Analysis of the monocyte chemoattractant protein 1 -2518 promoter polymorphism in patients with multiple sclerosis

Cytokines and chemokines like the proinflammatory chemokine, monocytechemoattractant protein 1 (MCP-1) are important for the recruitment of inflammatory cells into multiple sclerosis (MS) lesions. Recently, a nucleotide substitution from adenosine to guanosine (A-->G) at position -2518 of the MCP-1 promoter was shown to be associated with increased MCP-1 expression. We analysed MCP-1 genotypes in 634 MS patients and 405 healthy controls. The allelic frequencies were comparable between both groups. No correlation was found between genotype and disease course, disease severity or age of disease onset. Although statistically no+ significant mRNA expression and MCP-1 secretion were elevated in patients carrying the mutant allele. Thus, our data could not reveal any association between the MCP-1 -2518 polymorphism and susceptibility to or clinical disease course of MS.     

Monocyte chemoattractant protein-1 promoter -2518 polymorphism and schizophrenia in the Korean population

The purpose of the present study was to investigate the association between the monocyte chemoattractant protein-1 (MCP-1) promoter -2518 polymorphism and schizophrenia. One hundred and twenty-three schizophrenic inpatients and 114 healthy controls participated in this study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Genotype and allele distributions in patients with schizophrenia were not significantly different from those of the controls. However, distributions of genotypes and alleles were marginally different when considering subjects with positive and negative symptomatology. The present study therefore calls for further studies on the potential role of the MCP-1 promoter -2518 polymorphism in clinical heterogeneity of schizophrenia.     

No association of the MCP-1 promoter A-2518G polymorphism with bipolar disorder in the Korean population

It has been suggested that bipolar disorder is associated with altered immune function. Monocyte chemoattractant protien-1 (MCP-1) is a chemokine that influences both neural and immune functions. We thus hypothesized that MCP-1 may be related to the development or pathophysiology of bipolar disorder. In this case–control study, we investigated the association between the A-2518G single nucleotide polymorphism (SNP) of the MCP-1 promoter and bipolar disorder. Patients with bipolar disorder (n = 183; bipolar I = 145, bipolar II = 38) and healthy controls (350) were recruited for the study. No significant allelic or genotypic association was detected between the A-2518G polymorphism and any sample of bipolar disorder patients. When we pooled the healthy controls and the cases of bipolar I disorder from previous Korean studies and this study, we again found no significant association. No significant difference in either allele frequency or genotype distribution was observed between bipolar I and bipolar II disorders. There was no difference in the age at onset of bipolar disorder among the three genotype groups. Our data suggest that the A-2518G polymorphism of MCP-1 is not a major susceptibility factor for bipolar disorder in the Korean population. However, the physiological role of MCP-1 is highly suggestive of its being associated with bipolar disorder, and further analyses of other SNPs of MCP-1 remain to be performed.     

Association of polymorphisms in monocyte chemoattractant protein-1 promoter with diabetic kidney failure in Korean patients with type 2 diabetes mellitus

Monocyte chemoattractant protein-1 (MCP-1) is suggested to be involved in the progression of diabetic nephropathy. We investigated the association of the -2518 A/G polymorphism in the MCP-1 gene with progressive kidney failure in Korean patients with type 2 diabetes mellitus (DM). We investigated -2518 A/G polymorphism of the MCP-1 gene in type 2 DM patients with progressive kidney failure (n=112) compared with matched type 2 DM patients without nephropathy (diabetic control, n=112) and healthy controls (n=230). The overall genotypic distribution of -2518 A/G in the MCP-1 gene was not different in patients with type 2 DM compared to healthy controls. Although the genotype was not significantly different between the patients with kidney failure and the diabetic control (p=0.07), the A allele was more frequent in patients with kidney failure than in DM controls (42.0 vs. 32.1%, p=0.03). The carriage of A allele was significantly associated with kidney failure (68.8 vs. 54.5%, OR 1.84, 95% CI 1.07-3.18). In logistic regression analysis, carriage of A allele retained a significant association with diabetic kidney failure. Our result shows that the -2518 A allele of the MCP-1 gene is associated with kidney failure in Korean patients with type 2 DM.     

Association of HSPA1B SNP rs6457452 with Alopecia Areata in the Korean Population

The heat shock 70?kDa protein 1B (HSPA1B), which has been well-studied among the famous heat shock proteins HSPA1A/B/L, is related to autoimmune diseases, including Alopecia Areata (AA). In this study, the association of a 5’-untranslated region (5’UTR) SNP rs6457452 and a promoter SNP rs2763979 (‐1140C?>?T) of HSPA1B with AA was investigated in 236 controls and 228 AA patients. Statistical analyses using the multiple logistic models were done, according to the onset and the clinical features of AA, including the age of onset, family history, type of AA lesion, nail involvement and body hair involvement. The results showed that rs6457452 was associated with the onset of AA (p?<?0.002). In the analysis of clinical features of AA, rs6457452 was weakly related to the age of onset (p?≤?0.04) and that rs2763979 was only weakly related to the type of AA lesion (p?=?0.041). In conclusion, we suggest that the 5’UTR SNP rs6457452 of HSPA1B may be associated with the onset of AA and the T allele of rs6457452 may confer the reduced susceptibility to AA in the Korean population.     

Association of monocyte chemoattractant protein 1 (MCP-1) gene polymorphism with lupus nephritis in Egyptian patients

Background and study aimMonocyte chemoattractant protein-1 (MCP-1) is a member of CC chemokine that plays an important role in the recruitment of monocytes/macrophages into renal tubulointerstitium. A biallelic A/G polymorphism at position ∼2518 in the MCP-1 gene was found to regulate MCP-1 expression. MCP-1 and its A/G gene polymorphism have been implicated in the pathogenesis of some renal diseases. The aim of the study was to investigate the role of the MCP-1 gene polymorphism as early predictors of the development of glomerulonephropathy in SLE patients. We also aimed to measure the serum and urinary levels of MCP-1 in patients with SLE, to find out its relation to clinical disease activity.Methods140 SLE patients (100 with nephritis and 40 without nephritis) and 80 controls were included in this study. MCP-1 gene polymorphism was analyzed by polymerase chain reaction. Serum and urine MCP-1 level were measured using high-sensitivity enzyme-linked immunosorbent assay.ResultsThe A/A genotype was more common in controls than in SLE patients, whereas both the A/G (P < 0.000) and G/G (P < 0.000) genotypes were more frequent in SLE patients. Carriers of G allele of the MCP-1 ∼2518 polymorphism had more than 7 fold increased risk to develop glomerulo-nephropathy in patients with SLE. High MCP-1 circulating levels production from patients with A/G and G/G genotypes was significantly higher than in A/A genotype. In addition there were significant differences in the mean levels of serum MCP-1 (P < 0.001) and urinary MCP-1 (P < 0.001) between patients and controls.ConclusionThe present study provides a new evidence that the presence of MCP-1 A (-2518) G gene polymorphism and high circulating MCP-1 levels can play an important role in the development of SLE and nephropathy in Egyptians.     

Allelic frequency of the MCP-1 promoter -2518 polymorphism in the Korean population and in Korean patients with rheumatoid arthritis, systemic lupus erythematosus and adult-onset Still's disease.

The frequency of the monocyte chemoattractant protein-1 (MCP-1) -2518 G-type polymorphism in Koreans is significantly higher than the frequencies reported for Caucasians and Afro-Americans. The G- vs. A-allele profile in patients with systemic autoimmune diseases is similar to that in healthy Koreans, and does not appear to contribute to elevated MCP-1 production in patients.     

Association of UCP1 genetic polymorphisms with blood pressure among Korean female subjects

Recent studies have provided some clues with regard to the relationship existing between uncoupling protein 1 (UCP1) and blood pressure in animal experiments. In an attempt to determine the genetic polymorphisms that are associated with blood pressure in humans, we have analyzed genetic polymorphisms in UCP1 gene. In this study, we assessed the association between UCP1 genotypes and systolic blood pressure (SBP) and diastolic blood pressure (DBP), in a population comprised of 832 Korean female subjects, using a general linear model, which was adjusted for age and body mass index (BMI). Among 4 genetic polymorphisms and the haplotypes constructed from them, haplotype3 of UCP1, UCP1-ht3[GAGA], evidenced significant associations with SBP (p=0.005) and DBP (p=0.013). However, this haplotype was not significantly associated with obesity phenotypes, including BMI or fat mass (p>0.05), thereby suggesting that its association with blood pressure was independent of obesity phenotypes.     

The MCP-1 promoter -2518 polymorphism in Behcet's disease: correlation between allele types, MCP-1 production and clinical symptoms among Korean patients

OBJECTIVE: To compare the G vs. A variation at the MCP-1 promoter -2518 position among normal Koreans and Behcet patients, and to investigate possible association of this polymorphism with disease pathogenesis. METHODS: The allele type of -2518 polymorphism was determined by restriction fragment length polymorphism of Pvu II. The level of MCP-1 in serum and culture supernatent was measured by sandwich ELISA. RESULTS: The average serum level of MCP-1 in Behcet patients was 2.37 times higher than in normal controls. The serum MCP-1 concentration was higher in G-allele carriers than in AA homozygotes, and symptoms accompanying graver cases of Behcet's disease, such as gastrointestinal inflammation and uveitis, were more frequent in patients with the G-allele. However, the frequency of G-allele in patient group was not higher than that in healthy Koreans, probably due to the dominance of G-allele in general Korean population. When stimulated in vitro with IL-1beta and LPS, the mononuclear cells from patients carrying the G-allele showed a steeper increase in MCP-1 production than the boost observed in AA homozygotes. CONCLUSION: Although the allele frequency of MCP-1 promoter -2518 polymorphism is not likely to be the reason for the elevated serum MCP-1 level in Korean patients with Behcet's disease, it is possible that proinflammatory factors induced in patients' serum cause stronger activation of MCP-1 expression from the G-type promoter, as well as increased incidence of uveitis and gastric ulcer, among carriers of the G-allele.     

Angiotensin-converting enzyme gene insertion/deletion polymorphism in Korean patients with systemic sclerosis

To determine whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with the development and clinical features of systemic sclerosis (SSc) in Korean, we studied seventy two Korean patients with SSc fulfilling the ACR preliminary classification criteria. The controls were 114 healthy, disease free Koreans. ACE I/D genotypes were determined by PCR method using oligonucleotides. Sixty eight patients (94.4%) were women and age at diagnosis was 43.5+/-12.6 yr old (mean+/-SD). Thirty nine patients (54.2%) had a diffuse type of SSc. There were no statistical differences in the frequencies of all ACE I/D genotypes and D allele between patients and controls, and neither between diffuse and limited types of SSc. ACE I/D gene polymorphism was not associated with the development of SSc in Korea. The investigation for the pathogenesis of SSc requires more studies about the role of other candidate genes such as endothelin, TGF-beta, nitric oxide, or angiotensin II receptor in addition to the ACE genes.     

GSTM1, GSTT1 and GSTP1 polymorphisms in the Korean population

The isoenzymes of the glutathione s transferase (GST) family play a vital role in phase II of biotransformation of many substances. Using a multiplex polymerase chain reaction and a direct sequencing analysis, the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated in 1,051 Korean male subjects. We found that 53.8% of the individuals had the GSTM1 null genotype and 54.3% had the GSTT 1 null genotype. The genotypic distribution of GSTP1 was Ile105/Ile105 in 68.4%, Ile105/Val105 in 29.1% and Val105/Va105 in 2.5%. The most frequently observed combination of GSTM1, GSTP1 and GSTT1 genotypes was Null type/Ile105/Ile105/Null type, while the combination of Non-null type/Val105/Val105/Non-Null type was not observed. We found that the genotype distributions of three GST isoenzymes in the Koreans are similar to those reported in Asians and previously reported Koreans. We believe our results, which are represented by a large population, are reliable estimates of the frequencies of the polymorphic GST alleles in the Koreans and will help future researches on GST polymorphisms.     

甘草甜素抑制肺纤维化大鼠肺组织单核细胞趋化蛋白-1的表达

目的: 观察甘草甜素对博来霉素(BLM)诱导的大鼠肺纤维化的干预作用及可能机制。方法: 随机将大鼠分为对照组、肺纤维化模型组、甘草甜素干预组。气管内注入博莱霉素造成动物模型后,于当天开始每天给药,分别于7 、28 d处死,取肺组织,行嗜伊红染色、Masson染色；检测肺组织匀浆中羟脯氨酸(HYP) 的变化; RT-PCR法测肺组织单核细胞趋化因子-1 mRNA的表达,免疫组化测肺组织单核细胞趋化因子-1蛋白的表达。结果: 干预组肺纤维化程度轻于模型组; 肺组织匀浆羟脯氨酸(HYP)含量显著低于模型组( P<0.01) ;在模型组 MCP-1第7 d表达就明显升高，第28 d下降，但仍高于对照组，干预组与模型组有同一规律，但均减弱，第7、28 d与模型组(M组)比较，P<0.05。结论: 甘草甜素能减轻博莱霉素诱导的大鼠肺纤维化，这种作用可能部分是通过抑制MCP-1的表达而实现。     

MCP-1启动子-2518位点基因多态性与云南汉族SLE的研究

目的研究单核细胞趋化蛋白-1（MCP-1）启动子-2518位点基因多态性与云南汉族系统性红斑狼疮（SLE）及狼疮性肾炎（LN）的联系。方法采用聚合酶链反应（PCR）与限制性片段长度多态性（RFLP）方法对61例SLE患者（SLE合并LN患者28例,SLE未合并LN患者33例）和65例正常对照的MCP-1启动子-2518位点基因多态性分布进行分型,以SPSS12．0分析软件分析该基因位点多态性情况。结果各组MCP-1启动子-2518位点基因型A／G较A／A、G／G出现的频率升高;各组MCP-1启动子A／A、G／G及A／G出现的频率无显著性差异（P〉0．05）。结论MCP-1启动子-2518位点基因多态性与SLE、LN的发病和病情之间均无联系。     

Leukotriene-related gene polymorphisms in patients with aspirin-intolerant urticaria and aspirin-intolerant asthma: differing contributions of ALOX5 polymorphism in Korean population

The pathogenesis of aspirin (acetylsalicylic acid, ASA)-intolerant urticaria (AIU) is still poorly understood but it has recently been suggested that it is associated with the overproduction of leukotriene (LT). This is supported by evidence that cyclooxygenase 2 inhibitor is given safely to patients with AIU. The present study was designed to investigate the role of genetic polymorphism of LT related genes in the pathogenesis of AIU via a case-control study. We screened single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in leukotriene synthesis in the Korean population with AIU (n = 101), ASA-intolerant asthma (AIA, n = 95) and normal healthy controls (n = 123). Genotype was determined by primer extension reactions using the SNapShot ddNTP primer extension kit. Among 8 SNPs of four LT related genes, the polymorphism of ALOX5 at positions of -1708 G > A showed significant difference in genotype frequency between AIU and AIA (p = 0.01). Furthermore, there were significant differences observed in the frequencies of two ALOX5 haplotypes between the AIU group and AIA group (p < 0.05). However, there were no differences in allele, genotype, or haplotype frequencies of ALOX5 between the AIU group and the normal control group. These results suggested that ALOX5 has a differing contribution in two major clinical pathogenesis related to ASA-sensitivity.     

Effects of diphencyprone on expression of Bcl-2 protein in patients with Alopecia areata

Background: Alopecia areata (AA) development is attributed to a T cell involved autoimmune process. Apoptosis is one of the suspected culprits in pathogenesis of this disorder. This disorder can be treated by contact sensitizers like diphencyprone (DPCP). We investigated the effects of treatment with DPCP on the expression of Bcl-2 protein in hair follicle epithelial cells of AA patients and its relation to clinical response to treatment.

Materials and Methods: Patients with chronic and extensive AA who had not received any treatment for at least 6 months were included. Furthermore, 3-mm punch biopsies were obtained from the affected areas before starting the treatment, and, six months after DPCP application, punch biopsies of the same size were taken from the following groups of patients: Group 1: six patients with complete hair regrowth, Group 2: six patients with partial regrowth, and Group 3: six patients with no regrowth. The samples were studied by immunohistochemistry to detect and compare the rate of Bcl-2 expression.

Results: Level of Bcl-2 expression in respondent patients (Group 1) was significantly higher after DPCP treatment (36.50?±?4.23) compared to pretreatment state (3.67?±?1.406, P?<?0.001). Similar finding was observed in second group with partial regrowth (17.67?±?1.745 versus 5.33?±?2.076, P?<?0.01). Such significant change was not observed in third group (4.75?±?1.315 versus 3.50?±?0.645, P?>?0.05).

Conclusion:The results of this study indicate the positive effect of DPCP on regulation (inhibition) of apoptotic process in patients with AA.     

CD16+ monocytes in breast cancer patients: expanded by monocyte chemoattractant protein-1 and may be useful for early diagnosis

Human peripheral blood monocytes are a heterogeneous population, including CD14⁺CD16^‐‘classical’ monocytes and CD14⁺CD16⁺‘proinflammatory’ monocytes. CD16⁺ monocytes are expanded in various inflammatory conditions. However, little is known about the CD14⁺CD16⁺ monocytes in patients with breast cancer. We detected CD14⁺CD16⁺ monocytes in 96 patients with breast cancer and 54 control subjects using flow cytometry. Receiver‐operating characteristic (ROC) curve analysis was used to determine the feasibility of CD14⁺CD16⁺ monocytes as an indicator for diagnosis of breast cancer. We found that the frequency of CD14⁺CD16⁺ monocytes showed a significantly greater increase in breast cancer patients than in controls (16·96% versus 10·84%, P < 0·0001). The area under the ROC curve for CD14⁺CD16⁺ monocytes was 0·805 [95% confidence interval (95% CI): 0·714–0·877, P = 0·0001]. Furthermore, the levels of CD16⁺ monocytes were significantly negatively associated with the tumour size and pathological staging. In vitro, we showed that CD14⁺CD16⁺ monocytes were expanded significantly when the purified CD14⁺ monocytes were exposed to Michigan Cancer Foundation (MCF)‐7 cells‐conditioned medium (MCF‐CM) or, separately, to monocyte chemotactic protein 1 (MCP‐1). Neutralizing antibodies against MCP‐1 inhibited the expansion of CD14⁺CD16⁺ monocytes by MCF‐CM. Collectively, our findings indicated that MCP‐1 can expand CD14⁺CD16⁺ monocytes in patients with breast cancer. Furthermore, the CD14⁺CD16⁺ monocyte may be a useful indicator in early diagnosis of breast cancer.     

Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican

The type 1 chemokine monocyte chemoattractant protein (MCP-1) has been implicated in the generation of inflammatory and neuropathic pain, but the underlying mechanism remains poorly understood. Here we show that mechanical hyperalgesia induced by intradermal injection of MCP-1 in the rat is blocked by the intrathecal administration of isolectin B4 (IB4)-saporin, a selective neurotoxin for IB4⁺/Ret⁺-nociceptors. MCP-1-induced hyperalgesia is also attenuated by intrathecal antisense oligodeoxynucleotides targeting mRNA for versican, a molecule that binds MCP-1 and that also renders the Ret-expressing nociceptors IB4-positive (+). Finally, peripheral administration of ADAMTS-4 or chondroitinase ABC, two enzymes that disrupt versican integrity by the degradation of the versican core-protein or its chondroitin sulfate glycosaminoglycan side chains, respectively, also attenuated MCP-1 hyperalgesia at the site of nociceptive testing. We suggest that versican's glycosaminoglycan side chains present MCP-1 to a CCR2 expressing cell type in the skin that, in turn, selectively activates IB4⁺/Ret⁺ nociceptors, thereby contributing to enhanced mechanical sensitivity under inflammatory conditions.     

Lack of Toll-like receptor 4 and 2 polymorphisms in Korean patients with bacteremia

Toll-like receptors (TLRs) are pattern-recognition receptors that are important in innate immune responses to bacterial infection. The purpose of this study is to describe the prevalence of TLRs genetic variations in the bacteremic patients in Korea. A total of 154 patients with bacteremia and 179 healthy volunteers were included. The Asp299Gly and Thr399Ile allele of the TLR4 gene and Arg753Gln and Arg677Trp allele of the TLR2 gene were tested by PCR-RFLP. The DNA sequences were determined to confirm the PCR-RFLP results. Contrary to the expectation, no genetic polymorphisms were detected in both groups of this study, suggesting that it is very rare in Korean.