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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.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  Association of Vascular Endothelial Growth Factor Polymorphisms with Asthma in Tunisian Children 
Previous studies demonstrated that the vascular endothelial growth factor (VEGF) was being implicated in the airways inflammation and remodeling process in patients with asthma.
We explored the relationship of three polymorphisms in the VEGF gene with asthma in both case control and family studies.
We Genotyped a total of 210 children with asthma, 224 unrelated controls and 160 parents for the +936 C >T (rs3025039), −634 G > C (rs2010963) and −2549 −2567 del 18 of the VEGF promoter region. The Mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis for the +936 C > T, and −634 G > C polymorphisms.
Of the three polymorphisms studied, a borderline association with asthma was found for the G allele in the −634 G > C polymorphism (p = 0.059). No Statistically significant differences were observed for both +936 C > T, and −2549 −2567 del 18 polymorphisms between asthmatic patients and controls, considering either allelic or genotypic frequencies. The distribution of genotypes according to the severity status revealed a significant differences for the +936 C > T, and −2549 −2567 del 18 polymorphisms. In addition, association was found with the haplotypes inferred by the three polymorphisms and asthma susceptibility.
We suggest that VEGF Gene polymorphisms can be implicated in asthma.
PMCID: PMC2733104  PMID: 19787077
VEGF; polymorphisms; asthma
21.  RANTES, MCP-1, CCR2, CCR5, CXCR1 and CXCR4 Gene Polymorphisms are not Associated with the Outcome of Hepatitis B Virus Infection: Results from a Large Scale Single Ethnic Population 
Journal of Korean Medical Science  2007;22(3):529-535.
Recovery from hepatitis B virus (HBV) infection depends on the cellular immune responses. Chemokines and their receptors play significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of genes for the chemokines and their receptors. Between March 2002 and February 2004, a total of 957 single ethnic Korean patients were enrolled into two different groups; "HBV clearance group" (n=350), who have recovered from HBV infection, and "HBV persistence group" (n=607), who were repeatedly HBsAg-positive. The HBV persistence group was subdivided into "inactive carrier" and "HBV progression group (chronic hepatitis and cirrhosis)". We assessed polymorphisms in regulated and normal T-cell expressed and secreted (RANTES) at position -403, monocyte chemoattractant protein-1 (MCP-1) at position -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T and CXCR4 I138I using single primer extension assay. Genotype distributions of the "HBV clearance versus persistence group" and "inactive carrier versus HBV progression group" were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with RANTES -403, MCP-1 -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T, and CXCR4 I138I polymorphisms. In addition, no association of analyzed SNPs with HBV disease progression was found.
PMCID: PMC2693650  PMID: 17596666
Hepatitis B; Single Nucleotide Polymorphism (SNP); Chemokines; Chemokine Receptors
22.  Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children 
PLoS Genetics  2009;5(8):e1000623.
Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case–parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10×10−6 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79×10−7). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.
Author Summary
Asthma is a leading chronic childhood disease with a presumed strong genetic component, but no genes have been definitely shown to influence asthma development. Few genetic studies of asthma have included Hispanic populations. Here, we conducted a genome-wide association study of asthma in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents to identify novel genetic variation for childhood asthma. We implicated several polymorphisms in or near TLE4 on chromosome 9q21.31 (a novel candidate region for childhood asthma) and replicated one polymorphism in an independent study of childhood-onset asthmatics with atopy and their parents of Mexican ethnicity. Hispanics have differing proportions of Native American, European, and African ancestries, and we found less Native American ancestry than expected at chromosome 9q21.31. This suggests that chromosome 9q21.31 may underlie ethnic differences in childhood asthma and that future replication would be most effective in populations with Native American ancestry. Analysis of publicly available genome-wide expression data revealed that association signals in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of the overall GWAS findings and the multigenic etiology of asthma.
PMCID: PMC2722731  PMID: 19714205
23.  Association of ADAM33 gene polymorphisms with asthma in the Uygur population of China 
Biomedical Reports  2013;1(3):447-453.
Asthma is one of the most common chronic respiratory diseases, affecting ∼300 million children and adults worldwide. Previous studies identified a disintegrin and metalloprotease domain 33 (ADAM33) as an important susceptibility gene for asthma in patients of different nationalities; however, it is unknown whether this relationship exists in ethnically diverse populations. The present study focused on the association between single-nucleotide polymorphisms (SNPs) of the ADAM33 gene and asthma in the Uygur population of China. Three SNPs of ADAM33 (T1, S+1 and F+1) were genotyped in a case-control study among the Chinese Uygur population, involving 126 adult asthmatic patients and 126 healthy controls. The frequency of the ADAM33 T1 C allele among asthma patients was significantly higher compared to healthy controls (20.6 vs. 11.1%, P=0.003). The distribution of ADAM33 genotypes differed significantly between the two groups. The frequency of the T1 TC genotype was higher among patients compared to healthy controls [odds ratio (OR)=2.118, P=0.016] and the variant genotype, TC+CC, increased the risk of asthma (OR=2.244, P=0.005). Following adjustment for confounding factors, the ORs of TC and TC+CC for asthma were 2.317 and 2.522, respectively. There was a significant decrease in the forced expiratory volume (FEV1) levels in patients with the TC genotype compared to the TT genotype of T1. Haplotype analysis revealed that the frequencies of Hap5 (CAC) and Hap6 (CAT) were significantly higher among asthmatic patients compared to healthy controls (P=0.024 and 0.016, respectively). The genotype and allele frequencies of SNP S+1 and F+1 were not statistically different between asthmatic patients and controls. In conclusion, the ADAM33 T1 SNP may affect susceptibility to asthma in the Chinese Uygur population.
PMCID: PMC3917077  PMID: 24648966
a disintegrin and metalloprotease domain 33; single-nucleotide polymorphisms; asthma; Uygur population; haplotype
24.  β2-adrenergic receptor gene polymorphisms in normal and asthmatic individuals in the Eastern Province of Saudi Arabia 
Annals of Saudi Medicine  2011;31(6):586-590.
Several polymorphisms of the β2-adrenergic receptor (β2-AR) gene have been identified, including the amino acid substitution from arginine (Arg) to glycine (Gly) at codon 16 and from glutamine (Gln) to glutamic acid (Glu) at codon 27. These substitutions affect receptor function and show significantly more agonist-promoted receptor down-regulation than cells expressing the Arg 16/Gln 27 variants. Although the ethnic dependency of this polymorphism has been described in other populations, no studies investigating its relationship to asthma have been conducted in the Saudi population . Therefore, our main objective was to determine the prevalence of these two mutations among patients with asthma in the Eastern Province and in matched healthy controls.
A case-control study conducted at a university hospital among Saudi patients
Blood samples were collected from 73 asthmatic patients and from 85 controls, and the β2-AR gene polymorphisms at codon 16 and codon 27 were assessed by restriction fragment length polymorphism.
Although a significant difference was observed in genotype frequencies at codon 16 (Arg/Gly) between the asthmatic and normal control subjects (P<.05), no statistically significant difference was observed in allele frequencies between the two groups. In addition, no statistically significant differences were observed in genotype and allele frequencies at codon 27 (Gln/Glu) between the normal (control) and asthmatic groups (β2=0.75, P>.68). Using the THESIAS statistical program, no significant association of any haplotype with asthma was found.
Our findings indicate a poor association of individual single-nucleotide polymorphisms with asthma. However, further study is required to ascertain the interactions of different haplotypes and the response of patients with different haplotypes to various treatments.
PMCID: PMC3221129  PMID: 22048503
25.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC4077660  PMID: 24983943

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