CCR5Δ32 Polymorphism Research Articles

CC chemokine receptor 5 polymorphism in Italian patients with Behcet's disease

To evaluate the potential role of CC chemokine receptor 5 (CCR5)Δ32 polymorphism in the susceptibility to and clinical expression of Behçet's disease (BD) in a cohort of Italian patients. One hundred and ninety-six consecutive Italian patients satisfying the ISG criteria for BD were followed up for 8 years, and 180 healthy age- and sex-matched blood donors were molecularly genotyped for the CCR5Δ32 polymorphism. A standard microlymphocytotoxicity technique was used to serotype HLA-B51. The patients were subgrouped on the basis of the presence or absence of clinical manifestations. The distribution of the CCR5Δ32 genotype differed between BD patients and controls (P = 0.02). The CCR5Δ32 allele was more common in BD patients than in controls [P = 0.02, odds ratio (OR) 2.28 (95% CI 1.1, 4.8)]. Carriers of the CCR5Δ32 allele (Δ32/Δ32 + CCR5/Δ32) were significantly more common in BD patients than in controls [P = 0.02, OR 2.37 (95% CI 1.1, 5.1)]. Population-attributable risk was 7.1%. In categorizing patients according to gender, the association between CCR5Δ32 polymorphism and BD was similar in females and males (ORs 2.76 and 2.0, respectively). No significant differences were found when the frequencies of clinical manifestations were compared between CC5RΔ32 allele carriers and non-carriers. CCR5Δ32 polymorphism is associated with an increased susceptibility to develop BD. Chemokines may have a role in the pathophysiology of BD.

Ccr2-64i and Ccr5 Δ32 Polymorphisms in Patients with Late-Onset Alzheimer's disease; A Study from Iran (Ccr2-64i And Ccr5 Δ32 Polymorphisms in Alzheimer's disease).

Alzheimer's disease (AD) is a complex disease with multifactorial etiology. Inflammation has been proven to have an important role in the pathogenesis of AD. Both CCR2 and CCR5 genes expression increase in AD patients comparing to control subjects. CCR5 gene encodes a protein which is a member of the beta chemokine receptors family of integral membrane proteins. CCR5-Δ32 is a genetic variant of CCR5 and is characterized by the presence of a 32-bp deletion in the coding region of the gene, which leads to the expression of a nonfunctional receptor, and the CCR2-64I has a change of valine to isoleucine at codon 64, in the first transmembrane domain. It has been proved that both genes have important roles in different stages of inflammation. The frequencies of CCR5∆32 and CCR2-64I variations were determined in 156 AD patients and 161 control subjects using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods, and the results were compared among AD and healthy controls. Results :Statistical analysis showed no significant difference in the distributions of CCR5∆32 and CCR2-64I between the AD patients and healthy controls (P> 0.05). Stratifying the samples by gender, genetic background and presence of ApoEε4 allele showed no significant effect on the distributions of CCR5∆32 and CCR2-64I (P> 0.05). Our study did not show an association between CCR5∆32 and CCR2-64I variations and AD in the Iranian population. Further confirmatory studies with bigger number of samples are recommended.

Association between the chemokine receptor 5 delta32 polymorphism and rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the functional chemokine receptor 5 delta32 (CCR5-Δ32) polymorphism confers susceptibility to rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Meta-analysis was conducted on associations between the CCR5-Δ32 polymorphism and RA and JIA using (1) allele contrast and (2) the recessive, (3) the dominant, and (4) the additive models. Eleven population comparisons based on the data obtained from nine studies involving 13,412 subjects (RA 3,848, controls 4,095; JIA 1,599, controls 3,870) were considered. In all study subjects, meta-analysis showed a significant negative association between RA and the CCR5-Δ32 allele (OR = 0.771, 95 % CI = 0.694-0.866, p = 6.5 × 10(-7)). Stratification by ethnicity indicated a significant association between the CCR5-Δ32 allele and RA in Europeans (OR = 0.8001, 95 % CI = 0.709-0.904, p = 3.2 × 10(-5)). Meta-analysis showed associations between the CCR5-Δ32 allele and JIA in Europeans and oligoarticular type (OR = 0.797, 95 % CI = 0.690-0.921, p = 0.002; OR = 0.475, 95 % CI = 0.352-0.693, p = 9.5 × 10(-8)). This meta-analysis demonstrates that the CCR5-Δ32 polymorphism may confer susceptibility to RA and JIA in Europeans, and suggests that the CCR5-Δ32 allele protects against the development of RA and JIA.

Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies as predictive biomarker of response to adoptive therapy in metastatic melanoma patients.

8576 Background: Adoptive therapy with tumor infiltrating lymphocytes (TILs) induces objective responses (OR) in approximately 50% of patients with metastatic melanoma. The recruitment of TILs through CXCR3/CCR5-ligand chemokines is believed critical for immune-mediated rejection. Here, we investigated the predictive role of a gene-signature based on CXCR3/CCR5-ligand chemokine transcripts in pre-treatment melanoma biopsies, its biological role and its relation with CCR5-Δ32 polymorphism, which encodes a protein not expressed on cell surface. Methods: Expression of CXCR3/CXCR3-ligand transcripts (i.e CXCL9, 10, 11) and CCR5/CCR5-ligand transcripts (i.e. CCL3, 4, 5) were assessed in 113 pre-treatment tumor biopsies from patients enrolled in adoptive therapy trials: 24 patients achieved a complete remission (CR), 34 a partial remission (PR), and 55 did not respond (NR). Copy number variation and gene expression profile of these target genes were assessed in 15 biopsy-derived cell lines. CCR5-Δ32 was assessed by sequencing germinal DNA. Results: CXCL9, 10 and 11 and CCL5 clustered together and were selected for hierarchical clustering analysis based on the mean-centered gene expression values. A signature characterized by the over-expression of these genes was associated with the likelihood to achieve a clinical response (OR rate: PR+CR: 65% vs 38%, High vs Low, respectively, P=0.015). Neither correlation between the copy number variation and the gene-expression of the corresponding genes, nor correlation between the transcripts of the investigated genes between tumor biopsies and the matched cell lines was detected. Transcript expression of the target genes did not differ between CCR5-Δ32 (n =20) and wild type patients (n=93). Conclusions: Coordinate over-expression of CXCR3/CCR5 ligands in pre-treatment tumor samples was associated with responsiveness to treatment. However, the lack of correlation between in vivo and ex vivo data suggest the inflammatory status characterized by the up-regulation of these inflammatory chemokine genes is an in vivo multifactorial phenomenon.

Effect of CCR5-Δ32 heterozygosity on HIV-1 susceptibility: a meta-analysis.

BackgroundSo far, many studies have investigated the distribution of CCR5 genotype between HIV-1 infected patients and uninfected people. However, no definite results have been put forward about whether heterozygosity for a 32-basepair deletion in CCR5 gene (CCR5-Δ32) can affect HIV-1 susceptibility.MethodsWe performed a meta-analysis of 18 studies including more than 12000 subjects for whom the CCR5-Δ32 polymorphism was genotyped. Odds ratio (OR) with 95% confidence interval (CI) were employed to assess the association of CCR5-Δ32 polymorphism with HIV-1 susceptibility.ResultsCompared with the wild-type CCR5 homozygotes, the pooled OR for CCR5-Δ32 heterozygotes was 1.02 (95%CI, 0.88–1.19) for healthy controls (HC) and 0.95 (95%CI, 0.71–1.26) for exposed uninfected (EU) controls. Similar results were found in stratified analysis by ethnicity, sample size and method of CCR5-Δ32 genotyping.ConclusionsThe meta-analysis indicated that HIV-1 susceptibility is not significantly affected by heterozygosity for CCR5-Δ32.

Distribution of functional polymorphic variants of inflammation-related genes RANTES and CCR5 in long-lived individuals

Although persistent inflammation has been related to unsuccessful aging, a pro-inflammatory status is the common phenotype in older people. To assess for a genetic component in the inflammatory status of the oldest we studied the distribution of two polymorphic chemokine pathway genes, RANTES and CCR5, in elderly. RANTES −403G/A and RANTES Int1.1T/C polymorphisms and CCR5Δ32 polymorphism were genotyped in 104 elderly and 110 controls. RANTES −403A and RANTES Int1.1C alleles have been associated with pro-inflammatory and anti-inflammatory status, respectively. CCR5Δ32 abrogates functional receptor expression of the pro-inflammatory CCR5-mediated action. Prevalence of RANTES −403G allele, associated in other studies with high RANTES production, was reduced in elderly males, compared with controls. In addition, RANTES pro-inflammatory haplotype −403A-Int1.1T was overrepresented in elderly males, while RANTES anti-inflammatory haplotype −403G-Int1.1C was overrepresented in elderly females. Our results suggest a sex-specific RANTES inflammatory genetic determinant that could contribute to the known sex-related differences in aging.

Polymorphisms in the CC-chemokine receptor-2 (CCR2) and -5 (CCR5) genes and risk of myocardial infarction among Tunisian male patients

The aim of the present study was to investigate the association between CCR2-Val64Ile and CCR5-Δ32 variants and the estimation of haplotypes with MI in a sample of the Tunisian population. A total of 290 unrelated MI patients and 282 healthy controls were studied. The CCR2-Val64Ile and CCR5-Δ32 variants were analyzed by PCR-RFLP. Subjects carrying at least one copy of the CCR5-deletion allele were significantly more common in the control group, suggesting an atheroprotective effect (adjusted OR=0.44, 95% CI=0.28-0.72, p=0.001). Haplotype analysis showed that MI patients had significantly less 64Val-Del haplotype (9.9% vs. 21.3%, OR=0.30, 95% CI=0.21-0.43, p<0.001) and 64Ile-Ins haplotype (12.3% vs. 16.7%, OR=0.58, 95% CI=0.42-0.80, p<0.001). A protective effect of the CCR5-Δ32 polymorphism against MI in the Tunisian population was found.

Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases

HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end-joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Δ32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals.

Human genetic susceptibility to intracellular pathogens

Intracellular pathogens contribute to a significant proportion of infectious disease morbidity and mortality worldwide. Increasing evidence points to a major role for host genetics in explaining inter-individual variation in susceptibility to infectious diseases. A number of monogenic disorders predisposing to infectious disease have been reported, including susceptibility to intracellular pathogens in association with mutations in genes of the interleukin-12/interleukin-23/interferon-γ axis. Common genetic variants have also been demonstrated to regulate susceptibility to intracellular infection, for example the CCR5Δ32 polymorphism that modulates human immunodeficiency virus-1 (HIV-1) disease progression. Genome-wide association study approaches are being increasingly utilized to define genetic variants underlying susceptibility to major infectious diseases. This review focuses on the current state-of-the-art in genetics and genomics as pertains to understanding the genetic contribution to human susceptibility to infectious diseases caused by intracellular pathogens such as tuberculosis, leprosy, HIV-1, hepatitis, and malaria, with a particular emphasis on insights from recent genome-wide approaches. The results from these studies implicate common genetic variants in novel molecular pathways involved in human immunity to specific pathogens.

CC chemokine receptor 5 polymorphism in chronic periaortitis

Chronic periaortitis (CP) is a rare disease characterized by a fibro-inflammatory tissue surrounding the abdominal aorta, and includes non-aneurysmal [idiopathic retroperitoneal fibrosis (IRF)] and aneurysmal forms [inflammatory abdominal aortic aneurysm (IAAA)]. We investigated whether CC chemokine receptor 5 (CCR5)Δ32 polymorphism confers susceptibility to CP. One hundred CP patients and 180 healthy controls were genotyped for CCR5Δ32 polymorphism by molecular methods. The patients were subgrouped according to the type of CP (IRF or IAAA) and the presence of established atherosclerotic disease (ischaemic heart disease, cerebrovascular disease and peripheral arterial disease). The distribution of the CCR5Δ32 genotype differed between CP patients and controls (P = 0.01). The CCR5Δ32 allele was more frequent in CP patients than in controls [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. The distribution of the CCR5Δ32 genotype did not differ significantly between IRF patients and controls, whereas the CCR5Δ32 allele was more frequent in IAAA patients than in controls [P = 0.0001, OR 10.0 (95% CI 3.7, 27.3)]. Furthermore, the CCR5Δ32 allele occurred more frequently in IAAA than in IRF patients [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)]. The CCR5Δ32 allele frequency was higher in IAAA patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)], but not in IAAA patients with atherosclerotic disease and IRF patients with or without atherosclerotic disease. The CCR5Δ32 polymorphism might be associated with an increased risk of developing the aneurysmal form of CP, IAAA, particularly in patients without established atherosclerotic disease. Chemokines may have a role in the pathophysiology of CP.

Chronic periaortitis: a large-vessel vasculitis?

Chronic periaortitis is characterized by a fibro-inflammatory process spreading from the abdominal aorta and the iliac arteries. Originally, chronic periaortitis was considered a localized inflammatory response to severe aortic atherosclerosis. However, subsequent studies have shown that chronic periaortitis may also involve other arteries and present with features of auto-immune diseases. This article reviews the issue of large-vessel involvement in chronic periaortitis and its implications in the pathogenesis and nosography of the disease. In many reports, chronic periaortitis has been shown to involve not only the aorto-iliac axis but also other vascular segments such as the thoracic aorta, the proximal epiaortic arteries, the coronary, renal, and mesenteric arteries. Thoracic aorta involvement may manifest as thoracic periaortitis with or without aneurysmal dilatation, or simply as thoracic aorta aneurysm. Thoracic periaortitis can also be a feature of the so-called IgG4-related systemic disease, with which chronic periaortitis may sometimes be associated. Histopathologic studies of chronic periaortitis show adventitial inflammation and fibrosis, vasculitis of vasa vasorum, and adventitial lymphoid follicles with germinal centers, suggesting that chronic periaortitis could be a primary aortitis. Genetic studies have demonstrated an association with HLA-DRB1*03, a marker of auto-immunity, and with the CCR5Δ32 polymorphism, which has been mapped to a Th2 response. Taken together, these findings support the notion of a primary inflammatory or immune-mediated disorder. Chronic periaortitis is an inflammatory or immune-mediated disorder characterized histopathologically by adventitial inflammation and clinically by variable involvement of different arteries, mainly of large caliber. These findings raise the issue of whether chronic periaortitis should be considered a large-vessel vasculitis.

CCR5Δ32 Polymorphism Associated with a Slower Rate Disease Progression in a Cohort of RR-MS Sicilian Patients

Multiple sclerosis (MS) disease is carried through inflammatory and degenerative stages. Based on clinical feaures, it can be subdivided into three groups: relapsing-remitting MS, secondary progressive MS, and primary progressive MS. Multiple sclerosis has a multifactorial etiology with an interplay of genetic predisposition, environmental factors, and autoimmune inflammatory mechanism in which play a key role CC-chemokines and its receptors. In this paper, we studied the frequency of CCR5 gene Δ32 allele in a cohort of Sicilian RR-MS patients comparing with general Sicilian population. Also, we evaluate the association between this commonly polymorphism and disability development and age of disease onset in the same cohort. Our results show that presence of CCR5Δ32 is significantly associated with expanded disability status scale score (EDSS) but not with age of disease onset.

CCR5Δ32 variant and cardiovascular disease in patients with rheumatoid arthritis: a cohort study

IntroductionThe aim of our study was to analyze the influence of the CCR5Δ32 polymorphism in the risk of cardiovascular (CV) events and subclinical atherosclerosis among patients with rheumatoid arthritis (RA).MethodsA total of 645 patients fulfilling the American Rheumatism Association 1987 revised classification criteria for RA were studied. Patients were genotyped for the CCR5 rs333 polymorphism using predesigned TaqMan assays. Also, HLA DRB1 genotyping was performed using molecular-based methods. Carotid intima-media thickness, flow-mediated endothelium-dependent dilatation (FMD) and endothelium-independent vasodilatation, which were used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients with no clinical CV disease.ResultsA lower frequency of carriers of the CCR5Δ32 allele among patients with CV events (3.4% versus 11.3%, P = 0.025, odds ratio 0.28, 95% confidence interval (95% CI) 0.06 to 0.89) was observed. However, after adjusting for gender, age at time of RA diagnosis, and the presence of shared epitope, rheumatoid factor and classic CV risk factors in the Cox regression analysis, this reduction of CV events in CCR5Δ32 allele carriers was slightly outside the range of significance (P = 0.097; hazard ratio 0.37 (95% CI 0.12 to 1.19)). Carriers of the CCR5Δ32 deletion also showed higher FMD values than the remaining patients (CCR5/CCR5Δ32 patients: 7.03% ± 6.61% versus CCR5/CCR5 patients: 5.51% ± 4.66%). This difference was statistically significant when analysis of covariance was performed (P = 0.024).ConclusionsOur results show a potential influence of the CCR5Δ32 deletion on the risk of CV disease among patients with RA. This may be due to a protective effect of this allelic variant against the development of vascular endothelial dysfunction.

Chemokine (CCR) and fractalkine (CX3CR) receptors and end stage renal disease

Genetic polymorphisms of chemokines and their receptors were reported to be independent risk factors for inflammation associated disease. We explored the role of CCR5-Δ32, CCR5-G59029A, CX3CR1 V249I and T280M gene polymorphisms as susceptibility for end stage renal disease (ESRD). We genotyped 258 ESRD and 569 healthy controls by sequence-specific primers and RFLP and examined their association. There was significant difference in genotype frequencies of CCR5-G59029A (p = 0.005), and CX3CR1 V249I (p < 0.0001) between ESRD and controls. No homozygous individuals were observed for CCR5-Δ32. The haplotype analysis of all four studied genes reveled that haplotype +/A/T/I was more significant in patients and associated with higher risk (OR = 2.95) of ESRD. Further, the haplotype of CX3CR1 (T280M, V249I) gene showed 3.6-fold higher in an individual carrying T/I haplotype. No risk was seen for CCR5 haplotypes. These results highlight the role of CCR5 and CX3CR1 in ESRD.

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

A small subset of human immunodeficiency virus type 1 (HIV-1)-infected, therapy-naive individuals--referred to as long-term non-progressors (LTNPs)--maintain a favourable course of infection, often being asymptomatic for many years with high CD4(+) and CD8(+) T-cell counts (>500 cells μl(-1)) and low plasma HIV-RNA levels (<10 ,000 copies ml(-1)). Research in the field has undergone considerable development in recent years and LTNPs offer a piece of the puzzle in understanding the ways that persons can naturally control HIV-1 infection. Their method of control is based on viral, genetic and immunological components. With respect to virological features, genomic sequencing has shown that some LTNPs are infected with attenuated strains of HIV-1 and harbour mutant nef, vpr, vif or rev genes that contain single nuclear polymorphisms, or less frequently, large deletions, in conserved domains. Studies have also shown that some LTNPs have unique genetic advantages, including heterozygosity for the CCR5-Δ32 polymorphism, and have been found with excitatory mutations that upregulate the production of the chemokines that competitively inhibit HIV-1 binding to CCR5 or CXCR4. Lastly, immunological factors are crucial for providing LTNPs with a natural form of control, the most important being robust HIV-specific CD4(+) and CD8(+) T-cell responses that correlate with lower viral loads. Many LTNPs carry the HLA class I B57 allele that enhances presentation of antigenic peptides on the surface of infected CD4(+) cells to cytotoxic CD8(+) T cells. For these reasons, LTNPs serve as an ideal model for HIV-1 vaccine development due to their natural control of HIV-1 infection.

PUK23 ECONOMIC EVALUATION OF DIFFERENT TREATMENT MODALITIES IN ACUTE KIDNEY INJURY

OBJECTIVES: Pharmacological interventions that are of benefit in non-dialysis populations have thus far been disappointing in dialysis patients. Since clinical trials are expensive and time-consuming, adjunct strategies are needed to support decision making in prioritization of tracks for drug development. Genetic association studies may provide such a strategy when a genotype is associated with a well-defined molecular and functional phenotype. Previously an association with better survival was found in incident dialysis patients with systemic inflammation and a deletion variant of the CC-chemokine receptor 5 (CCR5δ32). Thus, we hypothesized that pharmacological CCR5 blockade could protect against inflammation associated mortality and estimated if such a treatment would be cost-effective. METHODS: Ascreen-and-treat strategy was modelled in which patients were screened for the CCR5δ32 polymorphism and patients with the wild-type genotype and high inflammation status were treated with CCR5 antagonists. a decision-analytic Markov model was used. Costs, utilities and clinical data on the association between CCR5 polymorphisms and mortality were all gathered from a single prospectively followed dialysis cohort (NECOSAD, n = 413). Univariate and probabilistic sensitivity analyses were performed. RESULTS: Pharmacological CCR5 blockade in patients with CCR5 wild-type and high inflammation status decreased mortality (RR = 0.61) and improved the probability of renal transplantation (RR = 2.41). The cost-effectiveness of the screenand- treat strategy was €18,557 per life-year gained and €21,896 per quality-adjusted life-year (QALY) gained. The main drivers of the cost-effectiveness were the costs of pharmacological CCR5 blockade and the reduction in relative risk of mortality. Threshold analyses were performed for these two parameters. CONCLUSIONS: Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potential cost-effective genetic screen-and-treat program. This study illustrates the potential of genetic association studies in drug-development programs, as a new source of Mendelian randomized evidence from an observational setting.

TNF-α levels are not increased in inflamed patients carrying the CCR5 deletion 32

Background and aims: Recently we reported on a genetically predisposed protection from C-reactive protein (CRP) related mortality in dialysis patients carrying the functional CC-chemokine receptor 5 deletion 32 allele (CCR5Δ32) mutation. Since CCR5Δ32 is associated with a less pro-inflammatory immune response in mice, we hypothesized that the observed protection is (in part) due to a less pro-inflammatory cytokine profile. Methods: Cross-sectional observational study including 263 incident dialysis patients aged 18–70years, without clinical signs of infection and/or acute vasculitis. TNF-α, IL-6, IL-10 and hsCRP levels were determined and studied in relation to the CCR5 genotype. Results: In the presence of elevated hsCRP, IL-6 concentration was higher irrespective of the CCR5 genotype. However, in patients with the CCR5 deletion, TNF-α did not differ in the presence/absence of elevated hsCRP and was not correlated with hsCRP levels in carriers of the CCR5Δ32 polymorphism. Conclusions: A possible underlying mechanism of the impact of CCR5Δ32 genotype on inflammation driven mortality in dialysis patients could be a reduced Th1 immune response as represented by decreased TNF-α levels.

CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients

The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5 Delta 32) leads to deficiency of the receptor. We hypothesized that CCR5 Delta 32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP <or= 10 mg/L (n = 225), those carrying the deletion allele with hsCRP <or= 10 mg/L (n = 55) had similar mortality, and those carrying the wild-type genotype with hsCRP > 10 mg/L (n = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP > 10 mg/L (n = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5 Delta 32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD.

Rantes –403g&gt;a Functional Polymorphism and Upper Urinary Tract Infections in Children

Introduction Chemokines play a key-role in leukocytes recruitment in the site of inflammation, through the interaction with trans-membrane receptors. Genes that codify these chemokines and their receptors may present polymorphisms, which influence the proteins' level of expression and/or function. We have recently described an increased susceptibility to the development of acute pyelonephritis in children with interleukin 8 –251A > T polymorphism, presenting the first episode of upper urinary tract infection. Functional polymorphism of RANTES chemokine and its receptor CCR5 have been also identified. Material and Methods We carried out an association study of RANTES-403 G > A and CCR5Δ32 in 273 children with the first episode of upper urinary tract infection (UTI). Control population was represented by 326 blood umbilical cord DNAs coming from the same geographic area. Results Statistical analysis showed that RANTES-403 G > A phenotypic frequencies in the UTI group significantly differed from those of the control population (p = 0,007). A significant difference persisted when the genotype AA + GA was compared with the GG one (p = 0,002). Furthermore, comparing the frequencies observed in acute dimercaptosuccinic acid scan (DMSA)-positive and DMSA-negative patient with those observed in controls, a significant difference did emerge (p = 0,023 and p = 0,008 respectively). In addition, RANTES-403 G > A polymorphism frequency was significantly different in patients with vesico-ureteric reflux compared with the control population (p = 0,020). No difference were observed in the genotype distribution of CCR5Δ32 polymorphism. Conclusions Our results show that RANTES-403GG genotype is associated with an increased susceptibility to upper urinary tract infection.

Association of CCR5-Δ32 polymorphism with HBV infection in special population of Guizhou Province

Association of CCR5-Δ32 polymorphism with HBV infection in special population of Guizhou Province