remains largely unexplored. We have investigated the frequency of the R/G 241 and K/E 469 ICAM-1 gene polymorphisms in 83 patients with BD disease and 103 healthy controls, all of Palestinian and Jordanian descent, and demonstrated an association between BD and the ICAM-1 E469 allele (Pc = 0.046, OR = 2.1). Among patients, no association was found between the presence of ocular disease and ICAM-1 polymorphisms. While the functional correlate of this polymorphism remains unclear, this finding indicates that a genetic polymorphism in the ICAM-1 gene domain, which is independent of the MHC, may contribute to disease.     

The intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism is not associated with ischaemic heart disease: an investigation using family-based tests of association.

The possible role of the K469E polymorphism in the intercellular adhesion molecule-1 (ICAM-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family-based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped for the ICAM-1 K469E polymorphism. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the ICAM-1 K469E polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the ICAM-1 K469E polymorphism is not associated with IHD.     

Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in endometriosis

Endometriosis is a gynaecological disease with a certain genetic background, but the locations of possible genomic aberrations are still poorly clarified. Intercellular adhesion molecule-1 (ICAM-1), which is a surface glycoprotein that promotes adhesion in immunological and inflammatory reactions, seems to play a role in this condition. The aim of this study was to examine the potential associations of ICAM-1 gene polymorphisms with endometriosis and its severity. Specifically, we have studied two polymorphic sites located in codons 241 (G/R241) and 469 (E/K469) of the ICAM-1 gene. Three hundred and sixty-three Italian Caucasian women of reproductive age who underwent laparoscopy for benign pelvic conditions were enrolled in the study. Endometriosis was documented and staged in 188 women while 175 subjects, in whom endometriosis was laparoscopically ruled out, served as the control group. The frequency of the R241 allele was only marginally higher in endometriosis patients than in controls [5.8 versus 2.9%, P = 0.05; odds ratio (OR), 2.1; 95% confidence interval (CI), 1-4.5]. However, a strikingly high frequency of this allele was found in patients with Stage IV endometriosis versus controls (8.6 versus 2.8%, P = 0.008; OR, 3.2; 95% CI, 1.3-7.9). In contrast, the allele and genotype frequencies of the E/K469 polymorphism did not differ significantly between endometriosis and control groups. While the functional correlate of the G/R241 polymorphism remains unclear, this finding indicates that a genetic polymorphism in the ICAM-1 gene domain may contribute to the susceptibility to endometriosis.     

Intercellular adhesion molecule-1 polymorphisms in Korean patients with Behcet s disease

Intercellular adhesion molecule-1 (ICAM-1) is expressed on vascular endothelial cells and its expression increases during the inflammatory response in patients with active Behcet's disease (BD). The ICAM1 gene mutations are associated with BD in Caucasians, but clinical features of the mutation phenotype are unknown. We analyzed ICAM1 polymorphisms in Korean BD patients to determine if there was an association between particular mutations and clinical symptoms. The prevalence of ICAM1R241G and ICAM1K469E polymorphisms was determined among 197 patients with BD and 248 healthy controls using BsrG1 and BstU1 PCR-RFLP. The frequency of both genotypes ICAM1469 * K/ * E and ICAM-1469 * E/ * E was significantly higher in BD patients compared with controls (66.0% vs 52.4%, p=0.004, OR=1.28, 95% CI 1.08-1.50) and the allele frequency of ICAM1469 * E was higher in patients with skin lesions (0.41), genital ulcers (0.41), vasculitis (0.43), ocular lesions (0.41) and arthritis (0.39) than in controls (0.31). Only one heterozygote, ICAM1241G/R, was detected in BD patients but the ICAM1241 * R mutation was not found in any of the 248 healthy controls. These results show that the ICAM1 mutation is associated with BD susceptibility, and is another genetic risk factor for BD among the Korean population.     

Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 cooperatively contribute to the cutaneous Arthus reaction

Immune complex (IC)-induced inflammation is mediated by inflammatory cell infiltration, a process that is highly regulated by expression of multiple adhesion molecules. The roles and interactions of ICAM-1 and VCAM-1, the major regulators of leukocyte firm adhesion, were examined in the cutaneous reverse-passive Arthus reaction using ICAM-1-deficient (ICAM-1-/-) mice and blocking mAb against VCAM-1. Within 8 h, IC challenge of wild-type mice induced edema, hemorrhage, interstitial accumulation of neutrophils and mast cells, as well as production of TNF-alpha and IL-6. All of these inflammatory parameters were reduced significantly in ICAM-1-/- mice. The blockade of VCAM-1 in wild-type mice did not affect any inflammatory parameters. In contrast, ICAM-1-/- mice treated with anti-VCAM-1 mAb had significantly reduced edema, hemorrhage, and neutrophil infiltration. Furthermore, VCAM-1 blockade in ICAM-1-/- mice suppressed cutaneous TNF-alpha and IL-6 production. Thus, VCAM-1 plays a complementary role to ICAM-1 in the cutaneous Arthus reaction by regulating leukocyte accumulation and proinflammatory cytokine production.     

Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis

The development of bleomycin-induced lung injury, a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. At present, the identity and role of the adhesion molecules involved in the fibrotic process are unknown. Therefore, bleomycin-induced pulmonary fibrosis was examined in mice lacking L-selectin (L-selectin(-/-)) expression, intercellular adhesion molecule-1 (ICAM-1) expression, or both. After 16 days of intratracheal bleomycin challenge, collagen deposition was inhibited in both L-selectin(-/-) and ICAM-1(-/-) mice when compared with wild-type littermates. Interestingly, collagen deposition was virtually eliminated in L-selectin/ICAM-1(-/-) mice relative to either the L-selectin(-/-) or ICAM-1(-/-) mice. Decreased pulmonary fibrosis was associated with reduced accumulation of leukocytes, including neutrophils and lymphocytes. Decreased mRNA expression of proinflammatory cytokines and transforming growth factor (TGF)-beta1 paralleled the inhibition of collagen deposition. The present study indicates that L-selectin and ICAM-1 play a critical role in pulmonary fibrosis by mediating the accumulation of leukocytes, which regulate the production of proinflammatory cytokines and TGF-beta1. This suggests that these adhesion molecules are potential therapeutic targets for inhibiting human pulmonary fibrosis.     

Adulthood-onset celiac disease is associated with intercellular adhesion molecule-1 (ICAM-1) gene polymorphism

Celiac disease (CD) is a multifactorial T-cell-mediated autoimmune disease characterized by gluten-triggered villous atrophy and malabsorption. Although human leukocyte antigen (HLA) class II genes are strong susceptibility factors, non-HLA genes likely contribute to most of CD predisposition. The intercellular adhesion molecule-1 (ICAM-1) gene is a good candidate for CD predisposition because its encoded protein acts as an adhesion and costimulatory receptor. Two single-base polymorphisms (G/A in exon 4 encoding G241R, and A/G in exon 6 encoding K469E) were analyzed in 180 French Caucasian CD case patients (110 patients diagnosed before the age of 15 and 70 patients after the age of 18), and 212 French Caucasian healthy controls. The R241 allele frequency was increased in CD case patients compared with controls (14.2% vs. 5.4% respectively, p = 0.000015, odds ratio [OR] for the R241 allele = 2.9, 95% confidence intervals [CI] = 1.7-4.8). After stratifying for age of disease onset, the R241 variant mainly conferred predisposition to CD occurring during adulthood (OR = 4.2, 95% CI = 2.3-7.5, Pc = 0.000004 for adulthood-onset CD vs. R = 2.1, 95%, CI = 1.2-3.9, Pc = 0.0047 for childhood-onset CD). Position 241 of ICAM-1 maps to the binding site for the integrin Mac-1 and might modify the strength of interaction between endothelium and immune cells. If confirmed in independent datasets, these results may be of importance in at-risk individuals to distinguish rapid from delayed progression to clinical CD.     

载脂蛋白E基因多态性与散发性老年性痴呆病的关系

目的:探讨载脂蛋白E(apoE)外显子4和增强子元件基因多态性与散发性Alzheimer病(AD)的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术分别检测apoE外显子4和内含子1内增强子元件(IE1)基因型。结果:(1)ApoE外显子4基因多态性:AD组ε3/4基因型频率(0.381)和ε4等位基因频率(0.226)显著高于对照组(P＜0.05)。(2)ApoEIE1基因多态性AD组G/G基因型频率(0.595)显著高于对照组(P＜0.05)。(3)有apoEε4个体患AD风险为无ε4个体的3倍,比值比为2.932,95%可信区间1.379~6.226;G/G基因型个体患AD风险为G/C、C/C个体的2倍,比值比为2.223,95%可信区间1.075~4.599;经统计分析发现apoEε4与IE1G/G呈非常显著性正相关(P＜0.01);排除apoEε4后发现IE1G/G与AD发病风险无关。结论:ApoEε4等位基因是个体发生AD的危险因素,IE1G/G增加AD发病风险是因其与ε4相关所致。     

Intercellular adhesion molecule-1 in patients with idiopathic interstitial pneumonia

This study focuses on a possible role of intercellular adhesion molecule-1 (ICAM-1) in interstitial pulmonary diseases. We determined a soluble form of ICAM-1 in serum and bronchoalveolar lavage fluid (BALF) using ELISA in patients with usual interstitial pneumonia (UIP), bronchiolitis obliterance organizing pneumonia (BOOP), or nonspecific interstitial pneumonia (NSIP). In addition, we investigated the expression of ICAM-1 in the lung tissues of these patients by means of immunohistochemical staining. Serum levels of soluble ICAM-1 were significantly higher in patients with UIP or NSIP than in healthy subjects, and were also high in patients with BOOP. The soluble ICAM-1 in BALF tended to be higher in patients with UIP, BOOP, or NSIP than in normal subjects. A significant correlation was seen between soluble levels of ICAM-1 in serum and BALF. In the immunostaining of ICAM-1 of the lung tissues, ICAM-1 expression was more pronounced in patients with UIP than in those with BOOP or NSIP. The increased expression of ICAM-1 was seen in type II alveolar epithelium and vascular endothelium in patients with interstitial pneumonia. A positive correlation was observed between the degree of ICAM-1 expression in the lung tissues and the BALF levels of soluble ICAM-1. The expression of ICAM-1 in type II alveolar epithelium suggests that ICAM-1 plays a specific role in the fibrotic process of the lung, and that the measurement of soluble ICAM-1 in sera and BALF could be a useful marker for evaluating the progression of fibrosis.     

冠状动脉粥样硬化性心脏病细胞间黏附分子1基因 K469E多态性的研究

目的探讨细胞间黏附分子1(intercellularadhesionmolecule1,ICAM1)基因K469E多态性及其血浆水平与中国汉族冠状动脉粥样硬化性心脏病(简称冠心病)之间的关系。方法利用巢式PCR和免疫酶联吸附测定技术对160例冠心病患者和164名非冠心病对照进行ICAM1基因K469E多态性及其血浆水平的检测和对比分析。结果冠心病组K等位基因频率、ICAM1血浆水平均高于非冠心病对照组(P<0·05);含K等位基因的个体ICAM1血浆水平(344.34±128.59μg/L)高于不含K等位基因的个体(303·54±108·74μg/L),差异有统计学意义(P=0.008);且其患冠心病(心肌梗塞)的危险性升高(P=0.006,OR=2·158,95%CI:1.250~3.727);K等位基因与吸烟在影响冠心病发生危险性方面有协同作用。结论在中国汉族人群中存在ICAM1基因K469E多态性,其中K等位基因有可能是冠心病的遗传危险因素。