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1.  CCL5/RANTES Gene Polymorphisms in Slavonic Patients with Myocardial Infarction 
Mediators of Inflammation  2011;2011:525691.
Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1 T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously.
PMCID: PMC3086320  PMID: 21547257
2.  Association between regulated upon activation, normal T cells expressed and secreted (RANTES) -28C/G polymorphism and asthma risk - A Meta-Analysis 
Regulated upon activation, normal T-cell expressed and secreted (RANTES) is one of the most extensively studied C-C chemokines in allergic inflammation. A growing body of evidence suggests that many cell types present in asthmatic airways have the capacity to generate RANTES, which directly supported the potential role of RANTES in asthma. A number of studies have evaluated the functional polymorphism -28C/G in the RANTES promoter region, which had been found to affect the transcription of the RANTES gene, in relation to asthma susceptibility. However, the results remain conflicting rather than conclusive. This meta-analysis on 1894 asthma cases and 1766 controls for -28C/G from 9 published case-control studies showed that the variant allele -28G was associated with significantly increased risk of asthma (GG+CG vs CC: OR=1.24, 95%CI=1.08-1.41) without any between-study heterogeneity.
In the stratified analysis by asthma type, age and ethnicity, we found that the increased asthma risk associated with -28G/C polymorphism was more evident in children (OR=1.24, 95%CI=1.06-1.45), Asian group (OR=1.27, 95%CI=1.04-1.56) and African group (OR=1.72, 95%CI=1.07-2.78). These results suggest that RANTES -28G/C polymorphism may contribute to asthma development, especially in children and in Asian population. Additional well-designed large studies were required for the validation of this association.
PMCID: PMC2828619  PMID: 20186291
RANTES; polymorphism; susceptibility; asthma; meta-analysis
3.  Polymorphisms of chemokine and chemokine receptor genes in idiopathic immune-mediated posterior segment uveitis 
Molecular Vision  2007;13:388-396.
Chemokines are important inflammatory mediators that play a crucial role in uveitis. Polymorphisms in chemokine genes can alter the expression of these genes in the inflammatory cells, which, in turn, can affect the clinical phenotype of the disease. The purpose of this study was to identify polymorphisms in chemokine genes that can predict visual outcome in patients with immune-mediated posterior segment uveitis.
This is a case-control study of 141 Caucasians with idiopathic immune-mediated posterior segment uveitis and 282 controls matched by age and ethnicity. Six polymorphisms in four genes, (MCP-1-2518A/G, RANTES-403G/A, RANTES-28C/G, CCR2 V64I, CCR5-59029G/A, and CCR5 32 bp deletion) were analyzed by sequence specific primers polymerase chain reaction.
Patients with G allele at MCP-1-2581 developed the disease at an early age as compared to patients with A allele corrected p value pc=0.003. Also patients with A allele at RANTES-403 position developed less severe disease and had better visual outcome when compared with patients with G allele (pc=0.02) Final visual acuity after 18 months was better in patients with 32 bp deletion of the CCR5 gene and in patients with the CCR2 wild-type genotype pc=0.02 and pc=0.04, respectively. Patients with the CCR2 64I allele also had a higher risk of developing an elevated intraocular pressure as compared to patients with the wild-type genotype (pc=0.007).
Though the utility for prediction of disease susceptibility of the studied polymorphisms in chemokine genes is in general not robust, we have found that polymorphisms in chemokine genes can influence the outcome of patients with idiopathic immune-mediated posterior segment uveitis. These associations require further analysis in other groups of patients.
PMCID: PMC2642933  PMID: 17417600
4.  Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer 
BMC Cancer  2008;8:382.
Inflammation has been implicated as an etiological factor in several human cancers, including prostate cancer. Allelic variants of the genes involved in inflammatory pathways are logical candidates as genetic determinants of prostate cancer risk. The purpose of this study was to investigate whether single nucleotide polymorphisms of genes that lead to increased levels of pro-inflammatory cytokines and chemokines are associated with an increased prostate cancer risk.
A case-control study design was used to test the association between prostate cancer risk and the polymorphisms TNF-A-308 A/G (rs 1800629), RANTES-403 G/A (rs 2107538), IL1-A-889 C/T (rs 1800587) and MCP-1 2518 G/A (rs 1024611) in 296 patients diagnosed with prostate cancer and in 311 healthy controls from the same area.
Diagnosis of prostate cancer was significantly associated with TNF-A GA + AA genotype (OR, 1.61; 95% CI, 1.09–2.64) and RANTES GA + AA genotype (OR, 1.44; 95% CI, 1.09–2.38). A alleles in TNF-A and RANTES influenced prostate cancer susceptibility and acted independently of each other in these subjects. No epistatic effect was found for the combination of different polymorphisms studied. Finally, no overall association was found between prostate cancer risk and IL1-A or MCP-1 polymorphisms.
Our results and previously published findings on genes associated with innate immunity support the hypothesis that polymorphisms in proinflammatory genes may be important in prostate cancer development.
PMCID: PMC2626602  PMID: 19099590
5.  Effect of RANTES gene promoter genotypes in patients with ulcerative colitis 
Biomedical Reports  2014;2(4):602-606.
A complex interaction of genetic and environmental factors is closely associated with the development of inflammatory bowel disease. Previous studies reported that the expression of the regulated upon activation, normal T-cell expressed and secreted (RANTES) gene is enhanced in the colonic mucosa of ulcerative colitis (UC). Quantitative differences in RANTES gene expression among numerous promoter genotypes have also been reported. The aim of the present study was to clarify the effect of RANTES promoter polymorphism on the risk of UC, including its clinical phenotypes. A total of 150 UC patients and 372 healthy control (HC) subjects participated in the study. The UC patients were classified by disease behavior, severity and extent of disease. Restriction fragment length polymorphism analysis was performed for polymorphisms at −28 C/G in the RANTES gene promoter region. Although no significant difference of the RANTES promoter genotype distribution was observed between the HC and UC groups, the G/G genotype was significantly higher among female (OR=3.95, 95% CI=1.22–12.82, P=0.03), non-steroid dependent (OR=3.37, 95% CI=1.16–9.85, P=0.03) and non-refractory (OR=3.76, 95% CI=1.29–10.98, P=0.02) UC patients. The G carrier was also found to be associated with an increased risk of rectal colitis (OR=2.21, 95% CI=1.12–4.39, P=0.03). The data indicate that the polymorphism of the RANTES promoter is not directly associated with the susceptibility to UC, but the −28 G allele is associated with female UC patients and mild clinical phenotypes of UC, including non-steroid dependency, non-refractory and rectal colitis.
PMCID: PMC4051492  PMID: 24944817
ulcerative colitis; RANTES promoter; polymorphism
6.  RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies 
PLoS ONE  2011;6(12):e25734.
The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.
Methods and Findings
We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75–1.42] and 1.11 [0.81–1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).
High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.
PMCID: PMC3232218  PMID: 22162987
7.  MCP-1 and RANTES Polymorphisms in Korean Diabetic End-Stage Renal Disease 
Journal of Korean Medical Science  2007;22(4):611-615.
Macrophage infiltration has been observed in the renal biopsy specimens of diabetic nephropathy (DN), and hyperglycemic state stimulates the renal expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) and MCP-1 (monocyte chemoattractant protein-1). Upregulation of RANTES and MCP-1 with infiltrating macrophages may play a crucial role in the development and progression of DN. Genetic polymorphisms of RANTES and its receptors were reported to be independent risk factors for DN. We genotyped single nucleotide polymorphism (SNPs) in the MCP-1 G-2518A, CCR2 G46295A, RANTES C-28G and G-403A in 177 diabetic end-stage renal disease (ESRD) patients and 184 patients without renal involvement (controls) in order to investigate the effects of these SNPs on DN in Korean patients with type 2 DM. There were no differences in the frequencies of SNPs and the distribution of haplotypes of RANTES promoter SNPs between two groups. In conclusion, there were no associations of MCP-1, CCR2 and RANTES promoter SNPs with diabetic ESRD in Korean population. Prospective studies with clearly-defined, homogenous cohorts are needed to confirm the effect of these genetic polymorphisms on DN.
PMCID: PMC2693807  PMID: 17728497
Diabetic Nephropathies; Kidney Failure, Chronic; Monocyte Chemoattractant Proteins; RANTES; Polymorphism, Single Nucleotide Polymorphisms; Diabetes Mellitus, Type 2
8.  Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus 
BMC Medical Genetics  2006;7:48.
Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1α, and MCP-1 for systemic lupus erythematosus.
The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1α, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay.
No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1α, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found.
These results suggest that the tested functional variation of RANTES, IL-8, IL-1α, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population.
PMCID: PMC1488833  PMID: 16719905
9.  The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese 
Chemokines play important roles in inflammation and antiviral action. We examined whether polymorphisms of RANTES, IP-10 and Mig affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS).
We tested the polymorphisms of RANTES, IP-10 and Mig for their associations with SARS in 495 Hong Kong Chinese SARS patients and 578 controls. Then we tried to confirm the results in 356 Beijing Chinese SARS patients and 367 controls.
RANTES -28 G allele was associated with SARS susceptibility in Hong Kong Chinese (P < 0.0001, OR = 2.80, 95%CI:2.11–3.71). Individuals with RANTES -28 CG and GG genotypes had a 3.28-fold (95%CI:2.32–4.64) and 3.06-fold (95%CI:1.47–6.39) increased risk of developing SARS respectively (P < 0.0001). This -28 G allele conferred risk of death in a gene-dosage dependent manner (P = 0.014) with CG and GG individuals having a 2.12-fold (95% CI: 1.11–4.06) and 4.01-fold (95% CI: 1.30–12.4) increased risk. For the replication of RANTES data in Beijing Chinese, the -28 G allele was not associated with susceptibility to SARS. However, -28 CG (OR = 4.27, 95%CI:1.64–11.1) and GG (OR = 3.34, 95%CI:0.37–30.7) were associated with admission to intensive care units or death due to SARS (P = 0.011).
RANTES -28 G allele plays a role in the pathogenesis of SARS.
PMCID: PMC1899505  PMID: 17540042
10.  Effect of host genetics on incidence of HIV neuroretinal disorder in patients with AIDS 
Approximately 10 to 15% of patients with AIDS but without ocular opportunistic infections will have a presumed neuroretinal disorder (HIV-NRD), manifested by reduced contrast sensitivity and abnormal visual fields. The loss of contrast sensitivity often is sufficient to impair reading speed. To evaluate the effect of host genetics on HIV-NRD, we explored validated AIDS restriction gene variants CCR5Δ32, CCR2-64I, CCR5 P1, SDF-3`A, IL-10-5`A, RANTES -403A, RANTES -28G, RANTES-In1.1C, CX3CR1-249I, CX3CR1-280M, IFNG-179T, MDR1-3435T, and MCP-1364G, each of which has been implicated previously to influence HIV-1 infection, AIDS progression, therapy response, and antiviral drug metabolism, and an IL-10 receptor gene, IL-10R1, in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort. In European Americans (cases=55, controls=290), IL-10-5`A variant and its promoter haplotype (HR=2.09, CI: 1.19–3.67, P = 0.01); in African Americans (cases=54, controls=180) RANTES-In1.1C and the associated haplotype (HR=2.72, CI: 1.48–5.00, P = 0.001), showed increased HIV-NRD susceptibility. While sample sizes are small and P values do not pass a strict Bonferroni correction, our results suggest that, in European Americans, an IL-10-related pathway, and, in African Americans, chemokine receptor ligand polymorphisms in RANTES are risk factors for HIV- NRD development. Clearly, further studies are warrented.
PMCID: PMC2908809  PMID: 20531015
AIDS; HIV-1; host genetics; HIV-neuroretinal disorder
11.  The CD14 C-159T polymorphism is not associated with asthma or asthma severity in an Australian adult population 
Thorax  2005;60(3):211-214.
Background: CD14 functions as a multifunctional receptor for bacterial cell wall components including endotoxin and lipopolysaccharide and is likely to play a role in the polarisation of T lymphocytes into Th1 and Th2 subsets, thereby influencing the cytokine profile and subsequent IgE production in response to antigen/allergen contact in allergic phenotypes. A functional C-159T polymorphism has been described in the promoter region of the gene and has been associated with increased gene expression, atopy, and non-atopic asthma in different ethnic populations. A study was undertaken to examine the association between the C-159T polymorphism and asthma, asthma severity, and atopy in a large Australian white population.
Methods: PCR-RFLP analysis was used to characterise the C-159T polymorphism in mild (n = 264), moderate (n = 225) and severe (n = 79) asthmatic patients and non-asthmatic controls (n = 443), including atopic (n = 688) and non-atopic (n = 323) individuals. Association analyses were performed using χ2 tests.
Results: There was no association between the polymorphism and asthma (p = 0.468) or asthma severity (p = 0.727), and only a very weak association with atopy (p = 0.084). A meta-analysis of all studies conducted to date revealed similar genotypic frequencies in white ethnic populations and confirmed that there was no overall association with atopy (p = 0.52) or asthma (p = 0.23), although there was significant between study heterogeneity (p = 0.01).
Conclusions: This study confirms that there is no association between the CD14 C-159T polymorphism and asthma or asthma severity and a weak association between this polymorphism and atopy in an adult population.
PMCID: PMC1747323  PMID: 15741437
12.  520 Involvement of Il-10 Gene Promoter Polymorphisms in the Susceptibility for Childhood Asthma 
Asthma and atopy have a complex background which may result from the interaction of genes and environments. Interleukin (IL)-10 is known to play various roles in immune-regulating and anti-inflammatory responses. The aim of this study was to evaluate the possible effect of the IL-10 promoter polymorphisms on susceptibility to childhood asthma.
We recruited 333 patients with atopic asthma, 55 with non-atopic asthma, and 248 normal controls. We performed a genetic association study of 3 genetic polymorphisms (IL-10–1082A>G, IL-10 –819T>C, –592A>C) of the IL-10 promoter.
There was no difference between atopic asthma, non-atopic asthma and normal controls in allele, genotype or haplotype frequencies of these IL-10 polymorphisms. However, the –1082A>G polymorphism and ATA haplotype in the IL-10 promoter gene were associated with airway hyperresponsiveness (AHR) and the –819T>C, –592A>C, and ATA and ACC haplotypes were also shown to be related with serum eosinophil cationic protein (ECP).
Our results suggest that the polymorphisms within the IL-10 promoter may have a disease-modifying effect in asthmatic airway.
PMCID: PMC3512647
13.  RANTES gene polymorphisms and risk of pediatric asthma: A meta-analysis 
Numerous studies have evaluated the association between regulated upon activation, normal T cells expressed and secreted (RANTES) gene polymorphisms (−403G/A and −28C/G) and risk of pediatric asthma. However, the results have been inconsistent. A meta-analysis of the association between RANTES gene polymorphisms and pediatric asthma risk was performed in the current study. A search for published literature was conducted in the Google Scholar, PubMed and the CNKI databases (January 2000 to April 2012) and seven studies were retrieved. The associations between RANTES gene polymorphisms and pediatric asthma risk were estimated by pooled odds ratio (OR) and 95% confidence interval (CI) using a fixed- or random-effects model. Meta-analysis results revealed no significant association between the −403G/A polymorphism and risk of pediatric asthma. In the subgroup analysis by ethnicity, no association was identified between the −403G/A polymorphism and pediatric asthma risk in Caucasian and Asian populations. In the −28C/G group, the meta-analysis indicated a significant association between the −28C/G polymorphism and pediatric asthma susceptibility among the total population (recessive model: OR, 1.34; 95% CI, 1.04–1.72). However, when the subgroup analysis was performed by ethnicity, no significant associations were identified in Asians and Europeans. This result suggests that the −28C/G polymorphism may not be associated with pediatric asthma risk, while the observed increase in the risk of pediatric asthma may be due to racial differences. Additional large-scale studies are required to provide conclusive evidence on the effects of RANTES gene polymorphisms on the risk of pediatric asthma.
PMCID: PMC3493796  PMID: 23226749
RANTES; pediatric asthma; meta-analysis; polymorphism
14.  Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics 
Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARγ regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA.
Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His).
Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04).
The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma.
PMCID: PMC2831569  PMID: 20224667
peroxisome proliferator-activated receptors gamma; aspirin; asthma; gene; polymorphism
15.  RANTES Gene G-403A Polymorphism and Coronary Artery Disease: A Meta Analysis of Observational Studies 
PLoS ONE  2012;7(10):e47211.
The G-403A polymorphism in RANTES gene may be involved in the development of coronary artery disease (CAD) through increasing RANTES-mediated leukocyte trafficking and activation. However, studies investigating the relationship between G-403A polymorphism and CAD yielded contradictory and inconclusive results. In order to shed some light on these inconsistent findings, a meta analysis was performed to clarify the role of G-403A polymorphism of RANTES gene in the susceptibility of CAD.
A systemic literature search of PubMed and EMBASE was conducted from their inception to March 23, 2012, to retrieve related studies. In addition, Conference Proceedings Citation Index-Science was searched, authors of relevant studies were contacted, and reference lists of the included studies and their related citations in PubMed were reviewed for additional pertinent studies.
A total of 8 eligible studies were identified, with a total of 4252 CAD cases and 2150 controls. There was no evidence of significant association between G-403A polymorphism and CAD risk in any genetic model or pairwise comparisons (additive model: OR = 1.046, 95% CI = 0.883–1.239, I2 = 65.9%; recessive model: OR = 1.140, 95% CI = 0.774–1.678, I2 = 53.1%; dominant model: OR = 1.000, 95% CI = 0.820–1.21), I2 = 62.6%; AA vs GG: OR = 1.141, 95% CI = 0.734–1.773, I2 = 61.2%; GA vs GG: OR = 0.993, 95% CI = 0.800–1.232, I2 = 64.6%). Subgroup analysis and meta regression indicated that ethnicity and genotyping method accounted for the significant heterogeneity among studies. In the stratified analysis by ethnic group, G-403A polymorphism was found to be associated with increased CAD risk in Caucasian population whereas its protective role was observed in Asian population in some but not all comparisons.
Data from the current meta-analysis do not support the existence of a relationship between G-403A polymorphism and the development of CAD, and large sample size study employing unified genotyping method is needed to further evaluate the influence of G-403A polymorphism on susceptibility of CAD.
PMCID: PMC3468465  PMID: 23071760
16.  Analysis of inflammation- and atherosclerosis-related gene polymorphisms in branch retinal vein occlusion 
Molecular Vision  2009;15:609-618.
Branch retinal vein occlusion (BRVO) is a common vision-threatening disease. Compression of the underlying retinal vein due to increased rigidity of the crossing artery has been implicated in the pathogenesis of BRVO. Among others, arterial hypertension and hypercholesterolemia, both of which contribute to atherogenesis, have been identified as risk factors. Atherosclerosis itself is a chronic low-grade inflammatory disease with a distinct pro-inflammatory cytokine pattern. In addition to their role in atherogenesis, some cytokines have been shown to exert procoagulatory effects, and may thus contribute to the development of BRVO by a second mechanism. Gene polymorphisms affecting the expression of inflammation-related cytokines are therefore candidates as potential risk factors for BRVO. The purpose of the present study was to investigate hypothesized associations between cytokine gene polymorphisms and the presence of BRVO.
The study comprised 398 patients with BRVO and 355 control subjects. Using 5′exonuclease assays (TaqMan), genotypes of the following functional single nucleotide polymorphisms were determined: interleukin 1 beta (IL1B) −511C>T, interleukin 1 receptor antagonist (IL1RN) 1018T>C, interleukin 4 (IL4) −584C>T, interleukin 6 (IL6) −174G>C, interleukin 8 (IL8) −251A>T, interleukin 10 (IL10) −592C>A, interleukin 18 (IL18) 183A>G, tumor necrosis factor (TNF) −308G>A, monocyte chemoattractant protein 1 (CCL2) −2518A>G, and RANTES (CCL5) −403G>A.
Neither genotype distributions nor allele frequencies of any of the investigated polymorphisms differed significantly between BRVO patients and controls (p>0.05). Arterial hypertension was found to be significantly more prevalent in BRVO patients than in controls (p<0.001). In a logistic regression analysis presence of arterial hypertension was associated with an odds ratio of 3.33 (95% confidence interval: 2.42–4.57) for BRVO.
As none of the investigated gene variants was significantly more prevalent in BRVO patients than among control subjects, our data suggest that these polymorphisms themselves are unlikely major risk factors for BRVO.
PMCID: PMC2664846  PMID: 19347053
17.  Single nucleotide polymorphisms of cathepsin S and the risks of asthma attack induced by acaroid mites 
To investigate association between the three single nucleotide polymorphisms (SNPs, rs146456111, rs143154304 and rs147260142) in cathepsin S (Cat S) and the risks of allergic asthma attack induced by the acaroid mites in the Chinese population. A case-control study was performed in 412 cases and 454 volunteers/controls to evaluate the effects of three SNPs in Cat S on the risks of asthma attack. The genotypes were determined using polymerase chain reaction (PCR) and cleaved amplification polymorphism sequence-tagged sites (PCR-RFLP). The frequencies of genotypes and alleles in these SNPs in the asthmatic group were also analyzed between the two groups. The locus of rs146456111 in Cat S gene, the allele frequency of A and C in asthmatic group were significantly different from the control group (χ2 = 184.425, P = 0.000), and the difference was significant regarding the distribution of the genotypes (AA, AC, and CC) between asthmatic subjects and normal controls (χ2 = 177.915, P = 0.000). Logistic regression analysis revealed that the AC, CC, and AC + CC genotypes were significantly increased with the risk of asthma (AC vs. AA, OR = 4.013, 95% CI = 2.989-4.751, P = 0.000; CC vs. AA, OR = 3.167, 95% CI = 2.483-3.785, P = 0.000; AC + CC vs. AA, OR = 3.418, 95% CI = 2.381-4.214, P = 0.000, respectively), compared with AA genotype. Moreover, by comparison with allele A, allele C (OR = 2.187, 95% CI = 1.743-2.281, P < 0.001) tended to increase the risk of asthma; For the locus of rs143154304, compared with the allele frequency G with A in control group, there was no difference (χ2 = 1.434, P = 0.231) in that of asthmatic group, as well as the distributions of the genotypes (AA, AG, and GG) between asthmatic subjects and normal controls (χ2 = 1.997, P = 0.369); Logistic regression analysis showed that the AG, GG, and AG + GG genotypes were no risk to asthma (AG vs. AA, OR = 0.991, 95% CI = 0.625-1.507, P = 0.968; GG vs. AA, OR = 0.812, 95% CI = 0.525-1.258, P = 0.352; AG + GG vs. AA, OR = 0.914, 95% CI = 0.612-1.366, P = 0.660, respectively) as compared with AA genotype. By comparison with allele A, G allele (OR = 0.888, 95% CI: 0.732-1.078, P = 0.231) failed to increase the risk of asthma; The allele frequencies A and G of rs147260142 in asthma group and control group showed no significant difference (χ2 = 0.162, P = 0.688), yet the distribution of the genotypes (AA, AG, and GG) in control group was different from that in asthmatic subjects (χ2 = 7.520, P = 0.023); Logistic regression analysis suggested that, in compassion with AA genotype, the AG, and AG + GG genotypes appeared to increases the risk of asthma (AG vs. AA, OR = 0.630, 95% CI = 0.439-0.903, P = 0.012; AG + GG vs. AA, OR = 0.710, 95% CI = 0.507-0.996, P = 0.047); However, the GG genotype (OR = 0.843, 95% CI = 0.576-1.234, P = 0.286) and the allele G (OR = 1.040, 95% CI = 0.860-1.258, P = 0.688) were not related to the risk of asthma. The SNP of rs146456111A/C may be susceptible to the risks of asthma in the Chinese population; however, The SNPs of rs143154304A/G and rs147260142A/G may be less likely associated with the asthma attack.
PMCID: PMC4358566  PMID: 25785111
Cathepsin S; acaroid mites; allergic asthma; single nucleotide polymorphism
18.  Interleukin-4 (IL4) and Interleukin-4 receptor (IL4RA) polymorphisms in asthma: a case control study 
IL4/IL4RA pathway plays an important role in atopy and asthma. Different polymorphisms in IL4 and IL4RA genes have been described. Particularly, -33C>TIL4 and 576Q>RIL4RA SNPs have been independently associated to atopy and asthma. The purpose of this study was to analyse these polymorphisms in a population of patients with a well-characterized asthma phenotype.
A total of 212 unrelated Caucasian individuals, 133 patients with asthma and 79 healthy subjects without symptoms or history of asthma or atopy and with negative skin prick tests were recruited. Lung function was measured by spirometry and asthma was specialist physician-diagnosed according to the ATS (American Thoracic Society) criteria and classified following the GINA (Global Initiative for Asthma) guidelines. Skin prick tests were performed according to EAACI recommendations. -33C>TIL4 was studied with TaqMan assay and 576Q>RIL4RA by PCR-RFLP technique. Hardy-Weinberg equilibrium was analysed in all groups. Dichotomous variables were analysed using χ2, Fisher exact test, Monte Carlo simulation test and odds ratio test. To model the effects of multiple covariates logistic regression was used.
No statistically significant differences between the group of patients with asthma and the controls were found when the allele and genotype distribution of -33C>TIL4 and 576Q>RIL4RA polymorphisms were compared. However, the T allele of the -33C>TIL4 SNP was more frequent in patients with persistent asthma. Multivariate analysis adjusted for age and sex confirmed that carriers of allele T had an increased risk of persistent asthma (OR:2.77, 95%CI:1.18–6.49; p = 0.019). Analysis of combination of polymorphisms showed that patients carrying both the T allele of -33C>TIL4 and the A allele of 576Q>RIL4RA had an increased risk of asthma. This association was particularly observed in persistent asthma [Fisher's p value = 0.0021, Monte Carlo p value (after 104 simulations) = 0.0016, OR:3.39; 95% CI:1.50–7.66].
Our results show a trend of association between the genetic combination of the T allele of -33C>TIL4 and the A allele of 576Q>RIL4RA with asthma. This genetic variant was more frequently observed in patients with persistent asthma. As long as this study was performed in a small population, further studies in other populations are needed to confirm these results.
PMCID: PMC1310519  PMID: 16313681
19.  Association between the N-acetylation genetic polymorphism and bronchial asthma 
Aims Since polymorphic N-acetyltransferase 2 (NAT2) has been suggested as a susceptibility factor for atopic diseases, the study was undertaken to investigate whether an association exists between acetylation polymorphism and asthma patients with atopy.
Methods The frequencies of NAT2 alleles and genotypes were determined by PCR/RFLP in a total of 210 asthma patients (extrinsic (n = 108) and intrinsic (n = 102) asthmatics) and 240 control subjects. Presence of the NAT2*4 (wild-type) allele defined a NAT2 genotype as rapid and combinations of mutant alleles NAT2*5 A, *5B, *5C, *6 A, and *7B as slow.
Results Genotypes coding for slow acetylation were detected in 70.4, 58.4 and 58.3% of extrinsic asthmatics, but intrinsic asthmatics and control subjects, respectively. The frequency of slow acetylators was higher among extrinsic asthmatics than intrinsic asthmatics, this difference did not reach statistical significance (odds ratio 1.02, 95% confidence interval 0.64, 1.63, P = 0.085). However, we found a relatively moderate, but significantly higher, increased frequency of slow acetylators among extrinsic asthma patients compared with control subjects (odds ratio 1.70, 95% confidence interval 1.04, 2.76, P = 0.042).
Conclusions This study shows an association between acetylation polymorphism and susceptibility to extrinsic asthma, but not to intrinsic asthma, suggesting a minor role of the NAT2 polymorphism in the development of atopic asthma.
PMCID: PMC1874484  PMID: 12492617
asthma; molecular genetics; NAT2
20.  Association of GST Genes Polymorphisms with Asthma in Tunisian Children 
Mediators of Inflammation  2007;2007:19564.
Background. A positive association between genetic polymorphism and asthma may not be extrapolated from one ethnic group to another based on intra- and interethnic allelic and genotype frequencies differences. Objective. We assessed whether polymorphisms of GST genes (GSTM1, GSTT1, and GSTP1) are associated with asthma and atopy among Tunisian children. Methods. 112 unrelated healthy individuals and 105 asthmatic (73 atopic and 32 nonatopic) children were studied. Genotyping the polymorphisms in the GSTT1 and GSTM1 genes was performed using the multiplex PCR. The GSTP1 ILe105Val polymorphism was determined using PCR-RFLP. Results. GSTM1 null genotype was significantly associated with the increased risk of asthma (P = .002). Asthmatic children had a higher prevalence of the GSTP1Ile105 allele than the control group (43.8% and 33.5%, respectively; P = .002). Also, the presence of the GSTP1 homozygote Val/Val was less common in subjects with asthma than in control group. We have found that GSTT1 null genotype (GSTT1 *0/*0) was significantly associated with atopy (P = .008). Conclusion. Polymorphisms within genes of the GST superfamily were associated with risk of asthma and atopy in Tunisia.
PMCID: PMC1852884  PMID: 17497028
21.  Association between colony-stimulating factor 1 receptor gene polymorphisms and asthma risk 
Human Genetics  2010;128(3):293-302.
Colony-stimulating factor 1 receptor (CSF1R) is expressed in monocytes/macrophages and dendritic cells. These cells play important roles in the innate immune response, which is regarded as an important aspect of asthma development. Genetic alterations in the CSF1R gene may contribute to the development of asthma. We investigated whether CSF1R gene polymorphisms were associated with the risk of asthma. Through direct DNA sequencing of the CSF1R gene, we identified 28 single nucleotide polymorphisms (SNPs) and genotyped them in 303 normal controls and 498 asthmatic patients. Expression of CSF1R protein and mRNA were measured on CD14-positive monocytes and neutrophils in peripheral blood of asthmatic patients using flow cytometry and real-time PCR. Among the 28 polymorphisms, two intronic polymorphism (+20511C>T and +22693T>C) were associated with the risk of asthma by logistic regression analysis. The frequencies of the minor allele at CSF1R +20511C>T and +22693T>C were higher in asthmatic subjects than in normal controls (4.6 vs. 7.7%, p = 0.001 in co-dominant and dominant models; 16.4 vs. 25.8%, p = 0.0006 in a recessive model). CSF1R mRNA levels in neutrophils of the asthmatic patients having the +22693CC allele were higher than in those having the +22693TT allele (p = 0.026). Asthmatic patients with the +22693CC allele also showed significantly higher CSF1R expression on CD14-positive monocytes and neutrophils than did those with the +22693TT allele (p = 0.045 and p = 0.044). The +20511C>T SNP had no association with CSF1R mRNA or protein expression. In conclusion, the minor allele at CSF1R +22693T>C may have a susceptibility effect in the development of asthma, via increased CSF1R protein and mRNA expression in inflammatory cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-010-0850-3) contains supplementary material, which is available to authorized users.
PMCID: PMC2921506  PMID: 20574656
22.  Association between RANTES Gene Polymorphisms and Asthma: A Meta-Analysis 
PLoS ONE  2014;9(6):e90460.
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 asthma. However, there still existed studies which did not confirm these correlations.
The objective of this study was to evaluate the relationship of RANTES and asthma using a meta-analysis.
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.
Eighteen studies were enrolled, including a total of 2558 cases and 2630 controls of −403 G/A, as well as 3311 cases and 4031 controls of −28C/G in this meta-analysis. The overall ORs and 95% CIs of −403 G/A were 1.19, 1.06–1.33 (P<0.001) and 1.25, 1.03–1.51 (P = 0.933) in dominant and recessive models, respectively. The overall ORs and 95% CIs of −28G were 1.23, 1.09–1.39 (P = 0.221) and 1.76, 1.32–2.34 (P = 0.356) in dominant and recessive models, respectively. No publication bias among studies was showed.
This meta-analysis showed that RANTES −403 G/A polymorphism was a risk factor for asthma, while −28C/G polymorphism were not associated with asthma.
PMCID: PMC4070887  PMID: 24963658
23.  The Role of RANTES Promoter Polymorphism in Functional Dyspepsia 
Altered inflammatory immune responses have been shown to be associated with functional gastro intestinal disorder. We aimed to clarify the effect of functional promoter polymorphism of RANTES, which is a potent chemoattractant peptide for memory T lymphocytes and eosinophils, on the risk of functional dyspepsia in a Japanese population. RANTES promoter C-28G polymorphism was genotyped in 246 subjects including 134 FD patients according to Roma III criteria and 112 non-symptomatic healthy controls. Although frequency of RANTES promoter polymorphisms in overall dyspeptic patients and non-symptomatic healthy controls did not show any significant differences, a significant association was found between G carrier and reduced risk of PDS according to Roma III criteria (age, sex, H. pylori infection adjusted OR  = 0.23, 95% CI = 0.06–0.80). We also found that the same genotype held a lower risk of PDS in H. pylori positive PDS subjects (age, sex adjusted OR = 0.11, 95% CI = 0.01–0.94). Our data suggest that RANTES promoter -28G carriers is associate with a reduced risk of PDS especially in H. pylori positive subjects.
PMCID: PMC2735638  PMID: 19794934
dyspepsia; polymorphism; Rome III; RANTES
24.  Plasmodium yoelii 17XL infection up-regulates RANTES, CCR1, CCR3 and CCR5 expression, and induces ultrastructural changes in the cerebellum 
Malaria Journal  2005;4:63.
Malaria afflicts 300–500 million people causing over 1 million deaths globally per year. The immunopathogenesis of malaria is mediated partly by co mplex cellular and immunomodulator interactions involving co-regulators such as cytokines and adhesion molecules. However, the role of chemokines and their receptors in malaria immunopathology remains unclear. RANTES (Regulated on Activation Normal T-Cell Expressed and Secreted) is a chemokine involved in the generation of inflammatory infiltrates. Recent studies indicate that the degradation of cell-cell junctions, blood-brain barrier dysfunction, recruitment of leukocytes and Plasmodium-infected erythrocytes into and occlusion of microvessels relevant to malaria pathogenesis are associated with RANTES expression. Additionally, activated lymphocytes, platelets and endothelial cells release large quantities of RANTES, thus suggesting a unique role for RANTES in the generation and maintenance of the malaria-induced inflammatory response. The hypothesis of this study is that RANTES and its corresponding receptors (CCR1, CCR3 and CCR5) modulate malaria immunopathogenesis. A murine malaria model was utilized to evaluate the role of this chemokine and its receptors in malaria.
The alterations in immunomodulator gene expression in brains of Plasmodium yoelii 17XL-infected mice was analysed using cDNA microarray screening, followed by a temporal comparison of mRNA and protein expression of RANTES and its corresponding receptors by qRT-PCR and Western blot analysis, respectively. Plasma RANTES levels was determined by ELISA and ultrastructural studies of brain sections from infected and uninfected mice was conducted.
RANTES (p < 0.002), CCR1 (p < 0.036), CCR3 (p < 0.033), and CCR5 (p < 0.026) mRNA were significantly upregulated at peak parasitaemia and remained high thereafter in the experimental mouse model. RANTES protein in the brain of infected mice was upregulated (p < 0.034) compared with controls. RANTES plasma levels were significantly upregulated; two to three fold in infected mice compared with controls (p < 0.026). Some d istal microvascular endothelium in infected cerebellum appeared degraded, but remained intact in controls.
The upregulation of RANTES, CCR1, CCR3, and CCR5 mRNA, and RANTES protein mediate inflammation and cellular degradation in the cerebellum during P. yoelii 17XL malaria.
PMCID: PMC1343570  PMID: 16359553
25.  Association of beta2-adrenergic receptor gene polymorphisms and nocturnal asthma in Saudi patients 
Annals of Thoracic Medicine  2011;6(2):66-69.
Two polymorphisms of beta2-adrenergic receptor (β2-AR) gene, namely the substitution from arginine (Arg) to glycine (Gly) at codon 16 and from glutamine (Gln) to glutamic (Glu) at codon 27, are linked with functional changes in the β2-AR in the respiratory system even though they are not deemed to be susceptibility genes for asthma per se. The objective of this study was to investigate this association in a subset of asthmatic patients, namely those with nocturnal asthma.
The β2-AR gene polymorphisms at codon 16 and 27 were assessed in 40 patients clinically diagnosed with nocturnal asthma and 96 normal controls. Genomic DNA was obtained from whole blood and genotyping was carried out by a PCR based restriction fragment length polymorphism technique.
There was a statistically significant difference in genotype frequencies at codon 16 (Arg/Gly) between nocturnal asthmatic patients and normal control subjects (P < 0.05). However, there was no statistically significant difference in allele frequencies between the two groups. In addition, there was a significant association between Arg16-Gly genotype with nocturnal asthma compared to homozygous Gly16 (codominant model P = 0.0033, OR = 3.69: 95% CI: 1.49-9.12). However, there were no statistically significant differences in genotype and allele frequencies at codon 27 (Gln/Glu) between the normal control and nocturnal asthmatic groups (χ2 = 1.81, P = 0.41). The results also indicate that linkage disequilibrium existed between the β2-AR codon 16 and β2-AR codon 27 polymorphism (|D´| = 0.577). The data for all haplotypes did not show a statistically significant association.
We present the genotype and allele frequencies of β2-AR gene polymorphisms in normal Saudi subjects and nocturnal asthmatic patients. There was a significant difference in genotype frequencies at codon 16 (Arg/Gly). However, our study indicates a poor association of individual single nuceotide polymorphisms with nocturnal asthma.
PMCID: PMC3081558  PMID: 21572694
Asthma; β2-adrenergic receptor; frequency; polymorphism; Saudi Arabia

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