Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis

It has been reported that a functional polymorphism in the promoter of the RANTES gene (-403G/A) is associated with atopic dermatitis in a German population. Although there are several reports on the association of RANTES promoter polymorphisms (-403G/A and -28C/G) with asthma, the association of these polymorphisms with atopic dermatitis has not yet been confirmed in other populations. We therefore aimed to test whether the RANTES promoter polymorphisms relate to atopic dermatitis in a well-defined Japanese population. We conducted an association study of upregulating promoter polymorphisms of RANTES (-403G/A and -28C/G) in 389 patients with atopic dermatitis and 177 healthy control subjects. There was a significant association between the upregulating variant of RANTES -28G and atopic dermatitis, while -403A variant showed a significant association with atopic dermatitis with high IgE productivity. These results support a role for RANTES promoter polymorphisms in susceptibility to atopic dermatitis.     

The RANTES promoter polymorphism: a genetic risk factor for near-fatal asthma in Chinese children

BACKGROUND: RANTES promoter polymorphisms were found associated with asthma/atopy in some studies but not others, possibly reflecting the genetic heterogeneity among different ethnicities and different asthma severity. OBJECTIVE: The purpose of this investigation was to test the genetic association between the RANTES -28C/G and -403G/A polymorphisms and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 children with mild-to-moderate asthma, 69 children with allergic disorders but no asthma, and 107 nonasthmatic nonatopic control children were genotyped through use of a PCR-based assay. RESULTS: No significant difference was demonstrated for frequency of the RANTES -28C/G polymorphism when the mild-to-moderate asthma, atopic/nonasthmatic, and normal control groups were compared. The RANTES -28G allele was present in a significantly higher proportion of the children with near-fatal asthma compared with the nonasthmatic nonatopic controls (odds ratio, 2.93 [1.41-6.06]; P =.006) and the children with mild-to-moderate asthma (odds ratio, 3.52 [1.73-7.16]; P =.001). The frequency of -28G allele carriage correlated with asthma severity. The RANTES -28G allele was also associated with an increased blood eosinophil count and a higher degree of bronchial hyperresponsiveness. The RANTES -403G/A polymorphism did not influence asthma/atopy susceptibility, blood eosinophil count, or bronchial hyperresponsiveness. Interestingly, a higher frequency of -403A allele carriage was observed in the moderate asthma subgroup compared with the mild asthma analog. CONCLUSIONS: We conclude that the RANTES -28C/G polymorphism exacerbates asthma severity, representing a genetic risk factor for life-threatening asthma attacks in Chinese children. In addition, the linkage disequilibrium between these 2 polymorphisms is a potential confounder that must be considered in the design and interpretation of RANTES gene association studies.     

CCL5/RANTES chemokine gene promoter polymorphisms are not associated with atopic and nonatopic asthma in a Spanish population

CCL5/RANTES, a member of the C-C chemokine family, is a potent eosinophil, monocyte, basophile and lymphocyte chemo-attractant at the site of inflammation. Recent studies revealed that a functional mutation at the -403 position in the promoter may have significance for atopic dermatitis, bronchial asthma, sarcoidosis, rheumatoid arthritis and HIV infection, and others. Another polymorphism in the -28 position has been reported. Our objective was to investigate the possible influence of the CCL5/RANTES promoter polymorphisms in the different types of bronchial asthma. CCL5/RANTES genotyping was performed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) in 306 asthmatic patients with non-atopic (n = 145) and atopic (n = 161) asthma and 242 controls. The 81.9% of the atopic asthma patients for -403G/A had the G allele and the A allele frequency was 18%. Of the non-atopic asthma patients, the G allele frequency was 79.7% and the A allele was 20.3%. Concerning the -28C/G polymorphism, the frequency of the CCL5/RANTES -28G allele in our patients is 2.8%, which is similar to Spanish adult population. After comparing patients with asthma, atopic patients, non-atopic patients and control population, we found no significant deviation in the distribution of the alleles or genotypes of CCL5/RANTES promoter polymorphisms in any tested comparison. Therefore, human CCL5/RANTES gene promoter polymorphisms are not associated with the different types of bronchial asthma in Spanish population.     

The effects of RANTES/CCR5 promoter polymorphisms on HIV disease progression in HIV-infected Koreans

Recent studies have reported that two single nucleotide polymorphisms (SNPs) in the RANTES gene promoter region, -403G/A and -28C/G, are associated with a slower rate of decline in CD4(+) T-cell number, whereas genetic polymorphisms within the CCR5 promoter are linked to acceleration of AIDS progression. In this study, we investigated the distribution of SNPs in the RANTES and CCR5 promoters and the association between these SNPs and HIV-1 disease progression in HIV-infected Koreans. Twenty-seven long-term non-progressors (LTNPs), 29 AIDS patients and 39 HIV-uninfected persons were enrolled in this study. SNPs for the RANTES and CCR5 promoters were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a direct sequencing method. In the analysis of RANTES promoter polymorphisms, the genotypic and allelic frequencies of the RANTES -28G mutation were significantly lower in HIV-infected patients than in HIV-uninfected persons (P = 0.005 and P = 0.001, respectively). The genotypic frequencies of RANTES -28G and -403A mutations did not differ significantly between LTNPs and AIDS patients. The frequencies of three CCR5 promoter polymorphisms, designated 59029 G/A, 59353T/C, and 59402G/A, did not differ significantly between HIV-uninfected and HIV-infected patients. However, the allelic frequency of CCR559353C was significantly higher in AIDS patients than in LTNPs (P = 0.003). These results suggest that RANTES-28G and CCR5 59353C mutations might be associated with HIV infection or pathogenesis in the Korean population.     

Effects of single nucleotide polymorphisms in the RANTES promoter region in healthy and HIV-infected indigenous Chinese.

We determined the occurrence of the single nucleotide polymorphisms (SNPs) -403A/G and -28C/G in the promoter region of RANTES in 1082 Chinese blood donors from northern and southern China and 249 HIV patients from southern China. Compared to healthy adults, Chinese AIDS patients had a significantly higher frequency of the -403G allele and haplotype I, -403G/-28C (P < 0.05), and a lower frequency of the -403A/A genotype (P < 0.01). Symptomatic patients had a higher frequency of the -28G allele and a lower frequency of the -28C/C genotype (P < or = 0.01). The plasma RANTES level was significantly lower in blood donors homozygous for haplotype I than in those who were homozygous for haplotypes II and III (P < 0.05). The frequency of the -403G allele was found to be higher in Chinese than in indigenous Africans, but lower than in Caucasians, Hispanics, and African Americans. The frequency of the -28G allele was comparable in Chinese and Japanese; this allele is rare in other ethnic groups. Results suggest that -403G may be associated with increased susceptibility to HIV infection, while -28G may be associated with advanced disease progression. The impact of SNPs on HIV infection appears to be unique in Chinese.     

Preferential transmission and association of the -403 G --> A promoter RANTES polymorphism with atopic asthma

Asthma is a complex inherited disease. The study was undertaken to identify the association of RANTES promoter polymorphisms with atopy and asthma using family-based association tests (FBATs) and generation-specific case-control analyses. We identified 154 nuclear families (453 individuals) in whom we established RANTES promoter status using the RFLP-PCR method. Of the two known promoter polymorphisms -403G/A and -28C/G, only the former appeared with a clinically relevant frequency. A total of 61 families were eligible for assessment of transmission of the allele with asthma and atopy by the pedigree disequilibrium test (PDT). Overall, allele frequency for -403A was 38.3% and 84 of 89 (94.3%) alleles were transmitted with physician diagnosed asthma (PDA) (P=0.001). All 89 children with atopy received the mutant allele, which was more than expected following Mendelian Laws of transmission (P=0.0001). In 303 unrelated parents, significant associations of the mutant allele were for atopy with or without asthma (P=0.001). In 150 unrelated children, significant associations were for atopy alone (P=0.001) and asthma (P=0.001). No associations were found for bronchial hyper-responsiveness (BHR). The -403 G --> A is transmitted with atopy and atopic asthma, although its contribution appears to relate more to atopy than asthma and BHR.     

Association between RANTES functional polymorphisms and tuberculosis in Hong Kong Chinese

Chemokines play a major role in leukocyte recruitment during the formation of tuberculous granulomas. We studied the association between genetic polymorphisms of three chemokines, monocyte chemoattractant protein-1 (MCP-1), RANTES (regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein-1alpha (MIP-1alpha), and tuberculosis (TB). The distribution of five functionally significant single-nucleotide polymorphisms (SNPs), MCP-1 -2518A/G, RANTES -403G/A, -28C/G and In1.1T/C as well as MIP-1alpha +459C/T was not found to be different between patients with TB and healthy control subjects of the Hong Kong Chinese population. However, differences in linkage disequilibrium (LD) of the SNPs of RANTES and in distribution of the haplotypes of RANTES between patients with TB and healthy controls (P<0.0001) were found. Two risk haplotypes of RANTES, A-C-T and G-C-C, at positions -403, -28 and In1.1, respectively, were identified. Furthermore, combining the genotypes of RANTES -403 and In1.1, two diplotypes GA/TT (P<0.001) and GG/TC (P<0.0001) showed strong association with TB. Our findings support the association between RANTES functional polymorphisms and TB.     

RANTES, MCP-1 chemokines and factors describing rheumatoid arthritis

The MCP-1/CCL2 as well as RANTES/CCL5 chemokines are potent chemoattractants involved in immunoregulatory and inflammatory processes of rheumatoid arthritis. Recent studies demonstrated elevated levels of MCP-1 and RANTES in plasma, synovial fluid, and the synovial tissue of patients with RA. To examine the relationship among MCP-1 and RANTES single nucleotide polymorphisms and circulating levels and rheumatoid arthritis (RA), a total of 156 RA patients and 125 controls were recruited into the study. An association of -855 C/G MCP-1 polymorphism to IgM RF within the RA patients was observed. The lowest circulating levels of RANTES were observed in the AA variant of RANTES -403 G/A polymorphism. Furthermore, an association of -403 AA variant to circulating levels of IL-15 and IL-10 was found. No associations of factors describing rheumatoid arthritis (RFs, ANA, anti-CCP-positive/negative, DAS 28 score and number of swollen joints) with MCP-1 levels, genotype distribution, allelic frequencies and/or frequencies of haplotypes composed of all three studied polymorphisms in promoter region of MCP-1, and RANTES polymorphism were observed. We conclude that the RANTES promoter polymorphism is associated to circulating levels of RANTES, IL15 and IL10. However, our findings suggest that polymorphisms in the MCP-1 and RANTES gene promoters do not contribute significantly to the interindividual RA susceptibility and/or severity in Caucasians.     

支气管哮喘患儿与RANTES单核苷酸多态性的相关性研究

目的探讨RANTES单核苷酸多态性(SNP)与哮喘易感患儿的相关性.方法采用聚合酶链反应方法对32例哮喘患儿和32例正常对照进行了RANTES-403及-28位点基因型分布和等位基因频率研究.结果病例组RANNTES-403位点G/G、G/A、A/A基因型频率分别为53.13%、40.62%、6.25%;对照组分别为50.00%、43.75%、6.25%(P＞0.05).两组突变等位基因-403A频率分别为26.53%和28.13%(P＞0.05).病例组RANTES-28位点C/C、C/G、G/G基因型频率分别为78.13%、18.75%、3.12%;对照组分别为90.63%、9.37%、0%(P＞0.05).两组突变等位基因-28G频率分别为12.50%和4.69%(P＞0.05).结论RANTES-403位点和-28位点SNP与哮喘发病可能没有直接的关系.     

Association of genetic variations in CCR5 and its ligand, RANTES with clearance of hepatitis B virus in Korea

Immunogenetic factors may play a role in determining the susceptibility of an individual to viral infection. The aim of current study was to investigate the association of clearance of hepatitis B virus (HBV) with promoter polymorphisms within the CC chemokine receptor 5 (CCR5) and its major ligand, regulated upon activation, normal T cells expressed and secreted (RANTES) genes. Five chemokine system polymorphisms (CCR5 Delta32, CCR5 promoter 59029G/A, 59353C/T, RANTES -403G/A, and -28C/G) were studied in a total of 698 subjects. The carriage of each genetic variant was compared among "spontaneously recovered" group (n = 243), "chronic carrier" group (n = 349), and "unexposed" group (n = 106). CCR5 59029G promoter variant was associated with clearance of HBV infection in an acute phase (OR = 1.71, P = 0.006, dominant model; OR = 2.17, P < 0.001, recessive model) and amelioration of hepatic inflammation (P = 0.003) with the control of HBV replication (P = 0.04) in chronic carriers. Interestingly, CCR5 59029 was linked completely to CCR5 59353, and CCR5 Delta32 homozygosity or heterozygosity was not found in any Korean patient. No association was seen with RANTES polymorphisms at position -403 and -28. The CCR5 59029G/CCR5 59353T polymorphism may play a role in the clearance of HBV infection.     

The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (-403 G-->A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The -403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the -403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 < or = 80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.     

Sequence variation in the promoter region of the cholinergic receptor muscarinic 3 gene and asthma and atopy

BACKGROUND: Muscarinic acetylcholine receptors are members of the superfamily of G protein-coupled, 7 transmembrane- spanning proteins. They are important in the development of airway hyperresponsiveness. In the lung the M3 receptor, encoded by the cholinergic receptor muscarinic 3 gene, is present in airway smooth muscle and mediates smooth muscle contraction. OBJECTIVE: We considered the cholinergic receptor muscarinic 3 gene as a possible candidate gene for bronchial asthma and initiated studies to identify polymorphisms in the promoter region. METHOD: We identified 4 single-nucleotide polymorphisms (-708A/G, -627G/C, -513C/A, and -492C/T) and 2 short tandem repeat polymorphisms, a tetranucleotide (CTTT)12-20 and a dinucleotide (GT)6-19 repeat. RESULTS: None of the identified single nucleotide polymorphisms were significantly more frequent in asthmatic patients (n = 76) compared with in healthy control subjects (n = 81). Furthermore, there was no evidence for nonrandom transmission of short tandem repeat polymorphism haplotypes to individuals with asthma or bronchial hyperresponsiveness (P >.50) in a large Hutterite pedigree. However, there was significant nonrandom transmission of haplotypes to individuals with skin test reactivity to cockroach allergens (global transmission disequilibrium test: chi2 = 38.55, P =.013). CONCLUSIONS: These results suggest a possible role for this gene in atopic disorders.     

Association of IL-13, RANTES, and leukotriene C4 synthase gene promoter polymorphisms with asthma and/or atopy in African Americans.

PURPOSE: IL-13, RANTES (Regulated on Activation, Normal T cells Expressed and Secreted), and cysteinyl leukotrienes are asthma and atopy mediators. Two RANTES -403(G to A) and -28(C to G), an -1055 IL-13(C to T), and a -444(A to C) leukotriene C4 synthase (LTC4S) single nucleotide polymorphisms (SNPs) have been shown in Caucasians and Asians as asthma and atopy risk factors. We studied these SNPs in African Americans with asthma and/or atopy. METHODS: We studied 61 patients with asthma and/or atopy and 129 to 157 newborn controls for the -403 RANTES, -28 RANTES, and -1055 IL-13 SNPs, as well as 47 patients and 60 newborn controls for the -444 LTC4S SNP. RESULTS: The two groups did not significantly differ at the genotypes of the -403 and -28 RANTES SNP. On the other hand, the mutant TT genotype for the -1055 IL-13 SNP was detected in 19.7% of patients versus 12.7% in controls (P < 0.04, OR 2.9, 95% CI 1.0-8.0), and the mutant T allele in 58.3% versus 36.6% in controls (P < 0.02, OR 2.4, 95% CI 1.1-5.2). In a similar fashion, for the -444 LTC4S SNP, the mutant AC genotype was detected in 19.1% versus 10.0% in controls (P > 0.28); mutant C allele had an OR of 2.1 (95% CI 0.7-6.3). CONCLUSION: African American asthmatics/atopics had higher frequency of the TT mutant gene for the -1055 IL-13 SNP and of its mutant T allele. Regarding the -444 LTC4S SNP, there was a definite difference, although not statistically significant, with an OR of 2.1 for the mutant AC genotype in patients. If these findings become reproduced by larger studies, it may suggest that IL-13 and LTC4S SNPs can be used as predictive markers for asthma/atopy in African Americans.     

Polymorphism of RANTES chemokine gene promoter is not associated with long-term nonprogressive HIV-1 infection of more than 16 years

To examine whether polymorphisms of the RANTES chemokine gene promoter are associated with long-term nonprogressive HIV-1 infection in white Spanish subjects, we performed a cross-sectional genetic association case-control study. Two-hundred sixty-seven white Spaniards were studied: 58 were HIV-1-infected long-term nonprogressors (LTNPs) of more than 16 years, 109 were HIV-1-infected usual progressors (UPs), and 100 were control subjects. Three RANTES single nucleotide polymorphisms (SNPs) at positions -28C>G, -109T>C, and -403G>A were assessed. The prevalence of the CCR5Delta 32 allele was also examined. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods. Genotype and allele frequencies between the 3 groups were compared by the chi2 test and the Fisher exact test. The distribution of allelic variants of RANTES in controls, UPs, and LTNPs, respectively, was 3%, 2%, and 5% for -28G; 4%, 2%, and 2% for -109C; and 18%, 18%, and 18% for -403A (P = not significant). The differences were still nonsignificant when we exclusively analyzed individuals not carrying the CCR5Delta32 allele. We conclude that LTNP of more than 16 years is not associated with SNPs in the RANTES gene promoter in white Spanish HIV-1-infected subjects.     

Variant in promoter region of platelet-derived growth factor receptor-alpha (PDGFRalpha) gene is associated with the severity and allergic status of childhood asthma

BACKGROUND: Upregulation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRalpha promoter polymorphism and severity of childhood asthma was examined. METHODS: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRalpha gene were genotyped in 277 unrelated allergic and nonallergic asthmatic children and 93 age-matched controls. Promoter haplotypes were constructed using SNP genotyping data. The serum level of PDGF-AA, the ligand for PDGFRalpha, was assayed by ELISA kits. RESULTS: The genotype distribution of SNP rs1800810 (-1171G/C) in nonallergic asthma was significantly different from controls (p=0.038), as well as its allele distribution (p=0.028). Using haplotype analysis, the combination frequency of the low expression of H1 homozygous and heterozygous genotype (H1/H1+H1/H2) was significantly higher in nonallergic asthma as compared to controls (OR=1.94, CI=1.11-3.39, p<0.02). The frequency of H2/H2 homozygous was higher in persistent asthma than in intermittent asthma (p=0.008, OR=2.625). In addition, the PDGF-AA serum level in H2/H2 homozygous haplotype was significantly lower as compared to non-H2/H2 homozygous haplotype both in asthmatic (138.1+/-62.9 vs. 249.7+/-97.1 ng/ml, p<0.05) and nonallergic asthmatic children (113.8+/-38.0 vs. 256.6+/-58.3 ng/ml, p<0.05). CONCLUSIONS: The developmental deficiency due to the low expression of PDGFRalpha may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRalpha expression that might lead to airway remodeling causing the severity of asthma.     

Effects of single nucleotide polymorphisms in the RANTES promoter region in healthy and HIV‐infected indigenous Chinese*

We determined the occurrence of the single nucleotide polymorphisms (SNPs) ?403A/G and ?28C/G in the promoter region of RANTES in 1082 Chinese blood donors from northern and southern China and 249 HIV patients from southern China. Compared to healthy adults, Chinese AIDS patients had a significantly higher frequency of the ?403G allele and haplotype I, ?403G/?28C (P < 0.05), and a lower frequency of the ?403A/A genotype (P < 0.01). Symptomatic patients had a higher frequency of the ?28G allele and a lower frequency of the ?28C/C genotype (P ≤ 0.01). The plasma RANTES level was significantly lower in blood donors homozygous for haplotype I than in those who were homozygous for haplotypes II and III (P < 0.05). The frequency of the ?403G allele was found to be higher in Chinese than in indigenous Africans, but lower than in Caucasians, Hispanics, and African Americans. The frequency of the ?28G allele was comparable in Chinese and Japanese; this allele is rare in other ethnic groups. Results suggest that ?403G may be associated with increased susceptibility to HIV infection, while ?28G may be associated with advanced disease progression. The impact of SNPs on HIV infection appears to be unique in Chinese.     

Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity.

BACKGROUND: Chemokines play an important role in the pathophysiology of asthma and allergy. Recently, polymorphisms in the gene regulatory region of monocyte chemoattractant protein 1 (MCP-1) and in the promoter region of RANTES have been found; these polymorphisms increase the expression of the chemokines. OBJECTIVE: We investigated whether the presence of the polymorphisms was associated with atopy or asthma and whether these alleles influenced the severity of asthma in affected individuals. METHODS: Three groups of subjects-160 children with asthma (disease severity being classified according to the Global Initiative for Asthma guidelines, modified for children), 151 children with nonasthmatic but allergic phenotype, and 303 children without allergic or asthmatic disorders-were screened with a PCR-based assay for genotyping. RESULTS: The frequency of the -2518G polymorphism in the gene regulatory region of MCP-1 was significantly higher in asthmatic children than in controls (P <.001; odds ratio [OR] = 2.0 [1.4-2.6]) and nonasthmatic atopic children (P <.001; OR = 2.0 [1.4-2.9]). The MCP-1 G/G genotype correlated with asthma severity. In asthmatic children, the MCP-1 -2518G allele was also associated with an increased blood eosinophil level. The promoter polymorphisms in the RANTES gene did not have a detectable effect on the susceptibility to asthma or allergy or on the blood eosinophil count. CONCLUSION: In this cohort of children, there are associations between carrying G at -2518 of the MCP-1 gene regulatory region and the presence of asthma as well as between asthma severity and homozygosity for the G allele. In asthmatic children, the MCP-1 -2518G polymorphism correlated with increased eosinophil levels. This variant of MCP-1 might belong to the predictor gene set for asthma.     

RANTES Gene Polymorphisms Are Not Associated with Rheumatoid Arthritis and Atopic Dermatitis: A Meta-Analysis

Background: A few recent studies have suggested that regulated on activation, normal T cell expressed and secreted (RANTES) polymorphisms (-403 G/A, -28C/G) are associated with rheumatoid arthritis (RA) and atopic dermatitis (AD). However, there still existed studies that did not confirm this correlation. Objective: The objective of this study was to evaluate the relationships of RANTES and RA and AD using a meta-analysis. Methods: Pubmed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers, and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Results: Eight studies were enrolled, including a total of 548 RA cases and 493 controls of -403G/A, 305 RA cases and 303 controls of -28C/G, and 705 AD cases and 578 controls of -403G/A in this meta-analysis. In RA, the overall OR and 95% CI of -403A were 1.41, 1.10–1.82 (p = 0.391) and 2.18, 1.30–3.66 (p = 0.335) in dominant and recessive models, respectively. The overall OR and 95% CI of -28G in RA were 1.35, 0.91–2.01 (p = 0.707) and 3.32, 1.29–8.52 (p = 0.559) in dominant and recessive models, respectively. Moreover, the overall OR and 95% CI of -403A in AD were 1.38, 1.08–1.76 (p = 0.421) and 1.06 and 0.65–1.72 (p = 0.361) in dominant and recessive models, respectively. Conclusions: This meta-analysis showed that RANTES -403G/A and -28C/G were not associated with RA and AD.     

Lack of association between atopic eczema/dermatitis syndrome and polymorphisms in the promoter region of RANTES and regulatory region of MCP-1

BACKGROUND: Chemokines play an important role in the pathophysiology of atopic eczema/dermatitis syndrome (AEDS) and allergy. Recently polymorphisms in the promoter region of RANTES (regulated on activation normal T cell expressed and secreted) and in the gene regulatory region of MCP-1 (monocyte chemoattractant protein-1) have been found, which increase the expression of these chemokines. The - 403A allele of the RANTES promoter region was found associated with AEDS in German children. We investigated whether the presence of these polymorphisms was associated with AEDS or allergy in Hungarian children. METHODS: One hundred and twenty-eight children with AEDS, 102 allergic children without AEDS and 303 children of comparable ages without allergic disorders were screened for genotype with a PCR-based assay. RESULTS: There were no significant differences in the frequency of these polymorphisms, or in the distribution of genotypes between the groups. The total IgE concentration, the white blood cell count and the blood eosinophil cell count did not differ between the genotypes. CONCLUSION: In this cohort of Hungarian children there was no association between - 28G, and - 403A alleles in the RANTES promoter, - 2518G polymorphism in the distal regulatory region of the MCP-1 and AEDS, or allergy.     

Effect of Genetic Polymorphism of ALOX15 on Aspirin-Exacerbated Respiratory Disease

Background: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome associated with chronic inflammation in the airways coincident with chronic rhinitis, sinusitis, recurrent polyposis and asthma. Eosinophils are the key inflammatory cells in the development of AERD. AERD has been attributed to abnormalities of the arachidonic acid metabolism, but the pathogenesis of AERD is not fully understood. Our aim was to investigate the genetic contribution of the arachidonate 15-lipoxygenase gene (ALOX15) to the development of AERD. Methods: We enrolled 171 patients with AERD, 229 patients with aspirin-tolerant asthma, and 195 normal healthy controls in a Korean population. Three polymorphisms (-427G/A, -272C/A, -217G/C) in the promoter region of ALOX15 were genotyped. The functional variability of the promoter polymorphisms were analyzed by luciferase reporter activity assay. Result: No significant difference in the genotype frequency of the ALOX15 genetic polymorphism was found. Peripheral total eosinophil count was significantly higher in the patients carrying the GG genotype of the -427G/A polymorphism (p = 0.016). Similarly, the patients carrying haplotype 1 (ht1) (GCG) of -427G/A, -272C/A and -217G/C showed a significantly higher total eosinophil count compared to the other haplotypes (p = 0.008) in the AERD group. The promoter activity of the ht1 (GCG) construct was significantly higher compared to that of the ht3 (AGG) construct in A549 and U937 cells (both p < 0.001). Conclusion: These results suggest that the promoter polymorphisms of the ALOX15 gene affect ALOX15 activity leading to increased eosinophil infiltration in AERD patients.