SDF1 Genotypes Research Articles

Protective Effect of the Combination of Wild-Type Genotypes (G/G and G/G) of CCR2-64V and SDF1-3A' Genes in Serodiscordant Couples in Yaounde-Cameroon.

There is growing evidence that polymorphisms in chemokine and chemokine receptor genes influence susceptibility to HIV infection and disease progression. However, not much is documented about the influence of these polymorphisms in HIV serodiscordant couples in Cameroon. The objective of this study therefore was to determine the prevalence and the effect of the polymorphisms of CCR5-Δ32, CCR5 promoter 59029 A/G, CCR2-64I and SDF1-3'A gene in HIV serodiscordant couples in comparison to HIV negative seroconcordant and HIV positive seroconcordant couples in Yaoundé-Cameroon. A total of 96 couples were recruited from five hospitals, of which 60 couples were HIV serodiscordant (test group), 18 HIV negative seroconcordant and 18 HIV positive seroconcordant couples were used as controls. Their genotypes for CCR5-Δ32, CCR5 promoter, CCR2 and SDF1 were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism. The allelic frequencies of these genes in the studied population were: 0%, 26.30%, 15.30% and 1.62% respectively for CCR5-Δ32, CCR5 promoter, CCR2 and SDF1. The frequency of the combination of CCR5 promoter and SDF1- (A/A+ G/G) wild-type genotype was higher in HIV-infected partners (82.92%) compared to uninfected partners (56.1%) in HIV serodiscordant couples (p= 0.0001). The combination of wild-type CCR2 and SDF1 genotypes (G/G + G/G) was higher among uninfected partners (80.48%) in HIV serodiscordant couples compared to the infected partners (60.97) (p= 0.005). HIV negative partner protection against HIV/AIDS infection may be attributed to the combination of wild-type genotypes (G/G and G/G) of CCR2 and SDF1 genes in HIV serodiscordant couples.

Association between SDF1-3′A or CXCR4 gene polymorphisms with predisposition to and clinicopathological characteristics of prostate cancer with or without metastases

In the present study, we aimed to investigate the association between SDF1-3'A and CXCR4 gene polymorphisms and the susceptibility and clinicopathological development of prostate cancer. SDF1-3'A and CXCR4 gene polymorphisms were assessed by polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP) in 149 healthy subjects and 152 patients with prostate cancer. There were no significant differences in the distributions of SDF-1 and CXCR4 genotypes between controls and prostate cancer patients. However, the patients with AA genotype of SDF1-3'A gene presented a higher risk for developing an advanced disease status as compared to patients with GG homozygotes (aOR = 2.02; 95 % CI = 1.05-3.90; P = 0.035). In addition, the distribution of AA genotype of SDF1-3'A gene was found significantly increased in the patients with bone metastasis in comparison to those without bone metastasis (aOR = 2.94; 95 % CI = 1.26-6.82; P = 0.012). On the other hand, CXCR4 gene polymorphism was not associated with the clinicopathological characteristics of prostate cancer. Our results suggest that SDF1-3'A and CXCR4 gene polymorphisms may not be risk factors for the susceptibility to prostate cancer. However, SDF1-3'A gene polymorphism may be associated with the progression and bone metastasis of prostate cancer in a Turkish men population.

Association Between Polymorphism of SDF1 (CXCL12) Gene and HIV-1 Susceptibility: A Meta-Analysis

Studies on the association between SDF1 genotype and HIV-1 susceptibility have generated inconclusive results. Therefore, we conducted a meta-analysis to summarize the findings of different studies. Articles reporting SDF1 gene polymorphisms among HIV-1 infected patients and controls were searched from PubMed up to June 2010. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the association of SDF1 genotype with HIV-1 susceptibility. As a result, 13 studies with 2421 cases and 3283 controls were included in the meta-analysis. Compared with the wild-type SDF1 homozygotes, the pooled OR for SDF1 heterozygotes and SDF1-3'A homozygotes were 1.07 (95% CI, 0.79-1.45), 1.38 (95% CI, 0.71-2.69) among exposed uninfected controls and 0.89 (95% CI, 0.75-1.07), 1.15 (95% CI, 0.80-1.63) among healthy controls. In conclusion, no statistically significant association between SDF1 genotype and HIV-1 susceptibility was detected in any models. Our data suggested that SDF1 genotype might have limited effect on HIV-1 susceptibility.

SDF-1 and CCR5 Genes Polymorphism in Patients with Head and Neck Cancer

The frequency of SDF1-3'A and CCR5Delta32 in patients with head and neck cancer were determined in this study. The frequencies of alleles and genotypes of SDF-1 and CCR5 were assessed by PCR method in 156 patients with malignant head and neck cancer, 125 (80.1%) cases with squamous cell carcinoma and 31 (19.9%) cases with salivary gland tumors and compared with 262 age-sex matched healthy control individuals. SDF-1 genotypes in patients with SCC of head and neck, but not with salivary gland tumors, showed a statistically significant difference compared to the normal group (P < 0.005 for SCC and P = 0.3 for salivary gland tumors). There were no significant differences in the frequencies of SDF1-3'A allele, CCR5 genotypes and alleles between patients and controls. Based on the present study SDF1-3A may be associated with the susceptibility of patients to SCC of head and neck cancer.

CCR2b-64I Allelic Polymorphisms in Advanced HIV-Infected Koreans Accelerate Disease Progression

Genetic polymorphisms of chemokine genes and chemokine-receptor genes in HIV-infected patients have been associated with delayed progression of this disease. The allelic frequencies of these genetic variants also differ between ethnic groups. To investigate the effects of the SDF1 and CCR2b genotypes on disease progression, survival of 200 HIV-infected persons for whom at least four subsequent immunologic data items had been collected was analyzed. A genotyping assay of SDF1 and CCR2b genes was carried out using polymerase chain reaction-restriction fragment length polymorphism analyses. HIV-infected persons heterozygous for the SDF1-3'A or CCR2b-64I alleles were included in the survival analysis, but homozygotes were excluded because of a very small sample number. Neither the CCR2b-+/64I allele nor the SDF1-+/3'A allele, separately or in combination, had a significant impact on survival during the asymptomatic period of HIV infection. However, CCR2b-+/64I alleles were associated with accelerated disease progression during the advanced period of HIV infection. The survival time of HIV-infected people with CCR2b-+/64I and SDF1-+/+ genotypes was significantly shorter than those of the other groups (p < 0.01), but this effect was not apparent in persons with CCR2b-+/64I alleles and SDF1-+/3'A genotypes. These results suggest that the effect of CCR2b-64I polymorphisms on disease progression may differ according to the stage of HIV infection and interactions with other gene variants.

Stromal cell-derived factor-1 chemokine gene variant in blood donors and chronic myelogenous leukemia patients.

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disorder that originates from a pluripotent stem cell expressing the bcr-abl oncogene. It is characterized by an abnormal release of the expanded, malignant stem cell clone from the bone marrow into the circulation. The stromal cell derived factor-1 (SDF-1) gene contains a common polymorphism, termed SDF1-3'A, in an evolutionarily conserved segment of the 3' untranslated region (UTR). In this work the SDF-1 genotypes of 25 patients (9-82 years old) who had been clinically and hematologically diagnosed with CML were compared with those of 60 healthy donors. In addition, the nature of bcr-abl hybrid mRNA and the association between demographic and hematological parameters were analyzed in cells from 12 CML patients (five women and seven men). All patients underwent blood collection during the chronic phase of disease after they received chemotherapy. b3a2 mRNA was detected in samples from eight of the CML patients and b2a2 mRNA was observed in four cases. An association between basophils and hemoglobin parameters was observed in that hemoglobin levels were higher in b2a2-expressing patients, and mean basophil levels were higher in patients expressing b3a2. Four of the CML patients (16%) were homozygous for 3'A allele. Of the patients who showed the presence of bcr-abl transcripts (N = 12), three presented the wt/wt genotype and nine were SDF1-3'A carriers. Three of the latter were homozygous for this mutation. It is possible that the bcr-abl fusion gene and the SDF1 genotype for 3'A allele have important implications for the pathogenesis of CML.

The effect of stromal cell-derived factor 1 (SDF1/CXCL12) genetic polymorphism on HIV-1 disease progression

The human immunodeficiency virus type 1 (HIV-1) epidemic is increasing in Brazil, and little information has been reported about the genetic host factors related to HIV-1 infection in the Brazilian population. A polymorphism in the conserved 3' untranslated region of the stromal cell-derived factor 1 (SDF1/CXCL12) gene has been related either to resistance to HIV-1 infection and delayed progression to AIDS or to rapid disease progression and death. A longitudinal study was conducted to evaluate the association of the SDF1 polymorphism and the progression of HIV-1 infection in 161 asymptomatic patients infected with HIV-1 (ASYMPT) and 617 patients with AIDS (SYMPT) from Londrina and the surrounding region, southern Brazil. The endpoints used were the development of AIDS, death, and the slopes of the CD4+ T cell counts and HIV-1 RNA plasma levels. Among the 161 ASYMPT patients, all of the 7 patients (4.3%) homozygous for the mutation remained asymptomatic (p=0.1906); 6 of them had not initiated antiretroviral therapy. Among the 617 patients with AIDS, 40 (6.5%) progressed to death. Of these, 33/388 (8.5%) did not have the SDF1-3'A allele, 6/196 (3.1%) were heterozygous and 1/33 (3.0%) was homozygous for the SDF1-3'A allele (p=0.029). The SDF1 genotypes were not associated with the surrogate markers of HIV-1 disease progression such as the CD4+ T cell decline and plasma HIV-1 RNA levels. The results observed in this study support the hypothesis that the mutation of SDF1-3'A could have a possible late-stage protective effect on HIV-1 disease progression in the Brazilian population.

Association of Stromal Cell–Derived Factor 1 Genotype with Diabetic Foot Syndrome and Macrovascular Disease in Patients with Type 2 Diabetes

Stromal cell–derived factor 1 (SDF-1) is a highly active chemokine that influences migration and trafficking of leukocytes (1) and hematopoietic progenitor cells(2). Patients with type 2 diabetes (T2DM) who carry the heterozygous SDF-1 3′A genotype (801G/A in the 3′ untranslated region) have increased insulin-dependent mobilization of adult progenitor cells (3), which are known to participate in angiogenesis and vascular repair (4). In contrast, homing of progenitor cells has been shown to contribute to diabetes-related vascular complications (5)(6). Because carriers of the SDF-1 3′A genotype have increased SDF-1 mRNA in peripheral blood mononuclear cells (7), genetic variations in SDF-1 expression might affect trafficking of inflammatory cells or dysfunctional precursors and thus predispose to diabetic complications. To investigate a possible influence of the SDF-1 genotype on the development of late vascular diabetic complications, we performed a case–control study in T2DM patients suffering from diabetic foot syndrome (DFS) and a cohort of T2DM patients almost free of late complications. All patients were recruited from the diabetes outpatient departments …

Anthropological implication of the SDF1-3'A allele distribution in Southeast Asia and Melanesia.

The distribution of the SDF1-3'A allele among 1848 individuals in Southeast Asia and Melanesia was studied with the polymerase chain reaction-restriction fragment length polymorphism assay. The SDF1-3'A allele frequency in the populations of mainland Southeast Asia ranged from 0.0 to 0.355, whereas in the populations of insular Southeast Asia and Melanesia, it ranged from 0.233 to 0.733, with an increasing cline from west to east. Correlation between SDF1-3'A frequency and longitude values was highly significant for the populations in the Pacific region (r = 0.867, P < 0.001). The geographic distribution of the SDF1-3'A frequencies in the Pacific region was interpreted by an admixture of Austronesians with the aboriginal people in situ. In addition, this study found high proportions of SDF1-3'A/3'A homozygous individuals in several populations, which will enable us to evaluate roles of the SDF1 genotypes in SDF-1 expression.

Protective effect of CCR5 delta 32 heterozygosity is restricted by SDF-1 genotype in children with HIV-1 infection.

To determine the influences on pediatric AIDS of a heterozygous 32 base pair deletion in the CC-chemokine receptor 5 gene (CCR5 wt/Delta 32) and a common polymorphism in the 3' untranslated region of stromal cell-derived factor-1 beta gene transcript (SDF1-3'A). The rate of HIV-1 disease progression and viral burden were compared according to the CCR5 and SDF-1 genotypes in 127 (58 Caucasians, 60 African-Americans and nine Hispanics) perinatally HIV-1-infected children. Regardless of ethnic background, the CCR5 wt/Delta 32 genotype was associated with a delayed onset of AIDS-defining infectious complications during the first 5 years of infection [relative hazard (RH) = 0.22; 95% confidence interval (CI), 0.012--1.02; P = 0.053]. Similarly, CCR5 wt/Delta 32 conferred an early protection against severe immune suppression and HIV-1 encephalopathy, but only in those without SDF1-3'A (RH = 0; 95% CI, 0--0.70; P = 0.020, and RH = 0; 95% CI, 0--0.71; P = 0.021, respectively). When examined before 5 years of age (n = 81), the children with CCR5 wt/Delta 32 had significantly lower levels of cell-associated HIV-1 DNA than wild-type homozygotes (P = 0.016, adjusted by race), while SDF1-3'A carriers had relatively higher levels (P = 0.047, adjusted by race). Although the disease-retarding effect of CCR5 wt/Delta 32 subsequently disappeared, time to death was still significantly delayed in the CCR5 Delta 32 heterozygotes without SDF1-3'A (RH = 0; 95% CI, 0--0.53; P = 0.008). In pediatric AIDS, the protective effect of CCR5 wt/Delta 32 is more pronounced in early years of infection and appears to be abrogated by the SDF1-3'A genotype.

Levels of CD34+ progenitor cells mobilized into peripheral blood are associated with SDF1 Gene variants

Hematopoietic growth factors (GF) have greatly facilitated the mobilization and collection of peripheral blood (PB) stem cells. However, some patients fail to mobilize sufficient numbers of hematopoietic progenitor cells (HPC) to ensure rapid and durable engraftment. Interactions between the chemokine SDF-1 and its receptor CXCR4 have been shown to play a central role in the homing of HPC. To investigate a possible additional role of SDF-1 in the mobilization of CD34+ progenitor cells into PB, we examined the association of SDF1 gene polymorphism with circulating CD34+ cell counts after GF-priming. 63 patients (pts) were studied (48 malignant lymphoma, 8 myeloma and 7 solid tumors), after mobilization with G-CSF alone (n=11), chemotherapy (CT) and G-CSF (n=36) or GM-CSF (n=16). PB CD34+ cell counts were assessed when leukocytes reached 1,000/μl and graft collection performed when CD34+ counts reached 20/μl. The SDF1 3′G/A genotyping was performed on PB mononuclear cell DNA by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) which can detect the G to A mutation. Out of the 63 pts, 21 were able to mobilize 50 CD34+ cells/μl or more in PB. Their characteristics were not statistically different from others in terms of diagnosis, age, sex, number of previous CT courses, previous radiotherapy, marrow involvement or mobilizing regimens. Distribution of SDF1 genotypes in normal controls and in patients according to their mobilizing capacity was as follows:These results provide evidence for an association of the SDF1 3′A allele with more efficient mobilization of CD34+ progenitor cells into PB and suggest an involvement of SDF-1 in mobilization mechanisms.

Shorter survival of SDF1-3'A/3'A homozygotes linked to CD4+ T cell decrease in advanced human immunodeficiency virus type 1 infection.

The SDF-1 3'A allelic polymorphism has been reported to influence either positively or negatively the progression of human immunodeficiency virus type 1 (HIV-1) disease. Therefore, the SDF-1 genotype of 729 HIV-1-infected individuals pooled from 3 distinct cohorts was determined. A statistically nonsignificant association between the SDF1-3'A/3'A genotype and accelerated disease progression was evident among seroconverters (n=319), but a striking correlation of decreased survival after either diagnosis of AIDS according to the 1993 definition or loss of CD4(+) T cell counts <200 was observed. The relative hazards for SDF1-3'A/3'A homozygotes, compared with heterozygotes and wild-type homozygotes were 2.16 (P=.0047), for time from diagnosis according to the 1993 Centers for Disease Control and Prevention AIDS case definition (AIDS-'93) to death, and 3.43 (P=.0001), for time from CD4(+) T cells <200 to death. Because no difference in survival was observed after diagnosis according to AIDS-'87, the association of the SDF1-3'A/3'A genotype with the accelerated progression of late-stage HIV-1 disease appears to be explained for the most part by the loss of CD4(+) T lymphocytes.

Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission.

Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3'A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T-tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.

The role of a stromal cell-derived factor-1 chemokine gene variant in the clinical course of HIV-1 infection

A G-to-A transition in the 3' untranslated region (UTR) of stromal cell-derived factor (SDF)-1 gene (SDF1-3'A) has recently been described, which in the homozygous state was associated with delayed disease progression. To analyse the effect of the SDF-1 polymorphism on AIDS-free survival and survival after AIDS diagnosis, also in relation to viral phenotype. Retrospective longitudinal study among 344 homosexual HIV-1-infected men. A more rapid progression to AIDS (Centers for Disease Control and Prevention 1993 definition) was observed in SDF1-3'A/3'A subjects than in wild-type (SDF1-wt/wt) subjects (relative hazard, 1.75; P = 0.07). Using death as an endpoint, accelerated progression was no longer observed (relative hazard, 0.93; P = 0.84), suggesting a late protective effect of the SDF1-3'A/3'A genotype. Indeed, survival after AIDS diagnosis was significantly delayed in SDF1-3'A/3'A subjects (relative hazard, 0.40; P = 0.02). No effect of the SDF1-3'A/wt genotype on disease progression was observed. Interestingly, a higher frequency of Kaposi's sarcoma was observed as the AIDS-defining event among SDF1-3'A/3'A (40.0%) and SDF1-3'A/wt (30.6%) subjects than in SDF1-wt/wt subjects (17.0%). At the end of the study the total frequency of syncytium-inducing (SI) HIV-1 variants was lower in SDF1-3'A/3'A subjects (22.2%) than in SDF1-3'A/wt (32.5%) and SDF1-wt/wt subjects (40.5%), although not significantly. SDF-1 genotype did not influence the rate of evolution to SI HIV-1. Progression to AIDS after the emergence of SI HIV-1 was accelerated in SDF1-3'A/3'A subjects compared with the SDF1-wt/wt genotypic group (relative hazard, 4.04; P = 0.06). In our study group, homozygosity for a G-to-A transition in the 3' UTR of SDF-1 is associated with an accelerated progression to AIDS but a subsequent prolonged survival after AIDS diagnosis.