CCR5 Polymorphisms Research Articles

The association between CCR5, NLRC4, and AIM2 gene polymorphisms and susceptibility to tuberculosis in the Iraqi population

Abstract. Khaleel B, Al-Alwani HRS, Asmar A. 2024. The association between CCR5, NLRC4, and AIM2 gene polymorphisms and susceptibility to tuberculosis in the Iraqi population. Biodiversitas 25: 1022-1029. In immunological reactions against Mycobacterium tuberculosis, chemokines and their receptors, including CXCR3, CCR5, and RANTES, play an important role in the migration and activation of cells. The inflammasome is a multiprotein complex that serves as a master regulator of inflammation. Genetic polymorphisms contribute to individual phenotypic differences, such as disease risk and drug response. The current study was done to find the polymorphism in the CCR5, NLRC4, and AIM2 genes in our population and to look into how this polymorphism is linked to getting tuberculosis. Seventy-five tuberculosis patients participated in this study, while the control group comprised twenty-five control healthy individuals. We took two milliliters of blood from the patients and the control group and placed them in an Ethylenediaminetetraacetic acid (EDTA tube), or DNA extraction. Real-time PCR was used to find changes in the genes for CCR5 (rs2227010, rs2734648, rs1799987, rs1799988, rs1800023, rs1800024), NLRC4 (C-rs479333), and AIM2 (CC-rs1103577). Some genotypes were more common in the patient group, including SNPs CCR5 (rs2227010, rs2734648, rs1799988, rs1800023, rs1800024), NLRC4 C-rs479333, and AIM2 CC-rs1103577. However, by using Two-Two cross table the genotype of SNP CCR5-rs1799987 was not significantly different between the patient and the controls. Patients also had a lot of certain alleles for the SNPs CCR5 (rs2227010, rs1799988, rs1800023, rs1800024) and NLRC4 (rs479333). However, the alleles for the SNPs CCR5 (rs2734648, rs1799987) and AIM2 CC (rs1103577) were not very different between patients and controls. This study concludes that a polymorphism in various SNPs of the CCR5, NLRC4, and AIM2 genes may be a risk factor for tuberculosis.

Polymorphisms of CCR5, IL-6, IFN-γ and IL-10 genes in Cuban HIV/AIDS patients

IntroductionGenetic studies have shown associations of several single nucleotide polymorphisms (SNP) with different rates of progression and variation in susceptibility to HIV infection. This study aimed to estimate the frequency of ccr5Δ32, IL-6-174G/C, IFN-γ+874T/A and IL-10-1082A/G polymorphisms in Cuban HIV-infected patients and a group of sero-discordant couples to assess their influence on risk and disease progression. MethodsA cross-sectional study was carried out on 120 subjects registered at the Institute of Tropical Medicine «Pedro Kour» (IPK) and the Ameijeiras Hospital from June 2018 until December 2019. The amplification of fragments of the ccr5, IL-6, IFN-γ and IL-10 genes was performed by polymerase chain reaction followed by identification of polymorphisms using the restriction fragment length polymorphism analysis for IL-6 with the restriction enzymes Nla III. Amplification Refractory Mutation System was used for IFN-γ and IL-10 genes. ResultsThe allelic and genotypic distributions of the genes ccr5, IL-6, IFN-γ and IL-10 did not differ significantly between the two groups. Cell counts and plasma viral load values did not differ significantly between genotypes of the ccr5, IL-6, IFN-γ and IL-10 genes. Only the IL-6 GC genotype was associated with higher viral load values. The combination of alleles of the four considered SNPs showed a highly significant increase in the risk of HIV infection for one of them, but with a very low frequency (<1%). ConclusionThis study contributes to evaluating the frequency of these polymorphisms and their influence on biomarkers of the progression of HIV infection in the Cuban HIV-population.

Influence of genetic polymorphism of the chemokine receptor CCR5 on clinical course of coronary artery disease and results of percutaneous coronary interventions

Influence of genetic polymorphism of the chemokine receptor CCR5 on clinical course of coronary artery disease and results of percutaneous coronary interventions

Abstract P178: Role Of The C-C Motif Chemokine Receptor 5 (CCR5) Polymorphism In A Mouse Model Of Kawasaki Disease-Induced Vasculitis

Introduction: Kawasaki disease (KD) is the most common form of vasculitis in young children. However, the etiology and the vulnerability of vasculitis are still enigmatic. In children, polymorphisms in CCR5 influence KD susceptibility and cardiovascular outcome, but the mechanisms are unclear. Therefore, the use of murine models is an attractive strategy to evaluate the interface between immune system and vasculitis in KD. We aimed to explore the mechanisms by which polymorphisms in CCR5 aggravates the vascular injury in KD by using the Candida albicans water soluble (CAWS) fraction model. Methods: Male (6-10-weeks-old) CCR5 deficient mice (CCR5 -/- ) and their counterpart (CCR5 +/+ ) were used. Results: After 28 days of CAWS treatment, CCL5 and CCR5 levels were increased in plasma [(pg/mL) CCR5 +/+ : 5.01 ± 0.7 n=5 vs . CCR5 +/+ CAWS: 18.71 ± 1.4* n=4, *p&lt;0.05], and heart (14-fold changes) of CCR5 +/+ , which was associated with a clear vasculitis in coronary and AA, as well as cardiac senescence (p21 expression), cell death (caspase-3 levels), and higher contractility to norepinephrine (NA) in AA [(mN) CCR5 +/+ : 3.60 ± 0.3 n=4 vs . CCR5 +/+ CAWS: 5.72 ± 0.2* n=4, *p&lt;0.05]. Remarkably, CCR5 -/- displayed a worse vasculitis level, further accumulation of cardiac p21 and caspase-3, and an exacerbated vascular response to NA (CCR5 -/- -CAWS: 6.70 ± 0.4 # n=5, # p&lt;0.05 vs . CCR5 +/+ CAWS). To understand the mechanisms, we performed a plasma proteome profile cytokine assay, which revealed that KD elevates the levels of various inflammatory mediators (IL-1β, IL-6, IL-17, and TNFα) and chemokines (CXCL2, 10, 11, 19, 12, and 13 and CCL2, 3, and 4), which were exacerbated in CCR5 -/- . Yet, CAWS induced an increase in cardiac neutrophil infiltration in CCR5 +/+ [(% in relation to 10 ^ 6 leukocytes) CCR5 +/+ : 2.5 ± 1.7 n=4 vs . CCR5 +/+ CAWS: 16.1 ± 3.2* n=4, *p&lt;0.05], which was worsened in CCR5 -/- (CCR5 -/- -CAWS: 30.2 ± 7.4 # n=4, # p&lt;0.05 vs . CCR5 +/+ CAWS). Conclusion: Deficiency in CCR5 aggravates the vasculitis levels and cardiovascular outcomes likely regulating neutrophil infiltration and cytokines production. Therefore, children with polymorphism in CCR5 might be more susceptible in developing a severe vasculitis during KD.

Significant association of MCP1 rs1024611 and CCR2 rs1799864 polymorphisms with colorectal cancer and liver metastases susceptibility and aggressiveness: A case-control study

BackgroundThe MCP-1/CCR2 axis is one of the major chemokine signaling pathways that play a crucial role in the tumor microenvironment and has been involved in triggering various tumor progression mechanisms, such as increasing the immunosuppressive cells recruitment and promoting tumor cell proliferation and invasiveness. AimThe current study investigated the association of MCP1 (rs1024611) and CCR2 (rs1799864) genes variants with the risk as well as prognosis of colorectal cancer (CRC) and colorectal liver metastases (CRLM). Subjects and methodsA retrospective cohort study involved 408 patients (284 CRC and 124 CRLM), and 284 healthy control was conducted. Genotyping of selected polymorphisms was performed by PCR-RFLP assays and confirmed by microchip and capillary electrophoresis. ResultsThe results highlighted a positive association between MCP1 rs1024611 (non-AA) and CCR2 rs1799864 (GA) genotypes with increased CRC and CRLM risk. Correlation between SNPs and clinicopathological characteristics revealed a positive association between MCP1 rs1024611 and CCR2 rs1799864 (dominant model) and CRC poor prognosis features. Kaplan-Meier survival analysis revealed a significant association between MCP1 rs1024611 non-AA carriers and decreased survival rate. Neoadjuvant treatment showed an improvement in CRC and CRLM survival rates among carriers of MCP1 and CCR2 wild-type genotype. FOLFIRI chemotherapy exhibits reduced survival rates for patients who carried mutated genotypes of MCP1 and CCR2 polymorphisms. ConclusionConsidering our results, we suggest That both MCP1 and CCR2 polymorphisms may constitute independent factors for CRC and CRLM occurrence and can be helpful targets for an efficient therapeutic approach.

Investigation of the Correlation Between the Polymorphism/Expression Level of RANTES and Its Receptor CCR5 Gene Promoter and Type 2 Diabetes Mellitus

This study aimed to explore relationship among RANTES -28 (rs2280788) C/G polymorphism or CCR5 59029 (rs1799987) A/G polymorphism, level of self-expression, and type 2 diabetes mellitus (T2DM). Clinical data were collected from 92 subjects with normal blood glucose (NC) and 97 patients with T2DM (DM). CCR5 levels on the surface of monocyte/lymphocyte and plasma RANTES levels were detected by flow cytometry. TaqMan real-time fluorescent quantitative PCR was used to detect genetic polymorphisms of RANTES rs2280788 and CCR5 rs1799987. There were no significant differences in frequencies of CCR5 rs1799987 genotype and A/G allele and frequencies of RANTES rs2280788 genotype and C/G allele, between subjects in NC and DM group (P > 0.05). Plasma RANTES level in DM group was significantly lower than NC group (P < 0.05), and difference came from patients with T2DM using insulin and subjects with normal blood glucose. CCR5 levels on the surface of monocytes and lymphocytes of patients in DM group were higher than NC group (P < 0.05). There was no significant difference in CCR5 level on the surface of monocytes and lymphocytes (or plasma RANTES level) among different genotypes of CCR5 rs1799987 (or RANTES rs2280788) (P > 0.05). RANTES level was positively correlated with age and TC and negatively correlated with diabetes course and HbA1c. CCR5 level on the surface of monocytes was positively correlated with drinking years, HbA1c, course of diabetes, and negatively correlated with TC. CCR5 on lymphocyte surface was positively correlated with diabetes course, smoking years, HbA1c, and negatively correlated with LDL, TC, HDL (P < 0.05). RANTES -28 (rs2280788) C/G polymorphism or CCR5 59029 (rs1799987) A/G polymorphism may not be associated with T2DM of Han nationality in Kunming and cannot affect RANTES and CCR5 expression. RANTES and CCR5 levels may be related to T2DM but may also be affected by age, blood lipids, HbA1c, diabetes course, drugs, and other factors.

Interleukin-10 Promoter and the CCR5 Polymorphisms in Iranian Azari Population with Multiple Sclerosis.

Changes in the expression of cytokines as the result of the single nucleotide polymorphisms (SNPs), can affect the incidence of multiple sclerosis (MS). To investigate the relationship between the frequencies of interleukin-10 (IL-10)-1082 A/G (rs1800896) and CCR5-delta32 genotypes and susceptibility to MS in the Iranian Azari population. IL-10-1082 A/G SNP and the CCR5-delta32 were genotyped in 152 patients suffering from MS and 242 healthy non-relatives by allele specific-PCR and simple PCR methods, respectively. The frequencies of AA (37.6%) and AG (55.9%) genotypes of IL-10-1082 were significantly high in the control (p = 0.021) and MS patients (p = 0.015), respectively, with no statistical difference between these groups. There was no significant difference in the CCR5 gene based on the possession of wild/wild and wild/del32 genotypes between MS patients and the control group. The del32/del32 genotype was not seen in any of the investigated groups. Tobacco (cigarettes and hookahs) consumption was higher among the MS patients (p=0.004), and this has the potential to raise the risk of MS in both the individuals and their family. However, it had no significant relation with the frequency of different genotypes of the IL-10-1082 and the CCR5. Our finding conclude on possible role of AA genotype of IL-10 -1082 as a protective factor in MS.

Frequency of CCR5-Δ32, CCR2-64I and SDF1-3'A alleles in HIV-infected and uninfected patients in Istanbul, Turkey.

Co-receptors involved in cell entry of the human immunodeficiency virus (HIV) and mutations in genes encoding their ligands may play a role in the susceptibility to infection and resistance to the progression of the infection. The best studied mutations that can exist in these genes are the CCR5-Δ32, CCR2-64I and SDF1-3'A mutations. The frequency of these mutations vary from continent to continent and even from region to region. However, there is limited information on their distribution throughout the Turkish population. Istanbul is the city with the highest number of documented HIV-infected patients in Turkey, which can be attributed to the population size. The aim of this study was to determine the distribution of three AIDS-related gene variants among HIV-infected and uninfected population in Istanbul, Turkey and to estimate the contribution of these variants to susceptibility or resistance to HIV. A total of 242 healthy individuals and 200 HIV-positive patients were included in the study. CCR5 polymorphisms were genotyped by polymerase chain reaction. CCR2 and SDF1 polymorphisms were genotyped using PCR restriction fragment length polymorphism (PCR-RFLP). The allelic frequencies for CCR5-Δ32, CCR2-64I and SDF1-3'A were 4.07%, 19.8% and 28.7%, respectively. No individual was found to carry the homozygous CCR5-Δ32 mutation in either cohort. No polymorphism was found to be significantly elevated in the HIV-infected cohort compared to the healthy group. The distribution of CCR5-Δ32, CCR2-64I, and SDF1-3'A variants does not differ between HIV-infected and uninfected patients. CCR2-64I and SDF1-3'A frequencies are relatively high where as the frequency of CCR5-Δ32 is low.

An association of the MCP-1 and CCR2 gene polymorphisms with oral lichen planus

The purpose of this study was to investigate the frequency of monocyte chemoattractant protein (MCP)-1 CCR2 gene polymorphisms in Turkish patients with oral lichen planus (OLP). A cohort of 50 patients with OLP and 142 control participants without OLP were recruited to investigate the frequency of MCP-1 and CCR2 gene polymorphisms. Chi-square and Fisher's exact tests were used. Student t test and analysis of variance were used to compare demographic data between groups. The MCP AA genotype was less common in the patient group (52%) than in the control group (66.2%; odds ratio [OR]=0.553; 95% confidence interval [CI], 0.287-1.065; P=.075). The MCP G allele was higher in the patient group (48%) than in the control group (33.8%; OR=1.808; 95% CI, 0.939-3.479; P=.075). The frequency of the MCP GG genotype was observed to be higher in the patient group (4%) than in the controls (0.7%; OR: 5.875, 95% CI:0.521-66,24; p = 0.106). The CCR2 64I64I genotype was more common in the patient group (6%) than in the control group (2.8%). All results were not statistically significant. We suggest that the G allele of MCP-1 and 64I64I genotype of CCR2 polymorphisms do not pose an increased risk for Turkish patients with OLP to develop oral squamous cell carcinoma.

The Relationship Between Chemokine and Chemokine Receptor Genes Polymorphisms and Chronic Obstructive Pulmonary Disease Susceptibility in Tatar Population from Russia: A Case Control Study.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease affecting primarily distal respiratory pathways and lung parenchyma. This study aimed to determine possible genetic association of chemokine and chemokine receptor genes polymorphisms with COPD in a Tatar population from Russia. SNPs of CCL20, CCR6, CXCL8, CXCR1, CXCR2, CCL8, CCL23, CCR2, and CX3CL1 genes and their gene-gene interactions were analyzed for association with COPD in cohort of 601 patients and 617 controls. As a result statistically significant associations with COPD in the study group under the biologically plausible assumption of additive genetic model were identified in CCL20 (rs6749704) (P = 0.00001, OR 1.55), CCR6 (rs3093024) (P = 0.0003, OR 0.74), CCL8 (rs3138035) (P = 0.0001, OR 0.67), CX3CL1 (rs170364) (P = 0.023, OR 1.21), CXCL8 (rs4073) (P = 0.007, OR 1.23), CXCR2 (rs2230054) (P = 0.0002, OR 1.32). Following SNPs CCL20 (rs6749704), CX3CL1 (rs170364), CCL8 (rs3138035), CXCL8 (rs4073), CXCR2 (rs2230054) showed statistically significant association with COPD only in smokers. The association of CCR6 (rs3093024) with COPD was confirmed both in smokers and in non-smokers. A relationship between smoking index and CCL20 (rs6749704) (P = 0.04), CCR6 (rs3093024) (P = 0.007), CCL8 (rs3138035) (P = 0.0043), and CX3CL1 (rs170364) (P = 0.04) was revealed. A significant genotype-dependent variation of Forced Vital Capacity was observed for CCL23 (rs854655) (P = 0.04). Forced Expiratory Volume in 1s / Forced Vital Capacity ratio was affected by CCL23 (rs854655) (P = 0.05) and CXCR2 (rs1126579) (P = 0.02). Using the APSampler algorithm, we obtained nine gene-gene combinations that remained significantly associated with COPD; loci CCR2 (rs1799864) and CCL8 (rs3138035) were involved in the largest number of the combinations. Our results indicate that CCL20 (rs6749704), CCR6 (rs3093024), CCR2 (rs1799864), CCL8 (rs3138035), CXCL8 (rs4073), CXCR1 (rs2234671), CXCR2 (rs2230054), and CX3CL1 (rs170364) polymorphisms are strongly associated with COPD in Tatar population from Russia, alone and in combinations. For the first time combination of the corresponding SNPs were considered and as a result 8 SNP patterns were associated with increased risk of COPD.

Association between the Genetic Polymorphisms of CCL2, CCL5, CCL8, CCR2, and CCR5 with Chronic Hepatitis C Virus Infection in the Chinese Han Population

ABSTRACT Background: Hepatitis C virus (HCV) infection is a global public health burden. Chronic HCV infection leads to the development of fibrosis, cirrhosis, liver cancer, and liver failure over time. Methods: A total of 250 patients with chronic HCV infection and 299 healthy blood donors were recruited. Sixteen candidate single nucleotide polymorphisms (SNPs) in chemokine (C-C motif) ligand 2 (CCL2), CCL5, CCL8, C-C chemokine receptor 2 (CCR2), and CCR5 were genotyped in all participants. Results: The rs1024610 AA genotype was significantly associated with decreased susceptibility to chronic HCV infection. Aspartate aminotransferase (AST) levels, AST/platelet ratio index, and the fibrosis 4 score were significantly lower in the CCL2 rs1024610 T allele and haplotype ATGC carriers. Moreover, expression levels of collagen IV (C–IV) and laminin (LN) were significantly higher in patients with the CCL5 rs2280788 C allele compared to the non-carriers. Similarly, the expression levels of C–IV, LN, and hyaluronic acid were significantly higher in patients with the CCL5 haplotype, TGCT. No significant differences were identified between the SNPs/haplotypes and plasma levels of CCL2, CCL5, CCL8, CCR2, and CCR5 in the healthy controls, and the rs1024610 allele alteration had no effect on CCL2 promoter activity. Conclusions: This is the first study to report an association between CCL2 rs1024610 and the risk of chronic HCV infection in the Chinese Han population. rs1024610 and ATGC haplotype in CCL2 were reasonable candidate markers of liver abnormalities. rs2280788 and TGCT haplotype in CCL5 are likely to play a significant role in liver fibrosis during chronic HCV infection.

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients.

BackgroundThe underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+T-cell turnover.MethodsWe evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery.FindingsThe circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response.InterpretationSDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance.FundingThis work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the 10.13039/501100004587Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII).

Effect of MCP-1 and CCR2 Genes Polymorphism on Development of Hepatocellular Carcinoma in HCV- Infected Patients in Sohag Governorate, Egypt

Background: HCC is the most common primary tumor of the liver .It is the fifth common cancer in men and the eighth common in women and is the second leading cause of cancer-related death in the world. The MCP-1 is a chemokine and a potent chemotactic factor for monocytes. MCP-1 expression in tumor cells is significantly linked to the extent of tumor-associated macrophage infiltration. Objectives: to detect the effect of MCP-1 and CCR2 Genes Polymorphism in development of HCC in HCV- related liver cirrhosis patients. Methodology: MCP-1-2518 A/G and CCR2 (V64Ile) genes polymorphism was assessed by real time PCR in 35 HCC patients and 30 HCV related LC. Serum MCP-1 was measured by ELISA. Results: For MCP-1 -2518 A G gene, HCC patients had a higher frequency of AG and GG genotypes than of AA genotype compared to other groups. For CCR2 (V64Ile), HCC patients had a higher frequency of GA and AA genotypes than GG genotype compared to other groups. Conclusion: There is a significant association between CCR2 (V64Ile) polymorphism, high serum MCP-1 level and HCC development in HCV- related liver cirrhosis patients.

A case-control association of RANTES (-28C >G) and CCR5-Delta32 polymorphisms with Parkinson’s disease in Indians

Recent studies have suggested that chemokines and their receptors are involved in several neurodegenerative disorders. Also, numerous lines of evidence have indicated that inflammatory processes are involved in the pathogenesis of Parkinson’s disease (PD). We have examined whether single nucleotide polymorphisms at the genes encoding chemokines RANTES (-28 C > G), RANTES (-403 A > G) MCP-1 (-2518 A > G), and chemokine receptors CCR2 (+190 G > A) and CCR5 (-Δ32) were associated with sporadic PD risk in the Indian population. This pilot case-control association study included 97 PD patients and 100 control subjects, who were all genotyped with PCR-RFLP for the five polymorphisms. There was no statistically significant difference in the genotype frequencies between the cases and controls for the MCP1 (-2518 A > G), RANTES (-403 A > G) and CCR2 (+190 G > A) polymorphisms. However, the results revealed a significant difference in the frequency of the heterozygous CG genotype for the RANTES (-28 C > G) polymorphism (OR = 0.49, p = 0.03) between the cases and controls. A negative association was demonstrated in the dominant model where, compared with the GG genotype, a higher frequency of the GC + CC genotype was observed in the controls. Also, a statistically significant higher frequency of the CCR5 heterozygous genotype WT/Δ32 in the controls was observed (OR = 0.31, p = 0.04). Combined genotype analysis revealed that the allele combination of G-A-G-C of CCR2 (+190G > A), MCP-1 (-2518 A/G), RANTES (-403 A/G) and RANTES (-28 C/G) respectively had a risk association with PD (OR = 6.18, p = 0.005).

New Knowledge About CCR5, HIV Infection, and Disease Progression: Is "Old" Still Valuable?

C-C chemokine receptor (CCR) 5 (CCR5) is the main HIV-1 coreceptor involved in virus entry and cell-to-cell spread during acute and chronic infections: such CCR5 and T cell tropic viruses are adapted to and replicate in CD4+ memory T cells. Polymorphisms in CCR5 regulate CCR5 expression, which, in turn, influences HIV infection acquisition and subsequent disease progression. Among these polymorphisms, a 32-bp deletion in the CCR5 open reading frame (CCR5 Δ32) and a single nucleotide polymorphism (SNP) in the promoter (-2459G/A) are the most well-characterized polymorphisms. CCR5 Δ32 provides partial to full protection against HIV infection and, therefore, serves as a basis for gene deletion studies attempting to achieve a permanent HIV cure. Recent studies have discovered that certain SNPs in the CCR region, not within CCR5, also affect CCR5 expression, HIV infection, and disease progression. Although these studies provide further valuable information regarding the role of human genetic variation in HIV/AIDS, they did not incorporate -2459G/A. In this article, the author summarizes the knowledge gained through the discovery of these new SNPs and introduces the idea that by not incorporating -2459G/A, less comprehensive conclusions may have been reached. Until a strategy that delivers a cure to the millions is found, every piece of information that may help curtail the HIV/AIDS threat to public health should be considered useful.

CCR5 Δ32 mutation and gene expression to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC phase III trials.

170 Background: Germline polymorphisms in CCR5 have been associated with treatment outcome in pts with mCRC receiving regorafenib and cetuximab-based treatment. CCR5 Δ32, a loss of function deletion, plays a key role in infectious diseases but data in CRC are scarce. We tested whether CCR Δ32 and CCR5 gene expression may be associated with outcome in mCRC pts receiving first-line treatment. Methods: The impact of CCR5 Δ32 was evaluated in 614 pts enrolled in the randomized FIRE-3 trial (FOLFIRI/cetuximab, cet, n = 313; FOLFIRI/bevacizumab, bev, n = 301). Gene expression was evaluated in 102 pts in the FOLFIRI/cet arm from FIRE-3 and 155 pts treated in the MAVERICC trial (FOLFIRI/bev, n = 76; FOLFOX6/bev, n = 79) from tumor tissue by HTG EdgeSeq Oncology Biomarker Panel and NanoString expression panel, respectively. The association between CCR5 Δ32 and clinical outcomes was evaluated using Cox regression and log-rank tests. Gene expression was dichotomized using an optimal cutoff and P-values computed using a permutation-based approach. Results: In FIRE-3, CCR5 Δ32 was significantly associated with worse PFS in patients with right-sided tumors (RT) receiving FOLFIRI/cet (n = 32; median PFS 3.41 vs 7.84 mo; HR 4.39, 95%CI 1.12-17.24; P= .022;). These associations were not observed in left-sided tumors or pts treated with bev. Lower levels of CCR5 expression trended to be associated with shorter PFS and OS in the same subgroup of RT treated in the cet arm ( P= .096 and P= .063 for PFS and OS, respectively). Lower CCR5 expression was associated with longer PFS in pts treated with FOLFIRI/bev in the MAVERICC trial, regardless of tumor side (mPFS 17.91 vs 11.04 mo; P= .03). A significant interaction between the impact of CCR5 expression levels on PFS and chemotherapy backbone was observed ( P= .019). Low CCR5 expression was associated with worse PFS in pts with RT treated with oxaliplatin (11.10 vs 13.80 mo; P= 0.023). Conclusions: Our results provide the first evidence that CCR5 Δ32 and CCR5 gene expression levels may predict outcomes in mCRC pts receiving first-line treatment with a differential effect depending on tumor location, biologic agent and chemotherapy backbone.

CCR2 Genetic Polymorphism And Its Potential Effect On HIV Acquisition In A Population Of Children Living In The Northern Region Of Cameroon.

Background and objectivesThe association of chemokine receptor-2 (CCR2) polymorphism with HIV transmission or disease progression remains highly controversial. The role of CCR2-64I allele in HIV infection may differ from one population to another because of their genetic background. The objectives of this study were to characterize the CCR2 genetic polymorphism and to determine its potential effect in HIV acquisition in children living in the Northern Region of Cameroon.Materials and methodsA cross-sectional study was carried out in five health facilities in the Northern region of Cameroon. DNA was extracted from the Buffy coat of each participant using the QIAamp®DNA mini kit. The DNA extract was then subjected to polymorphic analyses. CCR2 genotypes were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The Chi-Squared test was used for the assessment of the Hardy-Weinberg equilibrium.ResultsA total of 134 children under 15 years comprised of 38 HIV-exposed infected (28.36%) and 96 HIV-exposed un-infected (71.64%) participants were recruited. Prevalences of 44.78% wild type homozygous, 48.52% heterozygous and 6.7% mutant homozygous alleles were found in the overall population. An allelic frequency of 29.69% for the mutant allele CCR2-64I was found in HIV-exposed un-infected individuals as compared to 34.21% in HIV-infected children (p=0.47).ConclusionThe CCR2-64I allele is relatively common in the Northern Region of Cameroon, with a similar distribution among HIV-exposed un-infected and infected children. As this allele alone does not seem to confer protection against HIV-1 infection, further studies using genotype-combination of CCR2 polymorphism and other single nucleotide polymorphisms would be of great relevance in both HIV prevention and novel therapeutic strategies.

New mechanisms of CCR5-Δ32 carriers' advantage - Impact on progenitor cells and renal function.

CCR5 is a chemokine receptor expressed by various populations including leukocytes, smooth muscle cells and endothelium. Δ32 polymorphism of CCR5 gene has been connected with, inter alia, cardiovascular disease development. The aim of our study was to evaluate impact of CCR5 variant on CD34+ and CD34+VEGFR2+ cells - populations involved in cardiovascular system homeostasis and regeneration. We have examined 170 Polish subjects from Pomeranian region. The analysis concerned CCR5 polymorphism and flow cytometry evaluation of whole blood cells. Our results indicate that individuals with at least one CCR5-Δ32 allele are characterized by greater number of CD34+CXCR4+, CD34+VEGFR2+ and CD34+VEGFR2+c-Kit + cells than their wild type counterparts. This group also exhibits more beneficial values of renal function parameters. Maintaining greater size of CD34+ and CD34+VEGFR2+ populations as well as proper kidney function may constitute mechanisms that connect chemokine receptor polymorphism with cardiovascular system health.

Association of CCL2, CCR5, ELMO1, and IL8 Polymorphism with Diabetic Nephropathy in Malaysian Type 2 Diabetic Patients.

The unique variants or biomarkers of individuals help to understand the pathogenesis as well as the potential risk of individuals or patients to diabetic nephropathy (DN). The aim of this study was to investigate the association of a genetic polymorphism of monocyte chemoattractant protein-1 (CCL2-rs3917887), chemokine receptor 5 (CCR5-rs1799987), engulfment and cell mortality (ELMO1-rs74130), and interleukin-8 (IL8-rs4073) with the development of DN among Malaysian type 2 diabetes mellitus (T2DM) patients. More than one thousand diabetic patients were examined and a total of 652 T2DM patients were tested comprising 227 Malays (nonnephrotic=96 and nephrotic=131), 203 Chinese (nonnephrotic=95 and nephrotic=108), and 222 Indians (nonnephrotic=136 and nephrotic=86). DNA Sequenom mass ARRAY was employed to identify polymorphisms in CCL2, CCR5, ELMO1, and IL8 genes. DNA was extracted from the secondary blood samples taken from the T2DM patients. The alleles and genotypes were tested using four genetic models and the best mode of inheritance was chosen. CCR5 rs1799987 (G>A) showed strong association with the development of diabetic nephropathy only among the Chinese with OR=6.71 (2.55-17.68) 95% CI while IL8 rs4073 (T>A) showed association with nephropathy only among the Indians with OR=1.57 (0.66-3.71) 95% CI. The additive model was the best model for the mode of inheritance of all the genes. The contribution of genetic variants differs across ethnic groups or background. Further studies which involve environmental risk factors should be taken into consideration.

Significance of CCL2 (−2518A/G), CCR2 (190G/A) and TLR4 polymorphisms (896 A/G and 1196C/T) in tuberculosis risk in Indian population

Tuberculosis remains one of the major health burden worldwide; with substantial mortality in Indian population. Several host gene polymorphisms have been studied wherein association between variations in host genes and susceptibility or resistance to tuberculosis have been reported. In the present study, we aimed at investigating the effect of polymorphisms of CCL2, CCR2 and TLR4 genes on risk of acquiring tuberculosis in Indian population. The CCL2 (−2518A/G) and TLR4 (D299G or 896A/G & T399I or 1196C/T) gene polymorphisms were studied by PCR-RFLP method, while the CCR2 (V64I or 190G/A) gene polymorphism was done by ARMS-PCR method. Our findings revealed that the frequencies of the risk alleles ‘G’ and ‘T’ of TLR4 896 A/G and 1196C/T polymorphisms were significantly (p = 0.05) higher in TB cases than in healthy controls with higher odds (OR = 1.73 and 1.78 respectively). The risk allele ‘A’ of the CCR2 190G/A gene polymorphism showed a trend towards increased frequencies of ‘GA’ and ‘AA’ genotypes in TB patients as compared to healthy subjects with higher odds (2.06) of developing TB when in homozygous (AA) condition. Our findings indicate that the presence of variant alleles of genes CCR2 (190 G to A) and TLR4 (896A/G & 1196C/T) make Indian population vulnerable towards developing tuberculosis. Further, analysis with larger sample sizes is required to support our findings, which may allow application of these biomarkers for better management of tuberculosis in Indian population.