Polymorphisms of chemokine and chemokine receptor genes in Type 1 diabetes mellitus and its complications

Cytokines and chemokines have been implicated in the pathogenesis of Type 1 diabetes mellitus (T1DM) and its microvascular complications. Recently, genetic variants of monocyte chemotactic protein-1 (MCP-1), CC-chemokine receptor 2 (CCR2), CC-chemokine receptor 5 (CCR5) genes have been identified. The aim was to investigate whether genetic variants of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 Delta32 are associated with T1DM and its microvascular complications. Two hundred and sixty patients with T1DM with and without diabetic microvascular complications, and 104 normal controls were recruited for this study. Genotypes of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 delta32 were performed by polymerase chain reaction followed by digestion with appropriate restriction endonucleases. Frequencies of the MCP-1 A(-2518) allele (74.6% vs. 63.5%, p < 0.003) and A/A genotype (54.5% vs. 34.6%, p < 0.001, Pc = 0.002) were significantly higher in patients with T1DM compared with normal controls. CCR5 G(59029) was slightly increased in the patients with microvascular complications compared with the uncomplicated (21.4% vs. 10%, p < 0.03, Pc = ns). The frequency of haplotype G/G/W was slightly increased in the patients with diabetic complications compared to the uncomplicated (39.6% vs. 28.8%, p < 0.02, Pc = ns). These results suggest that polymorphisms of the MCP-1, CCR2 and CCR5 genes may be associated with T1DM and its complications.     

Impact of MCP-1 and CCR-2 gene polymorphisms on coronary artery disease susceptibility

Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p < 0.05). In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.     

Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer

The aim of our study was to determine the effect of monocyte chemotactic protein-1 (MCP-1), CC chemokine receptor 2 (CCR2), and CC chemokine receptor 5 (CCR5) gene polymorphisms on the susceptibility and clinicopathological characteristics of prostate cancer. Genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method in 156 histopathologically confirmed prostate cancer patients and 152 healthy subjects. Individuals with AA genotype or at least one A allele of CCR2 V64I gene polymorphism had a higher risk for prostate cancer as compared with those with GG genotype (p=0.010 and p=0.028, respectively). CCR5 Δ32/wt genotype and CCR5 Δ32 allele were also found to be involved in the susceptibility to prostate cancer (p=0.028 and p=0.030, respectively). However, there was no significant association between MCP-1-2518 A/G gene polymorphism and prostate cancer risk. Prostate cancer patients carrying AA genotype or at least one A allele of CCR2 V64I had significantly increased risk for high stage disease (p=0.002 and p=0.039, respectively) and metastasis (p=0.004 and p=0.022, respectively). The CCR2 A allele (64I allele) was significantly associated with high T stage (p=0.001) and metastasis (p=0.005) as compared with CCR2 G allele (64V allele). Our data indicate that gene polymorphism of CCR2 V64I may influence the susceptibility and clinicopathological characteristics of prostate cancer and CCR5 Δ32 allele may also be an important risk factor for prostate cancer in Turkish men population.     

Monocyte chemoattractant protein-1 in schizophrenia: -2518A/G genetic variant and protein levels in Armenian population

Monocyte chemoattractant protein-1 (MCP-1) has been proposed as a contributory factor in pathophysiology of schizophrenia. The aim of the current study was to explore the possible association of the MCP-1-2518A/G genetic polymorphism and plasma levels of MCP-1 in patients with paranoid schizophrenia. The MCP-1-2518A/G (rs1024611) polymorphism and blood levels of MCP-1 in patients with paranoid schizophrenia and healthy subjects were evaluated and compared. One hundred and three chronic patients with paranoid schizophrenia treated with neuroleptics and 105 healthy subjects were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and their MCP-1 plasma levels were measured by a solid-phase enzyme-linked immunosorbent assay (ELISA). When comparisons were made between patients and controls, the frequency of the MCP-1-2518*G minor allele (35% vs 23%, p=0.009, OR=1.77, 95% CI: 1.1-2.04) and also of the MCP-1-2518*G carriers (60% vs 40%, p=0.003, OR=2.27, 95% CI: 1.13-2.01) were higher in patients. The mean value of the MCP-1 plasma level in patients with schizophrenia was significantly higher than in controls. Interestingly, the patients with the GG genotype had the highest MCP-1 level (711.4 ± 211.4 pg/ml), followed by those with the AG genotype (472.1 ± 135.8 pg/ml) and AA (372.4 ± 180.2 pg/ml) homozygotes. In conclusion, we report here the association of the -2518A/G genetic polymorphism and increased plasma levels of MCP-1 with schizophrenia and nominate -2518*G minor allele as a risk factor for schizophrenia in Armenian population.     

Association of inflammatory chemokine gene CCL2I/D with bladder cancer risk in North Indian population

Chemokine genes have been proposed as good candidate genes for conferring susceptibility to Bladder cancer (BC). We examined the combined effect of multiple alleles of pro inflammatory chemokine genes for determining the risk of BC. We tested association of three gene polymorphisms of CCL2I/D (rs3917887), CCL2A2518G (rs1024611) and CCR2V64I (rs1799864) with BC risk in North Indian population. Genotypes were assessed in hospital-based case-control study comprising of 200?BC patients and 200 healthy controls. Genomic DNA was isolated from blood and genotyping done using PCR-RFLP method. In CCL2I/D polymorphism, the heterozygous genotype (I/D) showed high risk of BC p?相似文献   

Meta-analysis of MCP-1 promoter ?2518 A/G polymorphism and SLE susceptibility

The aim of this meta-analysis was to summarize results on the association of monocyte chemoattractant protein-1(MCP-1) promoter -2518 A/G polymorphism with systemic lupus erythematosus (SLE) susceptibility. We searches all the publications about the association between MCP-1 promoter -2518 A/G polymorphism and SLE from Pubmed, Elsevier Science Direct, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure. The meta-analysis was performed for genotypes AA verse GG, AA+AG verse GG, AA verse AG+GG, and A allele verse G allele in a fixed/random effect model. A total of 14 studies (2,333 cases and 2,391 controls) were included in the meta-analysis. When all groups were pooled, we had not observed significant association between A allele and G allele (OR = 0.94, 95 %CI = 0.79-1.12, P = 0.50). When analysis were restricted to more ethnically homogeneous populations, the similar results were found in European population and Asian population (OR = 1.05, 95 %CI = 0.75-1.46, P = 0.80; OR = 1.00, 95 %CI = 0.86-1.17, P = 0.99). However, we had not detected a significant association between MCP-1 promoter -2518 A/G polymorphism and SLE when examining the genotypes AA verse GG, AA+AG verse GG, AA verse AG+GG. The meta-analysis did not demonstrate the association between MCP-1 promoter -2518 A/G polymorphism and SLE.     

Monocyte chemoattractant protein-1-2518 G/A polymorphism,plasma levels,and premature stable coronary artery disease

Background We examined the -2518G/A polymorphism of the MCP-1 gene, its plasma levels, and premature stable CAD in a Chinese population. Methods The study comprised 132 patients with premature stable CAD (cases) and 153 controls. Genotypes were determined by ligase detection reaction-polymerase chain reaction sequencing and grouping. Plasma MCP-1 level was detected with enzyme-linked immunosorbent assay. Results No differences were found between genotype distribution and allele frequencies of MCP-1 gene -2518 G/A polymorphism (AA:18.1%; AG:51.5%; GG:30.3% in cases; AA:16.3%; AG:52.9%; GG:30.7% in controls; P = 0.918). The G allele prevalence was 0.561 in cases and 0.572 in controls (P = 0.786). No significant difference was found in plasma MCP-1 level between cases and controls [(47.50 ± 26.65) vs. (41.05 ± 15.71) pg/ml, P = 0.272)] or among the 3 genotypes [AA, (43.49 ± 10.50) pg/ml; AG, (46.09 ± 25.08) pg/ml; GG, (40.03 ± 18.13) pg/ml; P = 0.381]. Logistic regression analysis confirmed the lack of association between MCP-1-2518 G/A single nucleotide polymorphism and premature stable CAD after adjustment for confounding parameters. Conclusions The MCP-1-2518 G/A single nucleotide polymorphism does not affect plasma levels of MCP-1 or susceptibility to premature stable CAD in a Chinese population.     

The effect of chemokine receptor gene polymorphisms (CCR2V64I,CCR5-59029G>A and CCR5Δ32) on renal allograft survival in Pakistani transplant patients

Background

Gene polymorphisms of the chemokine receptors CCR2 and CCR5 (CCR2V64I, CCR5-59029G>A and CCR5Δ32) have been shown to be associated with renal allograft rejection. The aim of this study was to investigate the association of these polymorphisms with allograft rejection among Pakistani transplant patients.

Method

A total of 606 renal transplant patients and an equal number of their donors were included in this study. DNA samples were used to amplify polymorphic regions of CCR2V64I, CCR5-59029G>A and CCR5Δ32 by polymerase chain reaction using sequence specific primers. The amplified products of CCRV64I and CCR5-59029G>A were digested with restriction enzymes (BsaB1 and Bsp12861) respectively. The CCR5Δ32 genotypes were determined by sizing the PCR amplicons. The association of these polymorphisms with the biopsy proven rejection and other clinical parameters was evaluated using the statistical software SPSS v.17.

Results

In this study, the G/G genotype of CCR2V64I was associated with a high frequency of allograft rejection (p = 0.009; OR = 2.14; 95% CI = 1.2–3.7). Rejection episode(s) in the GA + AA genotypes were found to be significantly lower as compared to the GG genotype (p = 0.009; OR = 0.4; 95% CI = 0.2–0.8). The Kaplan–Meier curve also indicated a reduced overall allograft survival for patients with the G/G genotype of CCR2V64I (59.2 ± 1.4 weeks, log p = 0.008). There was a significant association with rejection by female donors possessing the CCR2 GG genotype (p = 0.02; OR = 2.6; CI = 1.1–6.3) and male donors with the CCR5-59029 GG genotype (p = 0.004; OR = 1.7; CI = 1.03–3.01).

Conclusion

This study shows an association of the CCR2V64I (G/G) genotype with renal allograft rejection. However, no such association was found for the CCR5 gene polymorphisms. Therapeutic interventions such as blocking the CCR2 receptor (especially G polymorphism) may yield better survival of renal allograft in this patient group. Further, chemokine receptors may be added to the spectrum of the immunogenetic factors that are known to be associated with renal allograft rejection.     

Association of cytokines genes (ILL, IL1RN, TNF, LTA, IL6, IL8, IL0) polymorphic markers with chronic obstructive pulmonary disease

The purpose of this study was to investigate the possible roles of the cytokines genes in the development of chronic obstructive pulmonary disease (COPD). Polymorphisms in the genes encoding IL1B, IL1RN, TNFA, LTA, IL6, IL8 H IL10 were investigated in COPD patients (N = 319) and healthy individuals (N = 403) living in Ufa, the Republic of Bashkortostan. We observed that IL1RN*2/IL1RN*2 genotype of ILRN gene was associated with susceptibility for COPD (9.8% vs. 4.67%; chi(2)= 5.45, df= 1, P = 0.02; OR = 2.21). Analysis of the LTA gene polymorphic locus A252G showed that in patients with COPD, the frequency of the GG genotype was significantly higher than that in the control group (7.84% vs. 3.72%; chi(2) = 5.00, df= 1, P = 0.025). The increase of this genotype was significant in case of stage IV of COPD (11.18% vs. 4.79%; chi(2) = 3.075, df= 1, P = 0.07). Frequency of genotype combination TNFA-308 G/G and LTA252 A/A significantly decreased in COPD group (38.55% vs. 46.93% in control group; chi(2) = 8.82, df= 1, P = 0.0039). The frequency of GG genotype of the IL6 gene was higher in the patients with stage IV of COPD (43.75% vs. 31.54%, chi(2) = 4.14, P = 0.041). Our results indicate that the genotype frequency of the T(-511)C, T3953C of IL1B, G(-308)A of TNFA, G(-1 74)C of IL6, A(-251)C of IL8 and C(-627)A of ILl0 genes polymorphisms was similar in COPD and healthy control groups.     

Association between MCP-1 -2518A/G Polymorphism and Cancer Risk: Evidence from 19 Case-Control Studies

Background

Single nucleotide polymorphisms (SNPs) may affect the development of diseases. The -2518A/G polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimation of the relationship between the -2518A/G polymorphism and cancer risk.

Methodology/Principal Findings

We performed a meta-analysis, including 4,162 cases and 5,173 controls, to evaluate the strength of the association between the −2518A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Overall, the results indicated that the −2518A/G polymorphism was not statistically associated with cancer risk. However, sub-group analysis revealed that individuals with GG genotypes showed an increased risk of cancer in digestive system compared with carriers of the A allele (GG vs. AA: OR = 1.43, 95%CI = 1.05–1.96, P_{heterogeneity} = 0.08; GG vs. AG/AA: OR = 1.29, 95%CI = 1.02–1.64, P_{heterogeneity} = 0.14). In addition, the increased risk of GG genotype was also observed in Caucasians (GG vs. AG/AA: OR = 1.81, 95%CI = 1.10–2.96, P_{heterogeneity} = 0.02).

Conclusion

This meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. Large-scale and well-designed case-control studies are needed to validate the findings.     

Functional monocyte chemoattractant protein-1 promoter −2518 polymorphism and systemic lupus erythematosus: a meta-analysis

The monocyte chemoattractant protein-1 (MCP-1) promoter −2518 A/G polymorphism has been reported inconsistently to be associated with systemic lupus erythematosus (SLE) and lupus nephritis (LN). The aim of this study was to explore whether the MCP-1 polymorphism confers susceptibility to SLE or LN. We surveyed studies on the MCP-1 polymorphism and SLE or LN identified by MEDLINE or manual searches. Meta-analysis was conducted on the AA genotype (recessive effect), AA, and AG genotypes (dominant effect), AA versus GG (genotype contrast), and on the A allele of MCP-1 in SLE and LN in each ethnic population studied and on all subjects. Ten studies, which included 1,739 SLE patients and 1,680 controls, were included in our meta-analysis. These consisted of two European, six Asian, one Latin American, and one mixed study. We did not find any association between the MCP-1 −2518 A/G polymorphism and SLE in all subjects or in ethnic groups. Meta-analysis also failed to reveal an association between the MCP-1 −2518 A/G polymorphisms and LN. This meta-analysis on 3419 subjects indicates that no association exists between the MCP-1 −2518 A/G polymorphism and SLE or LN.     

MCP-1 −2518 A/G functional polymorphism is associated with increased susceptibility to active pulmonary tuberculosis in Tunisian patients

Monocyte chemoattractant protein-1 (MCP-1) plays crucial role in protective immunity against Mycobacterium tuberculosis (MT). In this study, we examined whether single nucleotide polymorphism (SNP) −2518 A/G (rs 1024611) of MCP-1 affect the susceptibility to active tuberculosis (TB) in Tunisian populations. Genomic DNA from patients with active TB (168 cases of pulmonary TB and 55 cases of extrapulmonary TB) and ethnically controls (150 cases) was genotyped for the MCP-1 −2518 A/G SNP by polymerase chain reaction fragment length polymorphism (PCR-RFLP). We observed that −2518 G allele and GG genotype (high MCP-1 producer) frequencies were significantly more elevated in active pulmonary TB group in comparison to control group [34 vs. 22%; P = 0.0007; 15 vs. 5%, P corrected for the number of genotypes (Pc) = 0.015; respectively]. Additionally, they were associated with increased risk development of this clinical form of TB [odds ratio (OR) = 1.83, 95% confidence intervals (CI) = 1.26–2.66; OR = 3.1, 95% CI = 1.28–7.76; respectively]. However, wild type allele −2518 A and AA genotype were over-represented in control group (78 and 62%) and seem to be protective factors against TB. Moreover, −2518 AA genotype was more frequent in control group and was associated with resistance against development of active pulmonary TB (OR = 0.56, 95% CI = 0.35–0.89, Pc = 0.03). Our findings confirm the key role of −2518 A/G SNP of MCP-1 and support its association with resistance/susceptibility to the development of active pulmonary TB in the Tunisian population.     

Association of interleukin (IL)-12 and IL-27 gene polymorphisms with chronic obstructive pulmonary disease in a Chinese population

The pathogenesis of chronic obstructive pulmonary disease (COPD) is not fully understood, and environment and genetic factors have been investigated. Moreover, cytokine genes play an important role in COPD pathogenesis. However, the molecular mechanism of COPD induced by the factors is still unknown. The present study was undertaken to clarify a role of interleukin (IL)-12 16974A/C and IL-27 4730T/C, -964A/G, and 2905T/G polymorphisms in Chinese subjects with COPD. Polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) and sequence analyses were used to type IL-12 and IL-27 polymorphisms in 120 patients with COPD and 100 healthy controls. There were significant differences in the genotype and allele distribution of -964A/G and 2905T/G polymorphisms of the IL-27 gene among cases and controls in a Chinese population. When compared with the control group, subjects with AG genotype of the IL-27 -964A/G had a 2.22-fold decreased risk of COPD (odds ratio [OR] = 0.450, 95% confidence interval [CI]: 0.245-0.826; p = 0.009), and subjects with TG genotype of the IL-27 2905T/G had a 2.85-fold decreased risk of COPD (OR = 0.351, 95% CI: 0.137-0.899; p = 0.024). Compared with the TAT haplotype, the TGG haplotype was associated with a significantly decreased risk of COPD (OR = 0.29, 95% CI: 0.108-0.784; p = 0.010). Even after Bonferroni corrections, significant associations with COPD were observed for the AG genotype of the IL-27 -964A/G and the TGG haplotype of the IL-27 gene. Our data suggest that polymorphisms in the IL-27 gene may play a role in the development of COPD in Chinese population.     

The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer

The gene variants of the chemokine and chemokine receptor genes associated with inflammation may be involved in cancer initiation and progression. The aim of this study was to explore the possible association of monocyte chemoattractant protein-1 (MCP-1) A2518G, stromal cell derived factor 1 (SDF-1) 3′A and chemokine receptors CCR2A V64I, CCR5 Δ32, CCR5 59029 and CXCR4 gene polymorphisms with the risk and clinicopathological characteristics of bladder cancer (BC) in a Turkish population.     

Prevalence of alleles associated with HIV resistance in Russia

Genetic polymorphisms of CCR5, CCR2, and SDF1 genes have been associated with resistance during human immunodeficiency virus type 1 (HIV-1) infection and disease progression. In the present report, we studied the frequency and co-occurrence of CCR5Delta32, CCR5-59029A/G, CCR2-64I, and SDF1-3'A allelic variants among HIV-1-seronegative individuals (n = 171) in Moscow. Observed allelic frequencies were 0.0906 [95% confidence interval (CI), 0.06-0.1212] for CCR5Delta32, 0.4072 (95% CI, 0.3542-0.4602) for CCR5-59029G, 0.1061 (95% CI, 0.0728-0.1394) for CCR2-64I, and 0.2218 (95% CI 0.1715-0.2721) for SDF1-3'A. A significant linkage disequilibrium (p = 0.0034) between CCR2-64I and SDF1-3'A alleles was observed.     

Joint Effect of MCP-1 Genotype GG and MMP-1 Genotype 2G/2G Increases the Likelihood of Developing Pulmonary Tuberculosis in BCG-Vaccinated Individuals

We previously reported that the – 2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the – 1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the – 2518 MCP-1 genotype GG and the – 1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1.     

Interleukin 2 gene polymorphisms are associated with non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide. Interleukin-2 (IL-2) plays a key role in the proliferation of T cells and natural killer cells. It has been reported that polymorphisms in the IL-2 gene are associated with various cancers. The aim of this study was to examine the effect of polymorphisms in the IL-2 gene on the development of NHL in the Chinese population. IL-2-330T/G and +114T/G polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in 438 NHL cases and 482 age-matched healthy controls. Data were analyzed using the Chi-square test. Results showed that individuals with -330TG genotype or -330GG genotype had significantly increased susceptibility to NHL (Odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.05-1.85, p = 0.020 and OR = 2.04, 95%CI: 1.28-3.24, p = 0.002). Meanwhile, the +114T/G polymorphism did not show any correlation with NHL. When analyzing the haplotypes of these two polymorphisms, the prevalence of -330G/+114T haplotype was significantly higher in NHL cases than in controls (OR = 1.45, 95%CI: 1.12-1.88, p = 0.005). These data indicate that IL-2 gene polymorphisms may be new risk factors for NHL.     

Combined effect of CCR5-Delta32 heterozygosity and the CCR5 promoter polymorphism -2459 A/G on CCR5 expression and resistance to human immunodeficiency virus type 1 transmission

Exposed seronegative individuals (ES) with persistent high-risk sexual behavior may be less susceptible to human immunodeficiency virus type 1 (HIV-1) infection because they carry the chemokine receptor (CR) gene alleles CCR5 open reading frame (ORF) Delta32, CCR5 promoter -2459G, or CCR2 ORF 64I (CCR2-64I), all of which have been found to diminish HIV-1 infectivity and/or disease progression. To investigate this, we determined the haplotypes for these three genetic loci in 93 ES and 247 low-risk control individuals. To test if protective haplotypes exert their effect by modulating CR expression, we measured the protein expression of CCR5 and CXCR4 on circulating CD4+ T cells and CD14+ monocytes in 71 ES and 92 controls. To avoid investigator bias, the analysis was performed without knowledge of each subject's risk and genotype. The CCR5 -2459G allele was significantly enriched in ES Caucasian men, who constituted the majority (84%) of the ES cohort, compared to the control Caucasian men (P = 0.02). This increase was mostly attributable to a higher frequency of the -2459 A/G versus the -2459 A/A genotype in individuals heterozygous for the delta32 allele (P = 0.012). No protective influence of the CCR2-64I allele was observed. The haplotypes CCR5 ORF delta32/CCR5 -2459A (in complete linkage disequilibrium) and CCR5 ORF wt/CCR5 -2459G had a cumulative negative effect on the expression of CCR5, since we measured significantly reduced CCR5 densities on both T-helper cells and monocytes only when both haplotypes were present. Densities of CCR5 on lymphocytes and monocytes were correlated (r = 0.59; P < 0.0001), indicating concordance of CCR5 expression patterns across different cell types. We conclude that the CCR5 ORF delta32/wt-CCR5 -2459 A/G genotype combination offers an advantage in resisting sexual HIV-1 transmission and that this effect is mediated by a relative paucity of CCR5 on potential target cells of HIV-1.     

ICAM-1K469E 位点A 等位基因可降低EV71 手足口病发生率

目的:研究ICAM-1基因K469E位点、MCP-1A2518G位点基因多态性及sICAM-1、MCP-1在血清中表达水平与EV71手足口病的关系,探讨EV71型手足口病的遗传易感因素。方法:运用限制性片段长度多态性-聚合酶链反应(PCR-RFLP)检测急性期EV71感染阳性的手足口病患儿和正常儿童中ICAM-1K469E位点及MCP-1A2518G位点碱基变异情况,同时采用双夹心抗体法(ELISA)检测血清sICAM-l和MCP-1水平。结果:EV71手足口病组患儿血清中sICAM-l和MCP-1水平均显著高于正常对照组(P均<0.01)。EV71手足口病组ICAM-1K469E位点中,A等位基因的频率显著低于对照组(x2=6.897,P<0.01)。EV71手足口病组患儿MCP-1基因型分布、等位基因频率与对照组比较均无统计学意义(P>0.05)。结论:sICAM-1表达水平和其基因K469E位点多态性与EV71手足口病有关,A等位基因可降低EV71手足口病发生率。MCP-1表达水平与EV71手足口病感染有关,但MCP-1A-2518G位点基因多态性与EV71手足口病感染无关。