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.     

Association of vascular endothelial growth factor gene polymorphisms with susceptibility and clinicopathologic characteristics of colorectal cancer

Since vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor, we evaluated the potential association of two VEGF gene polymorphisms (-634G>C and 936C>T) with the susceptibility and the clinicopathologic characteristics of colorectal cancer (CRC). The VEGF genotypes were determined using fresh colorectal tissue from 465 patients who had undergone a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR/DHPLC assay. For the -634G>C polymorphism, the -634 GC or CC genotype was associated with a decreased risk of CRC (odds ratio [OR], 0.62; p=0.001) as a dominant model of C allele, whereas the 936 TT genotype correlated with advanced stage/ metastasis, a high serum level of CA19-9, and an higher grade in patients with CRC. In the haplotype analyses, haplotype -634C/936C and -634G/936T were associated with a decreased susceptibility of CRC (OR, 0.53 and 0.56; p<0.001, respectively). These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility or clinicopathologic features of CRC. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF gene polymorphisms in the development and progression of CRC.     

Vascular endothelial growth factor gene polymorphisms and pre-eclampsia

Vascular endothelial growth factor (VEGF) plays a crucial role in physiological vasculogenesis and vascular permeability and has been implicated in the pathogenesis of pre-eclampsia. Our present study was undertaken to identify associations between three functional VEGF gene polymorphisms, linked with altered VEGF gene responsiveness, and pre-eclampsia. The study involved 42 pre-eclamptic and 73 healthy control women who were genotyped for the -2578C/A, -634G/C and 936C/T polymorphisms of the VEGF gene. No significant association between genotypic or allelic frequencies in women with pre-eclampsia relative to controls was found. A statistically significant difference was found for allelic frequencies of the 936C/T polymorphism between women with severe pre-eclampsia and controls (odds ratio: 2.70; 95% confidence interval: 1.09-6.63; P = 0.019). VEGF gene polymorphisms studied are unlikely to be major predisposing factors for pre-eclampsia. The presence of the 936T allele probably has a considerable effect on disease modification.     

IL-10 genotype analysis in patients with Behçet's disease

Beh?et's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation, and skin lesions. The etiology of the disease is currently unknown but evidence suggests that there is a strong genetic component mediating the chronicity of the disorder. We have examined the association between polymorphisms at position -1082, and -819 in the promoter region of the gene encoding IL-10 in patients with Beh?et's disease from two distinct patient populations. The IL-10 -1082AA genotype was weakly associated with BD when all patients were analyzed as a group (pc = 0.04, OR 1.4, 95% CI 1.1-1.9), but not in the UK or Middle Eastern (ME) cohorts of patients alone compared to local controls. An association with IL-10 -819T was evident in all BD patients, (pc = 0.02, OR 1.5, 95% CI 1.1-2.0), and this was because of an association in the UK but not ME patients (pc = 0.0004, OR 2.1, 95% CI 1.4-3.3). The -1082A/-819T haplotype, which is linked to low production of this cytokine, was not significantly associated with Beh?et's disease. This link between BD, a chronic, relapsing, autoinflammatory condition, and a genotype associated with low IL-10 production provides evidence that abnormalities in the genetic control of cytokine levels may be relevant in influencing the immune response in Beh?et's disease in some patient groups.     

Haplotype association of IL-8 gene with Behcet's disease

Interleukin-8 (IL-8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of Behcet's disease (BD). To investigate the association of the genetic polymorphism of IL-8 and BD, we genotyped IL-8 -845 T/C, -738 T/A, -353 A/T, -251 A/T, +293 G/T, +678 T/C and receptors CXCR-1 +2607 G/C and CXCR-2 +785 C/T polymorphisms in 119 Korean patients with BD and 119 age- and sex-matched healthy blood donors. Then, single nucleotide polymorphisms (SNPs) and haplotypes were analyzed between patients and controls. There were no SNPs associated with BD. However, the frequency of haplotype TAT inferred from SNPs, IL-8 -353 A/T, -251 A/T and +678 T/C, was significantly higher in patients with BD than controls (5.9 vs 0.0%, P = 0.0001), as was haplotype ATC (6.7 vs 0.0%, P < 0.0001). The haplotype difference was still valid in human leukocyte antigen-B51-negative subjects. In conclusion, we found a significant difference in the distribution of IL-8 gene haplotypes between patients with BD and healthy controls. These results suggest that the genetic polymorphisms of proinflammatory chemokine IL-8 can contribute to the pathogenesis of BD.     

HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet's disease

The role of HLA-B*51 and other major histocompatibility complex (MHC) genes in Beh?et's disease (BD) remains unknown. We have performed HLA and tumour necrosis factor (TNF) polymorphism analysis in BD and evaluated their contribution to ocular disease. In this study, 102 patients and 115 controls of Middle Eastern descent were investigated by HLA and B*51 subtyping using novel primers, and by LT alpha NCo 1 and TNF 308 promoter polymorphism analysis. The frequency of the HLA-B*51 family of alleles was raised in patients compared to controls (66% vs. 15%, Pc=2.5x10(-12), OR=10.9). The odds ratio (OR) of this group of alleles for subgroups of patients was as follows: non-ocular patients 7.8, all ocular patients 12.6, blind patients >22. HLA-B*51 subtyping detected B*5101, 07, 08 and 09 alleles, with a similar frequency among patients and controls. HLA-Cw*1602 was associated with B*5108, but was not an independent risk factor for disease. The LT alpha (TNFB*2) allele was associated with HLA-B*51 among patients and the frequency of this allele was significantly higher among completely blind patients compared to both non-ocular patients (P=0.048, OR >3.6) and to healthy controls (P=0.022, OR >4.3). The rare TNF-2 polymorphism at the TNF -308 promoter position was associated with HLA-B*50 (not B*51), and was not associated with BD. Thus, in this population the HLA*B51 family of alleles is a strong risk factor for BD, and in particular the development of ocular disease. HLA-B*51 subtyping did not define new markers for BD. A primary role for TNF gne polymorphisms in BD was not identified, but co-expression of the TNFB*2 allele with HLA-B*51 may contribute to severity of ocular disease.     

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.     

Lack of Association of the Vascular Endothelial Growth Factor Gene Polymorphisms with Kawasaki Disease in Taiwanese Children

INTRODUCTION: Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that mainly occurs in infants and children. Clinical and histopathologic findings suggest that vascular endothelial growth factor (VEGF) is involved in the coronary artery lesions (CALs) development in KD. This study hypothesized that specific VEGF gene polymorphisms and their haplotypes are associated with KD susceptibility and CAL development in Taiwanese children. SUBJECTS AND METHODS: The VEGF -2578 A/C, -634 G/C, and +936 C/T single-nucleotide polymorphisms (SNPs) were genotyped in 156 children with KD and 672 ethnically matched healthy controls using the Pre-Developed TaqMan Allelic Discrimination Assay. RESULTS: No significant differences in genotype, allele, carrier, and haplotype frequencies of the three SNPs were found between healthy controls and children with KD or between patients with and without CAL. CONCLUSION: Our data suggest that VEGF -2578 A/C, -634 G/C, and +936 C/T SNPs do not confer increased susceptibility to KD or to CAL development.     

TNF and TNF receptor polymorphisms in Korean Behcet's disease patients

Behcet's disease (BD) is an autoimmune disease characterized by recurrent oral ulcers, genital ulcers, erythema nodosum, and uveitis. Genetic factors are considered important in its pathogenesis. The serum level of tumor necrosis factor (TNF) is elevated in patients with active BD, and its production is elevated in monocytes and in the gamma delta T cells of BD patients. A dramatic response to anti-TNF-alpha antibody treatment further supports the role of TNF in BD. In this study, we investigated genetic polymorphisms of TNF alpha -308 G/A, TNF beta +252 G/A, and TNFR2 196 R/M in 94 Korean BD patients and age- and sex-matched healthy controls to investigate the role of TNF and TNF receptor polymorphisms in BD. The polymerase chain reaction-restriction fragment length polymorphism was used to identify the TNF-alpha promoter (G = TNFA1, A = TNFA2) and TNF-beta intron polymorphisms (G = TNFB1, A = TNFB2), and polymerase chain reaction-singly-strand conformation polymorphism was used to identify TNFR2 196R/M polymorphism (T = TNFR2M, G = TNFR2R). No differences were found in the TNF-alpha, TNF-beta or TNFR2 polymorphisms of the patients and the healthy controls. The allele frequencies of TNFA1/A2 were 0.94/0.06 in patients and 0.96/0.04 in healthy controls (p = 0.36, OR = 0.65, 95% CI = 0.26-1.63), for TNFB1/TNFB2 these were 0.42/0.58 in patients and 0.44/0.56 in controls (p = 0.68, OR = 0.91, 95% CI = 0.61-1.38), and for TNFR2R/TNFR2M 0.23/0.77 in patients and 0.21/0.79 in controls (p = 0.62, OR = 1.13, 95% CI = 0.69-1.84). In conclusion, this study found no differences of TNF alpha -308 G/A, TNF beta +252 G/A or of the TNFR2 196R/M polymorphisms in Korean BD patients versus healthy controls. These findings suggest that the role of TNF in BD is not genetically determined, but can be functionally explained.     

Polymorphisms of the NOS3 gene in Tunisian patients with Behçet's disease

Behçet's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation and skin lesions. Reduced plasma nitric oxide (NO) levels in patients with BD have been implicated in the development of the endothelial abnormalities and thrombotic complications occurring in these patients. Polymorphisms in the endothelial nitric oxide synthase gene (NOS3) have been inconsistently associated with BD. This inconsistency may derive from population stratification secondary to ethnic diversity, and consideration limited to only one rather than combinations of polymorphisms. We studied three genetic variations in the NOS3 gene: a single nucleotide polymorphism in the promoter region ?786T>C, in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (4a4b) of the NOS3 gene in 100 unrelated Tunisian patients with BD and 148 healthy controls. In addition, we also examined the association of NOS3 gene haplotypes with BD. Analyses of the Glu298Asp, ?786T>C and 4a4b polymorphisms were made by the polymerase chain reaction (PCR) restriction fragment length polymorphism technique and PCR genotyping, respectively. The distribution of the Glu298Asp genotype differed significantly between patients with BD and controls (P = 0.01). Allele Asp298 was significantly more frequent in patients with BD than in controls (P = 0.005, OR = 1.70, 95% CI 1.14–2.54). In contrast, distribution of alleles and genotypes of ?786T>C and 4a4b polymorphisms was not different between the control and BD group. However, the frequency of Asp‐T‐4b haplotype was significantly higher in patients with BD than in healthy controls. By gender, the signification remained only for heterozygous men (P = 0.03) and homozygous women (P = 0.02). These results suggest that Glu298Asp polymorphism of the NOS3 gene is associated with BD susceptibility in Tunisian patients.     

CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet's disease

Cytotoxic T lymphocyte antigen 4 (CTLA4; CD152) is a costimulatory molecule expressed on activated T cells that plays a key inhibitory role during T lymphocyte activation. The gene encoding for CTLA4 has been suggested as a candidate for conferring susceptibility to autoinflammatory diseases. We investigated the polymorphisms of the CTLA4 gene [promoter region (−1722 T/C, −1661 A/G and −318 C/T) and exon 1 (+49 G/A)] and the differences of serum soluble sCTLA4 levels in 285 patients with Behcet's disease (BD) and 287 controls. The frequency of the CTLA4 −1661 GG genotype was significantly higher in BD patients than in controls [ P  = 0.019, odds ratio (OR) = 5.2, 95% confidence interval (CI) = 1.13–23.86]. Also, the genotype frequency for CTLA4 −1722 TC was significantly higher ( P  = 0.014, OR = 1.8, 95% CI = 1.13–2.99), while CTLA4 −1722 CC was significantly lower ( P  = 0.018, OR = 0.4, 95% CI = 0.20–0.87) in BD patients with ocular lesions compared with patients without this symptom. Serum sCTLA4 levels in BD patients were significantly lower, especially in BD patients with the CTLA4 +49 G allele, than those in healthy controls ( P  < 0.05). Although our understanding of the role of the CTLA4 gene and its protein product in BD is incomplete, these results suggest that single nucleotide polymorphisms of the promoter and exon regions in the CTLA4 gene are candidates that predispose to BD and that sCTLA4 may be related to the immunological abnormalities and disease expressions associated with BD.     

Interleukin‐2 gene polymorphism in Turkish patients with Behçet's disease and its association with ocular involvement

Behçet's disease (BD) is a chronic immune‐mediated systemic disease, characterized by oral and genital lesions and ocular inflammation. Several cytokine genes may play crucial roles in host susceptibility to BD, because the cytokine production capacity varies among individuals and depends on the cytokine gene polymorphisms. The association of the interleukin (IL)‐2 gene polymorphisms with the susceptibility to BD was investigated in this study. DNA samples were obtained from a Turkish population of 97 patients with BD and 76 healthy control subjects. Polymorphisms of IL‐2 gene at position ?330 and +166 were determined using the polymerase chain reaction with sequence‐specific primers. In the patients with BD, there was a significantly increased frequency of IL‐2 ?330 GT genotype. Interestingly, we demonstrated that the frequencies of IL‐2 ?330 GT and IL‐2 + 166 GG genotypes were increased in BD patients with ocular involvement, whilst IL‐2 ?330 TT genotype was significantly decreased. Also, analysis of allele frequency demonstrated that the presence of G allele at position +166 of IL‐2 seems to be a risk factor for ocular involvement. These results reveal that IL‐2 ?330 GT genotype may be a susceptibility factor for BD, whereas IL‐2 ?330 TT genotype seems to display a protective association with BD. Additionally, IL‐2 gene polymorphisms might be associated with ocular involvement in BD.     

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.     

Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer's disease

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and blood vessel function. Recent evidence indicates that VEGF facilitates memory and learning through stimulating angiogenesis and neurogenesis in the rat hippocampal dendate gyrus. Abnormal regulation of VEGF expression has been reported in the pathogenesis of both atherosclerosis and motoneuron degeneration in amyotrophic lateral sclerosis, with low VEGF-producing polymorphisms (-2578 allele A and -634 allele G) conferring increased susceptibility for the development of the disorders. We tested whether these polymorphisms downregulating expression of VEGF might increase the risk of developing Alzheimer's disease (AD). So, we performed a case-control study in 362 Spanish AD patients and 428 healthy controls. The current study does not demonstrate an association between VEGF (-2578) and VEGF (-634) genotypes or haplotypes and AD.     

ORIGINAL ARTICLE: Association Study of Vascular Endothelial Growth Factor and Polymorphisms of its Gene with Ectopic Pregnancy

Citation Elito J Jr, Daher S, Fernandes da Silva MO, Marconi NMH, Pendeloski KPT, Moron AF, Camano L. Association study of vascular endothelial growth factor and polymorphisms of its gene with ectopic pregnancy. Am J Reprod Immunol 2010; 63: 120–125 Problem In ectopic pregnancy, increased levels of vascular endothelial growth factor are present. The aims of this study were to determine the association between ?634C/G, ?460T/C, and +936C/T vascular endothelial growth factor (VEGF) polymorphisms and ectopic pregnancy, and to determine whether serum levels of VEGF were affected by genetic factors. Method of study This is a case–control study wherein 74 women with a history of ectopic pregnancy in a tertiary care center were compared to 134 post‐menopausal controls with two pregnancies and no ectopic pregnancy for the genotyping of VEGF polymorphisms. For 35 patients with the diagnosis of ectopic pregnancy, serum concentrations of VEGF were obtained before the treatment. Genotyping of VEGF (?634C/G, ?460T/C, and +936C/T) polymorphisms was performed by PCR, followed by endonuclease digestion. ELISA was performed to evaluate the VEGF serum levels. Results The ?634C/G, ?460T/C, and +936C/T VEGF polymorphisms were not associated with ectopic pregnancy (P = 0.170, P = 0.285, and P = 0.700, respectively). The serum levels of VEGF were not associated with the genotype of ?634C/G, ?460T/C, and +936C/T VEGF polymorphisms (P = 0.702; P = 0.347, and P = 0.256, respectively). Conclusion There was no association between ectopic pregnancy and ?634C/G, ?460T/C, and +936C/T VEGF polymorphisms. There was no correlation between VEGF genotype and the expression of VEGF in blood samples.     

Endothelial nitric oxide synthase gene polymorphism is associated with Behçet's disease in Tunisian population

Nitric oxide (NO) is a molecule that plays a key role in many physiologic and pathologic processes. It is produced in vivo from the aminoacid l-arginine by a family of nitric oxide synthases (NOS). Endothelial NOS (eNOS) is a constitutively expressed isoform of NOS. The eNOS gene entails several polymorphisms, of which certain were investigated in Beh?et's disease (BD). We sought to establish the association of eNOS gene Glu298Asp polymorphism in exon 7 with susceptibility to BD. In this study, 135 Tunisian patients with BD and 157 healthy blood donor controls from the same geographic area were genotyped by polymerase chain reaction technique for eNOS polymorphism in exon 7. Our results showed that the distribution of the Glu298Asp genotype differed between BD patients and controls but did not reach statistical significance (p = 0.06). Allele Asp298 was significantly more frequent in healthy controls than in BD patients (p = 0.037, chi(2) = 4.33, OR = 1.01, 95% CI = 1.41-1.99). A significant difference was found (p = 0.004, OR = 1.26, 95% CI = 2.13-3.62) between BD patients with skin lesions and patients without this manifestation. Our findings suggest that Glu298Asp polymorphism of eNOS gene is associated with BD susceptibility as well as skin lesions.     

Analysis of vascular endothelial growth factor (VEGF) functional variants in rheumatoid arthritis

The vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic mediators related to inflammation-associated synovial angiogenesis. The aim of this study was to asses the role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants with rheumatoid arthritis (RA). The population under study was composed of a total of 753 unrelated RA patients and 801 healthy controls. The VEGF -1154 G-->A and -634 G-->C polymorphism genotyping was performed by real-time polymerase chain reaction technology, using TaqMan 5' allelic discrimination assay. No evidence of association was observed between the -1154 G-->A and the -634 G-->C VEGF polymorphisms, or inferred VEGF haplotypes with RA susceptibility or clinical manifestations. Our results suggest that the analyzed VEGF promoter polymorphisms may not play a relevant role in RA pathogenesis in our population.     

Matrix metalloproteinase-2, -9, -12, and tissue inhibitor of metalloproteinase 2 gene polymorphisms and cutaneous expressions in patients with Behçet's disease

Matrix metalloproteinases (MMPs) induce leukocyte migration into inflammation sites that lead to either promotion or repression of inflammation by activating or inactivating cytokines. An increased level of MMP-9 and a decreased level of MMP-2 have been observed in Beh?et's disease (BD). This study was performed to analyze the relationship between MMP-2, -9, -12 and the tissue inhibitor of metalloproteinase-2 (TIMP-2) promoter polymorphisms in developing BD. The expression of MMP-2 and -9 was also evaluated in the skin of BD. The MMPs and TIMP-2 polymorphisms were confirmed by using polymerase chain reaction-restriction fragment length polymorphism in 251 BD and 312 controls. Cutaneous expression of MMP-2 and -9 in 17 BD patients with erythema nodosum (EN) or EN-like lesion was compared with 14 patients with idiopathic EN by immunohistochemical stains. The frequency of MMP-2-1575*G/*G and MMP-2-735*C/*C genotypes was shown to be lower in BD, whereas MMP-9-1562*C/*C was significantly higher in BD compared with the controls. The frequency of common haplotype MMP-2-1575*G -735*C was significantly lower in BD patients than in controls (P = 0.0046, permutation P = 0.009). No significant differences were observed between BD and controls in the allele and genotype frequencies of MMP-12-82A>G or TIMP-2-418G>C polymorphisms. The tissue expression of MMP-2, shown by immunohistochemistry, was significantly lower in BD compared with the controls. However, the expression of MMP-9 was significantly higher in BD. These results suggest that MMP-2 and -9 could each modulate the development of BD in opposite directions. Major genotypes of the MMP-2-1575*G/*G and MMP-2-735*C/*C and the common MMP-2-1575*G -735*C haplotype may provide some protection against development of BD, while MMP-9-1562*C/*C may promote the disease. The reciprocal expression of MMP-2 and -9 in the skin tissue of BD was also confirmed.     

Association of MICA polymorphism with HLA-B51 and disease severity in Korean patients with Behcet's disease

The HLA-B51 allele is known to be associated with Behcet's disease (BD) in many ethnic group. However, it has not yet been clarified whether the HLA-B51 gene itself is the pathogenic gene related to BD or whether it is some other gene in linkage disequlibrium with HLA-B51. Recently, the Triplet repeat (GCT/AGC) polymorphism in transmembrane region of the MHC class I chain-related A (MICA) gene was identified. To investigate the association of MICA with BD, we studied the MICA polymorphism in 108 Korean BD patients and 204 healthy controls in relation to the presence of HLA-B51 and clinical manifestations. The triplet repeat polymorphism was determined by polymerase chain reaction (PCR)-denaturing polyacrylamide gel electrophoresis (PAGE). The phenotype frequency of the MICA*A6 allele (relative risk, RR=2.15, p=0.002) and HLA-B51(RR=1.87, p=0.022) were significantly increased in the Korean patients with BD. A strong linkage disequilibrium was observed between the MICA*A6 and HLA-B51 in both the patients with BD and control subjects. Stratification analysis showed that MICA*A6 homozygosity was strongly associated with BD in the HLA-B51-negative population, and HLA-B51 was also associated with MICA*A6-negative population. In conclusion, MICA*A6 rather than HLA-B51 was strongly associated with Korean patients with BD, and the MICA*A6 allele is a useful susceptibility marker of BD, especially in the HLA-B5-negative     

Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males

BACKGROUND: Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA). METHODS: To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC). RESULTS: Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04). CONCLUSION: These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.