CCR5Delta32 Polymorphism Research Articles

Evaluating the Association between CCR5delta32 Polymorphism (rs333) and the Risk of Breast Cancer in a Cohort of Iranian Population

Background:CC chemokine receptor 5 (CCR5) is introduced as an immune response modulator. The activity of CCR5 influences breast tumour development in a p53-dependent manner. This study aimed to investigate the frequency of CCR5delta32 and its association with the risk of breast cancer in 1038 blood samples in North East of Iran.Methods:In this case-control study, we genotyped 570 control samples and 468 breast cancer patients by a gel electrophoresis-based gap-polymerase chain reaction (gap-PCR) method Mashhad, Iran. The data were analyzed using the SPSS software.Results:Of 570 controls included, 542 (95.09%) had CCR5delta32 wild/wild (W/W) genotype, 28 samples (4.91%) had CCR5delta32 wild/deletion (W/D) genotype and none of them were CCR5delta32 deletion/deletion (D/D) genotype (0%). While 428 samples of patients (91.45%) had CCR5delta32 W/W genotype, 40 samples (8.55%) had CCR5delta32 W/D and CCR5delta32 D/D homozygous was nil (0%) amongst cases. All samples were in the Hardy–Weinberg equilibrium (P>0.05). According to the allele frequency, D allele, as a risky allele, in the cases was more than the control samples (0.0427 vs 0.0245, respectively) (P=0.0206). Hence, W/D genotype may confer a risk effect (OR=1.77, CI: 1.09–2.90; P=0.0206) compared with WW genotype between case and control groups.Conclusion:There is a statistically significant association between CCR5W/D and breast cancer risk. CCR5 may be regarded as a target for the prevention of breast cancer in certain conditions such as interaction with p53 variants, which remains to be further investigated.

Lack of Association Between the CCR5-delta32 Polymorphism and Neurodegenerative Disorders.

Recent studies have suggested that diminished Ccr5 functioning has an effect on synaptic plasticity and hippocampal memory in mouse models. CCR5-delta32, a 32-bp frameshift deletion in human CCR5 encoding a nonfunctional receptor, has been reported to have a protective effect against human immunodeficiency virus infection but its role as a modifier of neurodegenerative disease has been minimally explored. We investigated whether the CCR5-delta32 polymorphism could have an effect in the context of human neurodegenerative diseases. We examined the frequency of the CCR5-delta32 polymorphism in a large and well-characterized cohort including 1425 patients with neurodegenerative dementias and 2032 controls. We did not observe a significant association between the CCR5-delta32 polymorphism and any of the neurodegenerative diseases screened in this study. However, we observed an earlier age of onset among neurodegenerative disease patients carrying the CCR5-delta32 allele. Although our findings were inconclusive, the earlier age of onset observed among neurodegenerative disease patients carrying the CCR5-delta32 allele suggests that the deletion may have a detrimental effect in the context of neurodegeneration.

CCL5 protein level: influence on breast cancer staging and lymph nodes commitment.

Many tumor cells express chemokines and chemokine receptors, and these molecules can contribute to distinct modes of metastasis processes. It is known that they play a crucial role inbreast cancer (BC) tumorigenesis and progression. Considering this, it was investigated a possible role for C-Chemokine receptor type 5(CCR5) polymorphism (rs333/delta32) by conventional polymerase chain reaction (PCR) and CCL5 (C-C motif chemokine ligand 5) protein level by immunosorbent assay (ELISA) in 47 BC patients (resulting in 47 tumoral tissue samples and 47 adjacent normal tissue samples). There was a significant difference between CCL5 level in tumoral and adjacent normal tissues for the same BC patients (p < 0.0001). A significant association was also found for CCL5 level in relation to lymph nodes commitment (p = 0.03). Likewise, there was a significant difference in CCL5 level from tumor tissue of stage III in relation to stage I (p < 0.02). On the other hand, it was verified that CCR5-delta32 polymorphism presented no significant association in relation to CCL5 protein level. Considering the present findings, we suggest that CCL5 may be involved in BC staging and metastasis process.

The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta-analysis.

The CC chemokine receptor 5 (CCR5) is a chemokine receptor which is widely expressed in several immune cells involved in the inflammatory responses. Previous published studies revealed the relation of the CCR5 gene (CCR5-delta32) with the risk of HIV-1 infection, but the results are debatable and inconclusive. Here by meta-analysis, we have systematically evaluated the relation between the CCR5-delta32 polymorphism and the risk of HIV-1 infection. A comprehensive search in PubMed, EMBASE, CNKI, Cochrane Library, and WanFang database was performed up to April 15, 2018. The pooled odds ratio (ORs) along with its 95% credible interval (95%CI) was used to evaluate the relation between the CCR5-delta32 polymorphism and HIV-1 infection risk. The study included 24 case-control studies involving 4,786 HIV-1 infection patients and 6,283 controls. Compared with the wild-type homozygous genotypes, the results showed that the CCR5-delta32 heterozygotes (OR=1.16, 95%CI=1.02-1.32) had an increased susceptibility to HIV-1 and the delta32 homozygous (OR=0.25, 95%CI=0.09-0.68) had significantly reduced the susceptibility to HIV-1 for healthy controls. Moreover, we have found the delta32 allele carriers (OR=0.71, 95%CI=0.54-0.94) had significantly cut down the HIV-1 infection susceptibility when using exposed uninfected (EU) as controls. We also conducted the stratified analysis by ethnicity, and there significant association was detected in Caucasian in delta32 allele carrier genotype. To summarize, our meta-analysis suggests that the CCR5-delta32 homozygous genotype (delta32/delta32) confer possible protection against HIV-1, especially the exposed uninfected groups.

Frequency of the CCR5-delta32 allele in Brazilian populations: A systematic literature review and meta-analysis

The CCR5 is a chemokine receptor widely expressed by several immune cells that are engaged in inflammatory responses. Some populations have individuals exhibiting a 32bp deletion in the CCR5 gene (CCR5-delta32) that produces a truncated non-functional protein not expressed on the cell surface. This polymorphism, known to be associated with susceptibility to infectious and inflammatory diseases, such as osteomyelitis, pre-eclampsia, systemic lupus erythematous, juvenile idiopathic arthritis, rheumatoid arthritis and HIV/AIDS, is more commonly found in European populations with average frequency of 10%. However, it is also possible to observe a significant frequency in other world populations, such as the Brazilian one. We performed a systematic review and meta-analysis of CCR5-delta32 genetic association studies in Brazilian populations throughout the country to estimate the frequency of this polymorphism. We also compared CCR5-delta32 frequencies across Brazilian regions. The systematic literature reviewed studies involving delta32 allele in Brazilian populations published from 1995 to 2015. Among the reviewed literature, 25 studies including 30 Brazilian populations distributed between the North, Northeast, South and Southeast regions were included in our meta-analysis. We observed an overall allelic frequency of 4% (95%-CI, 0.03–0.05), that was considered moderate and, notably, higher than some European populations, such as Cyprus (2.8%), Italy (3%) and Greece (2.4%). Regarding the regional frequency comparisons between North-Northeast (N-NE) and South-Southeast (S-SE) regions, we observed an allelic frequency of 3% (95%-CI, 0.02–0.04) and 4% (95%-CI, 0.03–0.05), respectively. The populations from S-SE regions had a slightly higher CCR5-delta32 frequency than N-NE regions (OR=1.41, p=0.002). Although there are several studies about the CCR5-delta32 polymorphism and its effect on the immune response of some infectious diseases, this report is the first meta-analysis study that provides a descriptive study of the distribution of CCR5-delta32 allele in Brazilian population.

Scientific-organizational aspects for developing an inventory of the donors of umbilical cord blood with CCR5 delta32/delta32 genotype for HIV infection treatment

Projections of the using umbilical cord blood for HIV infection cure consist in the transplantation of umbilical cord blood hematopoietic stem cells from the donors of homozygous CCR5 delta32 mutation carriers.This work presents the results of screening evaluation of umbilical cord blood samples from the donors, included in the public registry of the Pokrovsky stem cells bank, for identification of the homozygous CCR5 delta32 polymorphism carriers and their following HLA typing to see the perspectives for creating a public registry of CCR5 delta32/ CCR5 delta32 donors of the umbilical cord blood for treatment of HIV-infected patients. Total 2860 umbilical cord blood samples were examined from which 29 samples with CCR5 delta32 / CCR5 delta32 genotype were selected.High frequency of the HLA alleles most prevalent in the North-West region of the Russian Federation has been found in the donors of umbilical cord blood with wild CCR5 gene and among CCR5 delta32/delta32 donors.

CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk: a meta-analysis based on 20,625 subjects

Associations between CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk are inconclusive. To derive a more precise estimation of the association, we performed a meta-analysis by searching PubMed, EMBASE, Google scholar, and WanFang databases. A total of 20 eligible articles with 39 studies were included. Of those studies, there were 21 studies for CCR5-Delta32 polymorphism, 9 studies for CCR5-59029 polymorphism, and 9 studies for CCL5-403 polymorphism. Combined analysis revealed no associations between these polymorphisms and cancer risk. However, subgroup analysis by ethnicity suggested that CCR5-59029 polymorphism was associated with the risk of cancer among Asian populations (A vs. G: odds ratio (OR)=1.36, 95 % confidence interval (CI) 1.13-1.65, P H=0.27; AA vs. GG: OR=2.07, 95 % CI 1.37-3.12, P H=0.17; GA+AA vs. GG: OR=1.35, 95 % CI 1.03-1.77, P H=0.92; AA vs. GA+GG: OR=1.98, 95 % CI 1.01-3.88, P H=0.08), but not among Caucasian populations. CCL5-403 polymorphism was associated with the risk of cancer among African populations (A vs. G: OR=0.68, 95 % CI 0.55-0.83, P H=0.14; AA vs. GG: OR=0.51, 95 % CI 0.33-0.77, P H=0.52; AG vs. GG: OR=0.58, 95 % CI 0.42-0.80, P H=0.14; AG+AA vs. GG: OR=0.56, 95 % CI 0.41-0.75, P H=0.13), but not among Caucasian populations and Asian populations. Overall, this meta-analysis indicated that CCR5-Delta32 was not associated with the risk of cancer. CCR5-59029 polymorphism contributed to cancer risk among Asian populations, and CCL5-403 polymorphism was associated with the decreased risk of cancer among African populations.

CCR5delta32 in systemic lupus erythematosus: implications for disease susceptibility and outcome in a Brazilian population

The aim of this study was to analyze the allelic and genotypic frequencies of the CCR5delta32 polymorphism in systemic lupus erythematosus (SLE) patients and to investigate a possible association of this allele with SLE susceptibility and clinical outcome. A total of 367 SLE patients and 435 healthy controls were genotyped for the CCR5delta32 polymorphism. We observed that, in European-derived individuals, the frequency of the CCR5delta32 allele was smaller in patients than in controls (2.7% vs. 7.5%, OR 0.34, 95% CI 0.17-0.65, p Bonf=0.002), suggesting that this allele could be considered a protective factor for the disease. Regarding clinical manifestations, we observed that CCR5delta32 female African-derived carrier patients presented a higher predisposition to class IV nephritis when compared with absent nephritis/other class group (13.8% vs. 3.8%, OR 37.1, 95% CI 2.8-1854.7, p Bonf=0.030). A multivariate analysis including all female patients and controlling for the presence or absence of anti-dsDNA antibodies, ethnicity and age at diagnosis showed an increased relative risk of 3.9 times for patients carrying the CCR5delta32 allele to develop class IV nephritis as compared with noncarriers. Our data suggest that the CCR5delta32 allele is a protective factor for the disease in European-derived patients and a susceptibility factor to class IV nephritis in African-derived female patients.

SAT0174 CCR5DELTA32 is associated with class IV nephritis in systemic lupus erythematosus

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that involves many organs and systems. CCR5 is an important chemokine receptor involved in inflammation. It is mainly expressed on...

The CCR5-delta32 polymorphism as a model to study host adaptation against infectious diseases and to develop new treatment strategies

Humans respond differently toward exposure against pathogens and some individuals are completely resistant against transmission due to a genetically determined susceptibility. A rising number of such, so-called, host factors have been described during the last years, but their role for diagnostic or therapeutic application is still to be clarified. Here, we describe the biology of the chemokine receptor CCR5 and its polymorphism in the context of host adaptation and immune system function. Furthermore, the first clinical applications exploiting our knowledge of this chemokine receptor as a host factor are described.

CCL3L1Copy Number Is a Strong Genetic Determinant of HIV Seropositivity in Caucasian Intravenous Drug Users

A high copy number of CCL3L1, the most potent human immunodeficiency virus (HIV)-suppressive chemokine, associates with reduced HIV susceptibility. Whether CCL3L1 influences acquisition of multiple blood-borne infections (eg, hepatitis C virus [HCV], HIV, and hepatitis B virus [HBV] infections), which occur commonly among injection drug users (IDUs), is unknown. We determined CCL3L1 copy number by real-time polymerase chain reaction among 374 Caucasian IDUs from Estonia; 285 were HCV positive, 208 were HIV positive, 177 were HCV and HIV positive, and 57 were HCV and HIV negative. In univariate and multivariate analyses, HCV and HBV seropositivity and duration of IDU each strongly predicted HIV seropositivity. A high CCL3L1 copy number (>2) was associated with an 80% reduced risk of acquiring HIV infection after adjusting for age, sex, HCV and HBV status, CCR5-Delta32 polymorphism, and IDU duration (odds ratio, 0.20; 95% confidence interval, 0.09-0.45). By contrast, CCL3L1 gene dose did not influence HCV seropositivity. Among HCV-positive IDUs, there was a 3.5-fold overrepresentation and 65% underrepresentation of a high CCL3L1 copy number among HCV-positive, HIV-negative subjects and HCV-positive, HIV-positive subjects, respectively. Among IDUs with extensive exposure to HCV and HIV, CCL3L1 copy number is a major determinant of HIV seropositivity but not of HCV seropositivity. The contrasting distribution of a protective high CCL3L1 copy number among HCV-positive, HIV-negative IDUs versus HCV-positive, HIV-positive IDUs may reflect that HIV preferentially selects for subjects with a low CCL3L1 gene dose.

201-P: Association study of HLA-DRB1 and CCR5 delta32 polymorphism and EDSS correlation with multiple sclerosis in Brazilian patients

201-P: Association study of HLA-DRB1 and CCR5 delta32 polymorphism and EDSS correlation with multiple sclerosis in Brazilian patients

Frequency of the CCR5‐Δ32 polymorphism in the Maltese population at birth

In this study, the frequency of the CCR5-Delta32 polymorphism was estimated in the human population of Malta. The frequency of the CCR5-Delta32 allele was found to be 1.1% which was similar to that of other island populations, and agree with the north to south gradient observed across Europe.

Association of chemokines receptor (CCR5 Δ32) in idiopathic recurrent miscarriages among north Indians

Human reproduction is a complex process involving multiple factors for the success of pregnancy. Chemokines are one of the immunomodulators which may determine pregnancy outcome. In the present study, we have tested genetic association between CCR5 Delta32 polymorphism and idiopathic recurrent miscarriages (IRM) among north Indians. Two hundred patients and 300 age, sex and ethnically matched controls were genotyped for CCR5 Delta32 polymorphism, genotype and allele frequencies were compared in both the groups. IRM patients had a three times higher (5.5 vs. 1.7%) frequency of heterozygote genotype (P = 0.0335, OR = 3.43; 95% CI = 1.17-10.04). Allele frequency in IRM patients was 3.7 and 0.83% among controls and the differences were statistically significant (P = 0.0349, OR = 3.37; 95% CI = 1.16-9.76). Our results demonstrated that it had a higher frequency of CCR5 Delta32 at allelic level suggesting a possible susceptibility trend (OR = 3.43) and CCR5 Delta32 may be a potential genetic risk factor for IRM.

Association of CCR5-59029 A/G and CCR2-V64I variants with renal allograft survival.

Despite advances in the medical care of renal transplant recipients which have led to an improvement in allograft survival, renal allograft rejection is still a major obstacle to successful organ transplantation. Understanding the mechanisms contributing to allograft rejection will be of great importance for the development of efficient antirejection strategies. The aim of current investigation was to study the impact of polymorphisms of CCR5Delta32, CCR5- 59029 A/G and CCR2-V64I on renal allograft survival. Using PCR and PCR-RFLP methods in 84 renal transplant recipients, the influence of CCR5Delta32, CCR5- 59029 A/G and CCR2-V64I polymorphisms on renal allograft survival in two rejector and non-rejector groups were examined. Rejector group was defined as having rejection before 1 year and non-rejector group had stable graft function at least for 5 years. Significant reductions were found in the risk of renal transplant rejection in recipients possessing the CCR2-64I (A) allele (p=0.03) or 59029-A allele (p=0.03) compared to non-rejector group. There were no significant differences in the frequency of CCR5Delta32 polymorphism in rejector group compared to non-rejector group (p>0.05). It was possible to conclude that the chemokine receptors CCR2-V64I (A) and CCR5- 59029 A alleles may influence renal allograft survival.

CCR5 Δ32 Polymorphism: Associated with Gallbladder Cancer Susceptibility

Inflammation of gallbladder is an established risk factor for gallbladder cancer (GBC) pathogenesis. Chemokine receptors play crucial role in antitumour immunity and are involved in inflammation and pathogenesis of cancers. Present study was aimed to examine the role of CCR5 Delta32 polymorphism in conferring genetic susceptibility to GBC. Present case-control study included 144 proven GBC patients and 210 healthy controls. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistically significant difference was observed in distribution of CCR5+/Delta32 genotype (P = 0.028) [odds ratio (OR) = 2.850; 95% confidence interval (CI) = 1.1-7.2] and CCR5 Delta32 allele (P = 0.012) (OR = 3.145, 95% CI = 1.2-7.7) in GBC patients which was conferring high risk. Stratification of GBC patients showed significant association of CCR5+/Delta32 genotype and CCR5 Delta32 allele with GBC patients with and without gallstones. Analysis based on age of onset and gender suggested significant association of CCR5 Delta32 allele with early onset (<50 years) of the disease but only marginal influence of gender in CCR5 Delta32-mediated risk of cancer. Risk was further modulated by tobacco usage and significantly increased risk was observed in tobacco users with CCR5+/Delta32 genotype. In conclusion, CCR5+/Delta32 genotype and CCR5 Delta32 allele confer significant risk for GBC particularly in patients with early onset and tobacco usage. Role of CCR5+/Delta32 polymorphism in GBC susceptibility is independent of gallstone formation.

Analysis of the CC chemokine receptor 5Δ32 polymorphism in pediatric liver transplant recipients

In adult liver graft recipients, it has been shown that certain chemokine polymorphisms (CCR5Delta32) may correspond to ischemic type biliary lesions leading to chronic graft dysfunction. The aim of our present study was to assess the importance of CCR5Delta32 polymorphism in a cohort of pediatric liver graft recipients with regard to acute or chronic graft dysfunction. A total of 137 children post-liver transplantation have been included for genetic analysis (CCR5Delta32 polymorphism), and the incidence of acute and chronic graft dysfunction was analyzed. The most common diagnosis leading to LTx was biliary atresia (56.2%), the median age was 14 months, and 33.5% of the patients received a living-related graft. In all, 110 of the subjects were found to have the CCR5 wild type, 25 children were heterozygous for CCR5Delta32, and two patients were homozygous. Of 137, 44 (32.1%) developed acute graft rejection, nine out of 137 (6.6%) chronic graft dysfunction (vanishing bile duct syndrome), and 84 (61.3%) children had neither acute nor chronic graft rejection. There was no significant correlation between acute graft rejection or chronic graft dysfunction and the CCR5Delta32 allele in the study population. We conclude that CCR5Delta32 polymorphism may not play a role in acute or chronic liver graft dysfunction in children.

Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy.

Chemokines influence both tumor progression and anti-tumor immune response. A 32-bp-deletion polymorphism in the chemokine receptor 5 gene (CCR5Delta32) has been shown to result in a non-functional protein. This study was aimed at evaluating the potential impact of this gene polymorphism on disease progression and treatment outcome in patients with melanoma. CCR5 genotyping was performed by PCR on DNA extracted from serum samples of 782 cutaneous melanoma patients with known disease history and long-term clinical follow-up. Genotypes were correlated with patient survival and types of treatment. Of 782 melanoma patients, 90 (11.5%) were heterozygous and 12 (1.5%) were homozygous for CCR5Delta32. Analyzing the complete cohort, the disease-specific survival from date of primary diagnosis was not influenced by CCR5 status. Similarly, no significant impact could be detected on the treatment outcome of stage III patients. In 139 stage IV patients receiving immunotherapy, CCR5Delta32 was associated with a decreased survival compared to patients not carrying the deletion (median 12.5 vs. 20.3 months, P = 0.029). Multivariate analysis revealed the CCR5 genotype as an independent factor impacting disease-specific survival in this patient population (P = 0.002), followed by gender (P = 0.019) and pathological classification of the primary (pT; P = 0.022). The presence of the CCR5Delta32 polymorphism in patients with stage IV melanoma results in a decreased survival following immunotherapy and may help to select patients less likely to benefit from this type of treatment.

The presence of functional CCR5 and EBV reactivation after allogeneic haematopoietic stem cell transplantation

EBV reactivation is a serious complication affecting the recipients of allogeneic haematopoietic stem cell transplants (allogeneic HSCT). Recent reports have suggested that EBV reactivation induces increased expression of C-C chemokine receptor-5 (CCR5) or its ligands. Therefore, the 32-nucleotide deletion within the CCR5-encoding gene (CCR5Delta32 polymorphism) was analysed in 92 recipients of allogeneic HSCT and their donors and related with EBV load. In addition in 30 patients, at the same time points employing a real-time PCR technique, the number of viral copies and CCR5 transcripts were assessed. The incidence of EBV reactivation 2-3 months after transplantation was significantly lower in patients carrying the CCR5Delta32 allele (P=0.008). The association was confirmed in multivariate analysis, in which recipient CCR5Delta32 (OR=0.166, P=0.026) in addition to recipient age (OR=1.536, P=0.034) were identified as independent risk factors for EBV reactivation. Moreover, EBV reactivation was more frequently seen when patients and their donors were lacking the CCR5 deletion mutation as compared to other donor-recipient pairs (P=0.022). The CCR5 expression was significantly higher in the group of patients having EBV reactivation than in those lacking it (R=25.354, P=0.024). These results suggest that the expression of functional CCR5 plays a role in initiation/perpetuation of EBV reactivation.

Variations in genetic influences on the development of asthma throughout childhood, adolescence and early adult life

Asthma is likely to be due to many aetiological factors, the effect of each varying considerably with age. Now that there are well established candidate genes for asthma, using genetics to examine age-related susceptibility to asthma offers a new approach to understanding the basic underlying mechanisms. Since few long-term, longitudinal asthma studies exist, opportunities to examine age-related genetic susceptibility have been limited, but have produced some specific findings. The CCR5Delta32 polymorphism renders the chemokine receptor nonfunctional and is associated with reduced asthma susceptibility in children but not adults. In CD14 C-159T, the -159C allele has been associated with increased atopy in mid-childhood, but not in young adults. IL-12beta is a promoter polymorphism associated with reduced lung function in girls but not boys in mid-childhood only. Regarding the beta(2)adrenoceptor, results from three studies suggest that Arg16 can be associated with impaired airway function in infancy and Gly16 with asthma and wheeze in mid-childhood. Age-related genetic susceptibility studies are likely to make a major contribution to understanding basic mechanisms in asthma, but the limited number of suitable cohorts has meant that to date few studies have been reported.