Polymorphisms in the promoter region of RANTES and the regulatory region of monocyte chemoattractant protein-1 among Chinese children with systemic lupus erythematosus

OBJECTIVE: Chemokines play an important role in the physiology and pathophysiology of acute and chronic inflammatory processes. We investigated whether chemokines such as RANTES (regulated upon activation, normally T cell expressed and secreted) promoter and monocyte chemoattractant protein-1 (MCP-1) regulatory polymorphisms were associated with systemic lupus erythematosus (SLE) in Chinese children. METHODS: Forty-six patients with SLE and 107 healthy children of comparable ages were studied for genotypes with polymerase chain reaction-based assays. RESULTS: The frequency and distribution of genotypes of the -28(C/G) RANTES gene polymorphism were significantly different between the 2 groups (p < 0.001), and the RANTES -28G allele was significantly more frequent in patients with SLE than in healthy controls (23.9% vs 11%; p = 0.006, OR 2.37, 95% CI 1.25-4.28). There was no significant difference in the frequency or in the distribution of genotypes of the -2518(A/G) MCP-1 and the -403(G/A) RANTES gene polymorphisms between patients and controls (p = 0.32 and p = 0.19, respectively). The RANTES -28G allele was also significantly associated with higher initial levels of antinuclear antibody, lower levels of C3, and higher incidences of central nervous system lupus. CONCLUSION: In the Chinese population, children with RANTES -28C/G polymorphisms have increased risk of developing SLE. Healthy controls with the C/G or G/G genotype were 2.37 times more likely to have SLE compared to those with the C/C genotype.     

Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study

OBJECTIVE: To examine whether polymorphism in the RANTES gene is associated with HIV disease outcome. DESIGN: RANTES, a ligand of the major HIV co-receptor, CCR5, is known to block HIV-CCR5 interactions. Recently, two single nucleotide polymorphisms in the RANTES gene promoter region, designated -403G/A and -28C/G, have been described. Both polymorphisms can affect in-vitro promoter activity, and the RANTES -403A, -28G haplotype has been associated with a slower CD4 cell count decline rate in a Japanese cohort. METHODS: We compared RANTES compound genotype frequencies between HIV-positive and exposed-uninfected participants of the Multicenter AIDS Cohort Study (MACS) and rates of progression to AIDS for MACS seroconverters. RESULTS: We found that the two most common RANTES promoter compound genotypes, G1 (-403G/G, -28C/C) found in 67% of Caucasians, and G4 (-403G/A, -28C/C) found in 23% of Caucasians, were associated with altered risk of HIV transmission and progression, particularly in individuals who lacked the protective CCR5 mutation, CCR5delta32. In this study, individuals with a G4 compound genotype were more likely to acquire HIV than individuals with a G1 compound genotype (OR 1.72, P = 0.016) and the risk increased when individuals possessing CCR5delta32 were omitted from consideration (OR 2.13, P = 0.005). Among seroconverters lacking CCR5delta32, those who had the G4 compound genotype progressed significantly slower to AIDS-1993 than those with the G1 compound genotype (median time to AIDS 7.6 versus 5.4 years; RH 0.65; P = 0.007). CONCLUSIONS: These data implicate the RANTES-403A allele as a risk factor for HIV transmission and as a protective factor for HIV progression.     

RANTES -28G delays and DC-SIGN - 139C enhances AIDS progression in HIV type 1-infected Japanese hemophiliacs

The relationships between host immune factors and HIV-1 disease progression are still in dispute. Unlike CCR5Delta32, which has been found to delay disease progression of HIV-1, there still remain several factors whose effect on the clinical course is unconfirmed. To clarify the relationships, we selected seven single-nucleotide polymorphisms (SNPs) out of the previously reported factors, namely, RANTES promoter -28G/-403A, RANTES In1.1C, SDF-1 3'A, IL-4 promoter -589T, and DC-SIGN promoter -139C/-336C, and examined these in Japanese HIV-1-infected hemophiliacs (n = 102). The genotypes were examined by the direct sequencing method, and the distributions of genotype and allelic frequencies were compared between two groups, slow progressors (n = 54) who did not develop AIDS more than 10 years after intravenous infection and others (progressors) (n = 48). The allelic frequency of RANTES -28G was significantly higher in slow progressors (0.185) than in the progressor group (0.074) [p = 0.023, OR = 0.35, 95% CI (0.142, 0.880)]. DC-SIGN promoter -139C, and appeared in progressors with significantly higher allelic frequency (0.333) than slow progressors [0.204, p = 0.040, OR = 1.95, 95% CI (1.039, 3.677)]. With RANTES -403A, RANTES In1.1C, SDF-1 3' A, IL-4 -589T, and DC-SIGN -336C, no significant difference was observed in allelic frequencies between the two groups. These results suggest that RANTES -28G was associated with delayed AIDS progression, while DC-SIGN -139C was associated with accelerated AIDS progression in HIV-1-infected Japanese hemophiliacs.     

Tumor necrosis factor-alpha promoter -308 A/G polymorphism and rheumatoid arthritis susceptibility: a metaanalysis

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) promoter -308 A/G polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. We investigated whether TNF-alpha -308 A/G polymorphism confers susceptibility to RA. METHODS: We conducted a random effect metaanalysis on the association of genotypes A/A (recessive effect), A/A + A/G (dominant effect), A allele, and A/A vs G/G genotypes of the TNF-alpha -308 polymorphisms with RA overall and within different ethnic populations. RESULTS: Fourteen studies, 10 of Europeans, 3 of Latin Americans, and one Asian, were included in this metaanalysis. An association between RA and the TNF-alpha -308 A allele was not found in the overall population (OR 1.005, 95% CI 0.715-1.412, p = 0.976). However, stratification by ethnicity indicated that the TNF-alpha A allele was significantly associated with RA in Latin Americans (OR 2.004, 95% CI 1.158-3.467, p = 0.013). Conversely, there was no association detected for the TNF-alpha A allele with RA patients from the European samples (OR 0.911, 95% CI 0.684-1.212, p = 0.520). The OR for the A/A + A/G genotype, the A/A genotypes, and the A/A vs G/G genotypes in samples overall and in each ethnic group showed a similar trend to those for the TNF-alpha A allele. CONCLUSION: This metaanalysis demonstrates that the TNF-alpha -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans, but not in Europeans.     

RANTES G-401A polymorphism is associated with allergen sensitization and FEV1 in Chinese children

G-401A polymorphism in RANTES promoter was associated with near-fatal asthma and atopic dermatitis in children. We studied whether gain-of-function mutations in RANTES gene were associated with asthma and atopy-related traits in Chinese children. Plasma total and aeroallergen-specific IgE concentrations were measured using micro-particle immunoassay and fluorescent enzyme immunoassay, respectively. Restriction fragment length polymorphism was used to genotype RANTES G-401A and C-28G. One hundred and twenty-nine asthmatic children and 66 controls were recruited. Their mean logarithmic plasma total IgE concentrations were 2.53 and 1.98, respectively (P<0.0001). RANTES G-401A was not associated with physician-diagnosed asthma (P = 0.408). However, RANTES G-401A allele was significantly associated with IgE sensitization to cat (odds ratio 2.35; 95% CI 1.15-4.77; P = 0.010). Those homozygous for -401A had higher plasma cat-specific IgE levels (P = 0.034). Subjects having -401A were also more likely to have mold-specific IgE (odds ratio 3.82; 95% CI 1.24-12.14; P = 0.007). On spirometry, those with -401A/ A had lower forced expiratory volume in 1-s (FEV1; P = 0.044). RANTES C-28G was not associated with any outcome in this study. In conclusion, the gain-of-function mutation at -401 of RANTES promoter is associated with sensitization to cat and mold allergens and FEV1 in Chinese children.     

A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma

The CC chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) attracts eosinophils, basophils, and T cells during inflammation and immune response, indicating a possible role for this chemokine in asthma. Both the -403A and -28G alleles of the RANTES promoter region exhibit significantly enhanced promoter activity in reporter constructs in vitro. We therefore investigated the genetic influence of these alleles on the development of asthma using case-control analysis in a Japanese population (298 patients with asthma and 311 control subjects). Given the evidence for heterogeneity of asthma according to age at onset, we divided patients with asthma into three subgroups: 117 late-onset patients with asthma (onset at more than 40 years of age), 83 middle-onset patients with asthma (onset at 20 to 40 years of age), and 98 early-onset patients with asthma (onset at less than 20 years of age). The -28G allele was significantly associated with late-onset asthma (odds ratio = 2.033; 95% confidence interval, 1.379-2.998; corrected p < 0.0025) but was not associated with the other two asthma subgroups. The -403A allele was not associated with any of the asthma subgroups. Further evidence of the importance of the -28G allele was a significant increase in the production of RANTES in vitro in individuals who carried this allele. Our findings suggest that, among Japanese, the -28G allele of the RANTES promoter region confers susceptibility to late-onset asthma.     

树突状细胞免疫受体基因多态性与抗环瓜氨酸肽抗体阴性类风湿关节炎相关性研究

目的 在汉族人群中研究树突状细胞免疫受体(DICR)基因多态性与类风湿关节炎(RA)及其不同亚型的易感相关性.方法 采用病例-对照研究法,选取年龄及性别相匹配的RA患者523例和健康对照510名;采用Taqman探针法检测DCIR基因rs2377422和rs10840759位点单核苷酸多态性(SNP);检测RA患者抗环瓜氨酸肽(CCP)抗体水平,分析DCIR基因多态性与不同亚型RA相关性;采用实时荧光定量聚合酶链反应(PCR)方法,定量检测DCIR在RA患者(233例)及健康者(71名)中mRNA表达水平,并进一步分析不同DCIR基因型对DCIR表达水平的影响.统计学处理采用X检验和多因素Logistic回归检验,2组间比较采用曼-惠特尼U检验.结果 ①DCIR SNP rs2377422与汉族RA发病明显相关(等位基因:OR 1.26;95％CI 1.06～1.50,P=0.005;基因型CC与TT+TC:OR 1.34;95％CI1.18～2.06,P=0.004);②DCIR SNP rs2377422主要与抗CCP抗体阴性RA发病相关(等位基因:OR 1.46;95％CI1.10～1.93,P=0.0091;基因型CC与TT+TC:OR 1.58;95％CI1.01～2.47,P=0.043);③和健康对照相比,RA患者外周血中DCIR基因mRNA水平显著增高(0.47-0.10与0.17-0.03,U=6502,P=0.000 38),且携带DCIR rs2377422 CC基因型的RA患者,其DCIR表达水平进一步明显增高(CC与TT+TC:0.429±0.069与0.238±0.023,U=1861,P=0.002).结论 汉族人群中DCIR rs2377422多态性主要与抗CCP抗体阴性RA易感相关;RA患者DCIR基因表达水平明显增高;DCIR rs2377422多态性可明显影响DCIR基因的表达.     

Tumor necrosis factor-alpha and Interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients

Tumor necrosis factor and interleukin 10 have been implicated in the pathogenesis of rheumatoid arthritis (RA). Certain single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-10 and TNF genes have been associated with altered levels of circulating IL10 and TNF. We aimed to explore the association of IL-10 and TNF-alpha polymorphisms in Turkish RA patients. We analyzed the association of TNF-alpha (-308G/A, -238G/A, -376G/A) and IL10 (-1082G/A, -819C/T, -592C/A) polymorphisms in 98 Turkish patients with rheumatoid arthritis and 122 healthy subjects using ARMS-PCR. The correlation of these findings with RF positivity and erosive disease in RA patients was also sought. A significant association was found between having RA and -1082 G allele (p = 0.008; OR = 1.44, 95% CI 1.11-1.86). There was no association between RA and -819C/T polymorphism. Significant differences were observed in IL10 GCC and ACC haplotypes distribution between RA and control subjects (p = 0.006; OR = 1.46, 95% CI 1.13-1.89 and p = 0.011; OR = 1.43, 95% CI 1.09-1.88, respectively). No statistically significant association was found between TNF-alpha 308G/A, -238G/A, -376G/A polymorphisms and RA. No significant association was found between RF positivity and erosive disease and TNF-alpha, IL10 gene polymorphisms. In addition, when combined genotypes were analyzed, no significant difference was found between RA patients and healthy controls. Our findings suggest that IL-10 1082 G/A polymorphism or GCC, ACC haplotypes may be associated with RA in Turkish patients.     

RANTES gene polymorphism in polymyalgia rheumatica, giant cell arteritis and rheumatoid arthritis

OBJECTIVE: To investigate whether a biallelic polymorphism (A or G) occurring within the promoter region of the RANTES gene (position-403) is associated with polymyalgia rheumatica (PMR), giant cell arteritis (GCA) and rheumatoid arthritis (RA). METHODS: A PCR-RFLP method was used to genotype cases and controls for this polymorphism. 3 groups of patients were examined; these comprised GCA patients who did not exhibit features of PMR (n = 30), PMR patients who did not exhibit features of GCA (n = 53) and RA patients (n = 99). All patients and controls (n = 65) originated from the area surrounding Lugo, Galicia, NW Spain. RESULTS: A significant increase in the frequency of allele A was found in PMR patients compared with normal controls. A marginal increase of this allele frequency was observed in RA but not in GCA patients. CONCLUSION: This is the first report of an association of a RANTES gene polymorphisms with PMR and RA. Our data suggest a possible role for of RANTES in the development of both PMR and RA.     

Chemotactic cytokine receptor 5 (CCR5) gene promoter polymorphism (59029A/G) is associated with diabetic nephropathy in Japanese patients with type 2 diabetes: a 10-year longitudinal study

We previously showed that polymorphisms of the promoter area of chemokine receptor 5 (CCR5) gene (59029G/A) and its agonist, regulated upon activation, normal T-cell expressed and secreted (RANTES) gene (-28C/G) were new candidates for susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of these polymorphisms on the development and progression of diabetic nephropathy. We performed a 10-year retrospective study of 191 Japanese type 2 diabetic patients with normoalbuminuria at baseline. The subjects were classified into two groups: (1) those with persistent normoalbuminuria (group N) and (2) those with progression from normoalbuminuria to microalbuminuria or overt proteinuria (group P). Then, their association with CCR5 59029G/A and RANTES -28C/G polymorphisms was assessed. The frequency of the RANTES -28G(+) genotype did nor differ between the two groups, but the CCR5 59029A(+) genotype had a significantly higher frequency in group P than in group N (83% versus 71%, p=0.04). By discriminant analysis, only the CCR5 59029A(+) genotype showed an independent positive correlation with the onset or progression of nephropathy (p=0.03, odds ratio=2.41, 95% CI=1.09-5.33). Therefore, the CCR5 59029A(+) genotype seems to be related the etiology of diabetic nephropathy in Japanese type 2 diabetics.     

Polymorphisms in the IL4 and IL4RA genes in Colombian patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is considered a Th1-driven disease. Interleukin 4 (IL-4) binds to its receptor, promoting Th2 differentiation and limiting Th1 responses, but its role in the pathogenesis of RA is conflicting. We analyzed 2 polymorphisms of the IL4 gene and 4 polymorphisms of the IL4RA gene in patients with RA and in a control population, as well as rheumatoid factor (RF) seropositivity, titers of RF, and history of replacement joint surgery among patients with RA. METHODS: The study population consisted of 102 patients with RA and 102 matched healthy controls. Genotyping of IL4 -590, IL4RA +148, +1124, +1218, and +1902 was determined by restriction fragment length polymorphism-polymerase chain reaction (PCR) and sequence-specific primer-PCR. IL4 variable number tandem repeat polymorphism was determined by direct amplification. RESULTS: The IL4 -590TT genotype was significantly more frequent in patients with RA than in controls (p = 0.018, OR 3.34, 95% CI 1.08-11.04). The IL4RA +148A allele was significantly associated with the presence of RF (p = 0.0019, OR 2.55, 95% CI 1.55-4.86) and a history of articular joint replacement (p = 0.024, OR 2.08, 95% CI 1.04-4.18). The IL4RA +1902G allele was more frequently seen in patients with RA and high RF titers (p = 0.00067, OR 4, 95% CI 1.64-9.93). CONCLUSION: Highly complex pathways lead to the development of RA and may not be similar in all patients. Our findings of higher frequency of IL4 and IL4RA genotypes and alleles with RA, presence of RF, RF titers, and history of articular joint replacement support the polygenic expression of RA and the likely role of IL-4 in influencing its initiation and development.     

Endothelial nitric oxide synthase gene polymorphism is associated with systemic lupus erythematosus

OBJECTIVE: In systemic lupus erythematosus (SLE), endothelial nitric oxide synthase (eNOS) gene locus has been found to be suggestive of linkage with disease, nitric oxide (NO) is produced in significant amounts, and endothelial cell dysfunction is observed. eNOS gene polymorphism may affect both the synthesis of eNOS protein and its enzymatic activity. We examined the influence of eNOS gene polymorphisms on susceptibility to SLE. METHODS: Genomic DNA from 88 Northwestern Colombian women with SLE, as well as 199 controls matched for sex, age, and ethnicity, was genotyped for the -786T -- > C polymorphism in the promoter region, the intron 4 variable number of tandem repeats, and the Glu298Asp polymorphism in exon 7 of the eNOS gene by polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and allele frequency comparisons, a Hardy-Weinberg equilibrium test, and linkage disequilibrium (LD) analysis were performed. RESULTS: The intron 4b allele was associated with SLE (OR 2.2, 95% CI 1.29-3.60, pc = 0.005) as was the 4bb genotype (OR 2.9, 95% CI 1.61-5.33, pc = 0.0009), while the 4a allele was protective (OR 0.4, 95% CI 0.26-0.76, pc = 0.005), as was the 4ab genotype (OR 0.29, 95% CI 0.15-0.56, pc < 0.0001). In controls, all loci were in linkage disequilibrium (p < 0.02). In patients, intron 4 was in Hardy-Weinberg disequilibrium, due to an excess of homozygotes (p = 0.01). CONCLUSION: eNOS polymorphism influences SLE predisposition. Since intron 4bb genotype is responsible for higher levels of eNOS synthesis and intron 4 ab genotype is associated with lower synthesis, our results might provide insight into the elevated levels of NO observed in SLE patients.     

Association between functional haplotypes of vascular endothelial growth factor and renal complications in Henoch-Schönlein purpura

OBJECTIVE: High expression of circulating vascular endothelial growth factor (VEGF) has been reported in patients with Henoch-Sch?nlein purpura (HSP). We investigated the role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants in the susceptibility to HSP, to identify associations with severe systemic complications of HSP, in particular with renal complications. METHODS: Fifty-seven patients from the Lugo region of Northwest Spain with primary cutaneous vasculitis classified as HSP according to proposed criteria were studied. All patients were required to have had at least 2 years' followup. Patients and ethnically matched controls (n = 226) were genotyped for the VEGF -1154 G-->A and -634 G-->C polymorphisms using real-time PCR technology based on TaqMan 5' allelic discrimination assay. RESULTS: No significant differences in the allele or genotype frequencies for the 2 VEGF polymorphisms were observed between HSP patients and controls. However, the high VEGF producer VEGF -1154 G allele was increased in HSP patients with nephritis compared with healthy controls (p = 0.02, OR 2.13, 95% CI 1.11-4.08; pc = 0.04). Similarly, the high VEGF producer VEGF -634 C allele was increased in patients with nephritis compared to controls (p = 0.04, OR 1.66, 95% CI 1.01-2.73; pc = 0.08). The -1154G/-634C haplotype was associated with susceptibility to nephritis (p = 0.03, OR 1.71, 95% CI 1.01-2.89). A protective effect against nephritis was observed for the -1154A/-634G VEGF promoter haplotype (p = 0.02, OR 0.49, 95% CI 0.30-0.95). CONCLUSION: Our results suggest a potential implication of the VEGF -1154 G-->A and -634 G-->C polymorphisms in the development of nephritis in patients with HSP.     

Familial seropositive rheumatoid arthritis in North American Native families: effects of shared epitope and cytokine genotypes

OBJECTIVE: A number of North American native (NAN) populations have high prevalence rates of both rheumatoid arthritis (RA) and the shared epitope (SE). We examined the phenotype and familial incidence of RA in a NAN population, and investigated how the SE and cytokine genes may affect disease risk within affected families. METHODS: NAN patients with seropositive RA or polyarthritis rheumatoid factor (RF) positive juvenile idiopathic arthritis (JIA) were identified from clinical databases. Patients were recruited consecutively as they presented for clinic visits. Family pedigrees were constructed and consenting relatives were interviewed and examined. The risk of RA within families was calculated by multiple logistic regression. Input variables were the SE and cytokine genotypes. Probands and affected relatives were entered as the affected group, and unaffected relatives within families as the unaffected group. Results were confirmed among unrelated subjects, i.e., unrelated patients and unaffected relatives of other probands. RESULTS: The familial prevalence of RA was 0.50 (95% confidence intervals 0.30, 0.70) among 28 families studied. The interleukin 10 (IL-10) promoter -1082 G/A genotype decreased the odds of RA relative to the A/A genotype in affected families (OR 0.247, 95% CI 0.081, 0.751; p = 0.014) and among unrelated subjects (OR 0.203, 95% CI 0.064, 0.640; p = 0.006). The G/G genotype yielded an OR of 0.093 (95% 0.013, 0.676; p = 0.019) among unrelated subjects. The SE had no effect in these calculations. CONCLUSION: There was a high familial prevalence of RA in this NAN cohort. In susceptible NAN families, the risk of RA was reduced by IL-10 genotypes, whereas the SE did not affect risk. Study of healthy NAN controls is required to determine if these conclusions apply to this NAN population as a whole.     

Oestrogen receptor {alpha} gene polymorphisms in systemic lupus erythematosus

Objective: To analyse associations of two oestrogen receptor α (ORα) gene polymorphisms in 260 patients with SLE from northern Sweden. The two polymorphisms, PvuII T/C and the XbaI A/G, are located in the first intron of the ORα gene. Methods: All patients fulfilling at least four of the ACR criteria for SLE were consecutively recruited during one year. The SLEDAI score and SLICC damage index were recorded. 670 individuals from the same geographical area served as controls. DNA from the patients and controls was extracted and genotyped using the 5'' nuclease assay with an ABI PRISM 7900HT instrument. The genotype/phenotype relationships were calculated using SPSS. Results: The unusual PvuII C allele was associated with malar rash and the unusual XbaI G allele with photosensitivity (p = 0.001, OR = 2.53, 95% CI = 1.43 to 4.47 and p = 0.007, OR = 2.12, 95% CI = 1.22 to 3.66, respectively). The common XbaI AA genotype was associated with serositis (p = 0.013, OR = 1.92, 95% CI = 1.15 to 3.22). Based on the SLICC damage index associations of the common TT genotype and AA genotype with cognitive impairment were identified (p = 0.018, OR = 2.47, 95% CI = 1.17 to 5.25 and p = 0.018, OR = 2.75, 95% CI = 1.19 to 6.38 respectively). There was also an association of the XbaI AA genotype with the angina/coronary artery bypass variable (p = 0.042, OR = 2.58, 95% CI = 1.03 to 6.43). Of the variables describing disease severity and duration it was found that carriers of the unusual PvuII C allele showed a later onset of SLE (p = 0.02) and carriers of the unusual XbaI G allele a lower SLICC damage index. Conclusions: The unusual PvuII C and XbaI G alleles were associated with a milder form of SLE characterised by skin manifestations, later onset, and less organ damage.     

RANTES-403 polymorphism is associated with reduced risk of gastric cancer in women

Background Men are more susceptible to gastric cancer (GC) than women. However, the genetic factors associated with the sex difference are not well understood. Chemokines have been shown to modulate tumor behavior, and the sex-specific effect of the chemokine polymorphisms on the host susceptibility to several diseases has been reported. We aimed to determine the role of chemokine polymorphisms on host susceptibility to GC, with special interest on their sex-specific effect. Methods A hospital-based case-control study, including 177 patients with GC and 217 age-matched unaffected healthy controls, was performed in three major tertiary care hospitals. Genotyping for regulated upon activation, normal T-cell expressed and secreted (RANTES) −403 A/G and −28 C/G, CC chemokine receptor 5 (CCR5) deletion, and CCR2-V64I was performed using peripheral blood DNA. Results The RANTES −403 GA and AA genotypes were independently associated with a 2.3-fold reduced risk of developing GC (OR = 0.44, 95% CI 0.22–0.90, P = 0.025) compared with GG genotype in women, but not in men. The RANTES −28C/G and CCR2-V64I polymorphisms were not associated with different risk of developing GC. The tumor stage, histological features, and survival rate were not different when stratified by RANTES −403 and −28 and CCR2-V64I genotypes. Conclusions Our data indicate that women who inherit A allele at RANTES −403 may be at reduced risk of GC.     

Association of RANTES promoter polymorphism with juvenile rheumatoid arthritis

Objective

We recently reported that RANTES was a key molecule in the pathogenesis of juvenile rheumatoid arthritis (JRA) in a longitudinal cohort. This study was undertaken to investigate genetic associations between the RANTES −28 C/G and −403 G/A polymorphisms and JRA in a well‐documented cohort of patients who were followed up prospectively.

Methods

Patients with JRA (n = 107) and healthy children (n = 139) were genotyped through use of a polymerase chain reaction–based assay. Association of the RANTES promoter polymorphisms with results of laboratory tests, clinical variables, outcome after clinical remission, and response to intraarticular triamcinolone injection was evaluated in patients who were followed up for >1 year.

Results

JRA patients had a significantly higher frequency of the RANTES −28 G/G genotype, as compared with ethnically matched healthy controls. The RANTES −28 C/G polymorphism was associated with the duration of clinical remission, with patients carrying the RANTES –28G allele experiencing only 49% of the duration of remission experienced by patients who were RANTES −28 C/C homozygous. The RANTES −28 C/G polymorphism was associated with the duration of clinical response to intraarticular triamcinolone injection, with patients carrying the RANTES −28G allele showing shorter duration of clinical response. No significant association between the RANTES −403 G/A polymorphism and JRA was found in this Chinese population.

Conclusion

Our findings indicate that the RANTES −28 C/G polymorphism represents a genetic risk factor for JRA. It is noteworthy that this RANTES promoter polymorphism was also associated with an early relapse of disease after clinical remission and a shorter duration of clinical response to intraarticular administration of corticosteroids.

     

Association of CTLA4 gene A-G polymorphism with rheumatoid arthritis in Chinese

The aim of this study was to investigate the allelic association of a single nucleotide polymorphism in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with rheumatoid arthritis (RA) in Chinese people. One hundred and eighty-six unrelated adults with RA and 203 randomly selected normal adults were studied. All were ethnic Chinese living in Taiwan. The CTLA4 A-G polymorphism was genotyped with a polymerase chain reaction (PCR) and digestion with the restriction enzyme BstEII. The genotype and allele frequencies of CTLA4 in patients with rheumatoid arthritis differed significantly from those of adult controls (#E5/E5#=0.022 and #E5/E5#=0.037, respectively). Genotype CTLA4 49 G/G and allele G were associated with an increased risk of RA (RR=1.72, 95% CI=1.15–2.57, #E5/E5#=0.008; RR=1.39, 95% CI=1.02–1.89, #E5/E5#=0.037, respectively), whereas genotype A/G and allele A were associated with protection against RA (RR=0.58, 95% CI=0.39–0.87, #E5/E5#=0.008 and RR=0.72, 95% CI=0.53–0.98, #E5/E5#=0.037, respectively). We concluded that, the CTLA4 49 A-G polymorphism is associated with RA in Chinese patients from Taiwan.     

HO-1 promoter polymorphism associated with rheumatoid arthritis

OBJECTIVE: To investigate the role of the HO-1 gene as a novel functional candidate gene for rheumatoid arthritis (RA). METHODS: We performed a case-control study including 736 RA patients and 846 healthy controls of Spanish Caucasian origin. Two putative functional HO-1 promoter polymorphisms, a (GT)(n) microsatellite and a -413 A/T single-nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction-based methods. In addition, the intracellular expression of heme oxygenase 1 (HO-1) was determined in healthy individuals with different (GT)(n) genotypes. RESULTS: The distribution of HO-1 (GT)(n) short (S) alleles (< or =25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT)(n) alleles (P = 0.019) (odds ratio [OR] 0.8, 95% confidence interval [95% CI] 0.7-0.9) and the SS (GT)(n) genotype (P = 0.002) (OR 0.6, 95% CI 0.4-0.9). In contrast, the -413 HO-1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P = 7 x 10(-7), corrected P [P(corr)] = 3 x 10(-6)) (OR 0.4, 95% CI 0.3-0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, P(corr) = 0.03) (OR 1.2, 95% CI 1.0-1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT)(n) genotype showed a significantly higher percentage of HO-1 expression than did cells from LL homozygous individuals (P = 0.0003). CONCLUSION: In this study, we identified the HO-1 (GT)(n) microsatellite as a new genetic marker involved in RA genetics in our population.     

A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese

OBJECTIVE: The programmed death 1 (PD-1) molecule is a negative regulator of T cells, and a genetic association between PD-1 and systemic lupus erythematosus and rheumatoid arthritis (RA) in Caucasians has been reported. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with RA in the Chinese population. METHODS: Three single-nucleotide polymorphisms (SNPs), PD-1.1 G/A, PD-1.3 G/A, and PD-1.5 C/T, were genotyped in 180 patients with RA and 647 healthy controls in a case-control association study. Analyses of the association of genotypes and alleles with disease, haplotype construction, and linkage disequilibrium (LD) were performed. RESULTS: We constructed haplotypes with the alleles of markers PD-1.1 G/A and PD-1.5 C/T and found that the GT haplotype was overrepresented in patients with RA (31%) compared with controls (23%) (P = 0.001, odds ratio [OR] 1.54, 95% confidence interval [95% CI] 1.18-1.99). Among GT double homozygotes the risk of RA was increased even further (OR 2.31, 95% CI 1.31-4.08, P = 0.006). We also observed that the AA genotype of SNP PD-1.1 was associated with a decreased risk for developing RA (OR 0.38, 95% CI 0.15-0.99, P = 0.034). No association for SNP PD-1.5 in RA was found, and SNP PD-1.3 was nonpolymorphic in the Chinese population. CONCLUSION: Our results support the involvement of PDCD1 as a susceptibility gene for RA in the Chinese population.