CXCL12 Polymorphisms Research Articles

Investigating Association Level of CXCL12 with its SDF-1α 3'A Genetic Variant and CXCL10 with its 1443 Promoter Polymorphism in Type-1 Diabetes.

Type-1 Diabetes Mellitus (T1DM) is an autoimmune and heterogeneous disorder. In the present study, we aimed to examine whether there exists an association between serum CXCL10 (IP-10) level and its promoter polymorphism at position-1443 along with CXCL12 and its known SDF-1 3' A genetic variant as an angiogenesis chemokine in T1DM patients. Blood specimens were collected from 209 unrelated T1DM patients and 189 healthy subjects. The DNA samples were extracted from the subjects and analyzed for CXCL10 and CXCL12 polymorphisms using PCR-RLFP. The serum concentrations of CXCL10 and CXCL12 were also analyzed with ELISA. Following expert opinion and data analysis, we found significant differences between A/A, A/G, and G/G genotypes with A and G alleles of polymorphisms at position +801 (SDF-1α3'A) in CXCL12. No association was reported between CXCL10/-1443 promoter polymorphism and T1DM. In our assessment of promoter polymorphism, both T1DM patients and controls had GG genotypes in CXCL10/-1443. When patients were compared with controls, both serum CXCL10 and CXCL12 levels were found to be increased in type 1 diabetes with complications. Levels were not increased in patients without complications. Both CXCL10 and CXCL12 play fundamental roles in T1DM pathogenesis. Only the CXCL12 3'A (SDF-1α3'A) polymorphism is possibly necessary for the pathogenesis of T1DM, while the CXCL10-1443 promoter polymorphism is not.

Associations of CXCL12 polymorphisms with clinicopathological features in breast cancer: a case-control study

BackgroundPrevious studies suggested that CXCL12 was involved in the development, metastasis, and invasion of breast cancer, and genetic variants were associated with the diagnosis and prognosis of patients with breast cancer. The present study was aimed to assess the relationships between CXCL12 polymorphisms (rs1801157, rs2297630, and rs2839693) and susceptibility and clinicopathological features of breast cancer.MethodsA case-control study was conducted in 434 breast cancer patients and 450 health controls. Student t-test and chi-square test were used to analyze the differences of age distribution and genotype frequencies between the two groups. Correlations between polymorphisms and clinical parameters were also assessed by chi-square test. The potential effects of the three polymorphisms on CXCL12 were investigated by the public database.ResultsA statistical association was found between CXCL12 rs1801157 polymorphism and breast cancer risk, possibility of metastasis, and estrogen receptor status. Patients with rs2839693 C/T or C/T-T/T genotypes were more likely to be progesterone receptor-negative. However, no associations of rs2297630 polymorphism with breast cancer risk or any clinicopathological characteristics were observed. In addition, rs2297630 affected the splicing quantitative trait loci of CXCL12 in the subcutaneous fat, rs2839693 polymorphism affected the splicing quantitative trait loci of CXCL12 in the human breast mammary tissues.ConclusionsThose results indicated that CXCL12 polymorphisms might be potential diagnostic indicators, and more investigation is needed in the future.

Impact of PCSK9, WDR12, CDKN2A, and CXCL12 Polymorphisms in Jordanian Cardiovascular Patients on Warfarin Responsiveness and Sensitivity.

BackgroundThe main objective of this study is sought to determine the impacts of PCSK9, WDR12, CDKN2A, and CXCL12 polymorphisms on warfarin sensitivity and responsiveness in Jordanian cardiovascular patients during the initiation and stabilization phases of therapy.MethodsThis study took place at the anticoagulation clinic at Queen Alia Heart Institute (QAHI) in Jordan. DNA samples were collected from 212 cardiovascular patients and 213 healthy controls. Genomic SNPs genotyping was conducted using the MassARRAY System at the Australian Genome Research Facility.ResultsThis study assessed 10 polymorphisms (rs11206510 within the PCSK9 gene, rs6725887 and rs7582720 within the WDR12 gene, rs4977574, rs10757278, and rs1333049 within the CDKN2A gene, rs2862116, rs7906426, rs1746048, and rs268322 within the CXCL12 gene) in 212 Jordanian cardiovascular patients. Carriers of CDKN2A rs1333049, rs10757278, and PCSK9 rs11206510 polymorphisms had an increased risk of resistance during the initiation phase of warfarin therapy compared to those who do not carry it, or those who are carrying one polymorphism only (P < 0.05), while carriers of CXCL12 rs7906426 polymorphism had similar increased risk but during the stabilization phase of warfarin therapy (P < 0.05).ConclusionCarriers of CXCL12 rs2862116 polymorphism had an increased risk to be warfarin extensive responders compared to those with no or only one polymorphism (P = 0.01). However, the presence of PCSK9 rs11206510 polymorphism affects the warfarin maintenance doses (P ˃ 0.0001).

CXCL12 chemokine and CXCR4 receptor: association with susceptibility and prognostic markers in triple negative breast cancer

CXCL12/CXCR4 signaling has been implicated in breast carcinogenesis, and genetic polymorphisms in these molecules have been associated with different types of cancer. The present study analyzed genetic polymorphisms in CXCL12 (rs1801157, G > A) and CXCR4 (rs2228014, C > T) and CXCR4 immunostainingin tumor tissues from patients with triple negative breast cancer (TNBC) aiming to evaluate their possible role in its' susceptibility and prognosis. Genetic polymorphisms were analyzed in 59 TNBC patients and 150 control women; age-adjusted logistic regression showed no association when variants were considered in isolation; however, a statistically significant interaction was noted for heterozygosis for both allelic variants increasing the odds for TNBC (CXCL12-GA by CXCR4-CT: OR 7.23; 95% CI 1.15-45.41; p = 0.035). CXCL12 polymorphism was correlated negatively with proliferation index (Ki67) (Tau-b = - 0.406; p = 0.006). CXCR4 immunostaining was evaluated in 37 TNBC patients (22 with paired tumor-normal adjacent tissue). CXCR4 was detected more intensely in cell cytoplasm than in membrane, and was more expressed in tumor than in normal adjacent tissues, although not statistically significant. CXCR4 expression on the membrane of tumor cells was correlated positively with histopathological grade (Tau-b = 0.271; p = 0.036) and negatively with lymph node metastasis (Tau-b = - 0.478; p = 0.036). The present study indicates that CXCL12 and CXCR4 polymorphisms and CXCR4 immunostaining might have susceptibility and prognostic roles in TNBC pathogenesis.

CXCR4 polymorphism predicts progression-free survival in metastatic colorectal cancer patients treated with first-line bevacizumab-based chemotherapy.

We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.

Dual role of the CXCL12 polymorphism in patients with chronic lymphocytic leukemia.

The CXCL12 [chemokine (C-X-C motif) ligand 12] is a member of the CXC family of chemokines and interacts with its CXCR4 receptor. The CXCL12/CXCR4 axis is involved in regulation of proliferation, survival and trafficking of hematopoietic stem cells, including B lymphocytes and disruption within this signaling pathway has been implicated in pathogenesis of chronic lymphocytic leukemia (CLL). The aim of this study was to determine a potential association of the CXCL12 rs1801157 G > A polymorphism with susceptibility to CLL, the disease course and efficacy of therapy. Also, expression of the CD74 and CD38 proteins on B cells was analyzed in relation to clinical parameters and genotyping results. A total of 124 patients with CLL and 75 healthy controls were studied. CXCL12 genotyping was performed using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) method. The CD74 and CD38 surface expression was determined using flow cytometry. There was a significantly increased frequency of the A allele and AA genotype in CLL patients compared with control group (P < 0.001 in both cases). In addition, the A allele was overrepresented among patients with worse response to therapy in comparison to other genotypes (P < 0.001). On the contrary, patients carrying the A allele displayed lower grade of the disease at diagnosis more frequently than patients homozygous for the G allele (P = 0.037). Moreover, the AA homozygosity correlated with lower CD74 expression on B cells (P = 0.007). In conclusion, data from this study indicate that the CXCL12 rs1801157 G > A polymorphism may affect CLL development, disease progression as well as response to treatment.

Short Communication: CXCL12 rs1029153 Polymorphism Is Associated with the Sustained Virological Response in HIV/Hepatitis C Virus-Coinfected Patients on Hepatitis C Virus Therapy.

The immune response against HIV and hepatitis C virus (HCV) infection partly depends on chemokine-mediated recruitment of specific T cells. CXCL12 polymorphisms have been associated with AIDS progression and survival, but there are no data related to HCV infection. The aim of this study was to determine whether CXCL12 polymorphisms are related so as to achieve sustained virological response (SVR) after HCV therapy with pegylated-interferon-alpha/ribavirin (pegIFN-α/ribavirin) in HIV/HCV-coinfected patients. We carried out a retrospective study in 319 naive patients who started HCV treatment. The CXCL12 (rs266093, rs1029153, and rs1801157) and IL28B (rs12980275) polymorphisms were genotyped by using the GoldenGate assay. Genetic data were analyzed under an additive inheritance model. The overall rates of the SVR were 54.9% (175/319) and 41.5% (90/217) in GT1/4 patients and 83.2% (84/101) in GT2/3 patients. Patients with a favorable CXCL12 rs1029153 T allele had higher SVR rates than patients with the rs1029153 CC genotype (44% CC, 49% CT, and 61.3% TT; p = 0.025). No significant results for the rs266093 and rs1801157 polymorphisms were found. Patients harboring the favorable rs1029153 T allele had significantly increased odds of achieving SVR [adjusted odds ratio (aOR) = 1.55; 95% confidence interval (95% CI) = 1.01; 2.40; p = 0.047]. Moreover, no significant association was found when the study population was stratified by HCV genotype (data not shown), possibly due to the low number of patients in each group. In conclusion, in this study we found that the favorable CXCL12 rs1029153 T allele seems to be related so as to achieve an SVR in HIV/HCV-coinfected patients on pegIFN-α/ribavirin therapy.

Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.

635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.

The SDF-1α3′A Genetic Variation Is Correlated with Susceptibility of Asthma in Iranian Patients

Background and Aim. Chemokine/receptor axis is a predominant actor of clinical disorders. They are key factors of pathogenesis of almost all clinical situations including asthma. Correspondingly, CXCL12 is involved in the immune responses. Therefore, this study was designed to explore the association between gene polymorphism at position +801 of CXCL12, known as SDF-1α3′A, and susceptibility to asthma in Iranian patients. Material and Methods. In this experimental study, samples were taken from 162 asthma patients and 189 healthy controls on EDTA. DNA was extracted and analyzed for CXCL12 polymorphisms using PCR-RLFP. The demographic information was also collected in parallel with the experimental part of the study by a questionnaire which was designed specifically for this study. Findings. Our results indicated a significant difference (P < 0.0001) between the A/A, A/G, and G/G genotypes and A and G alleles of polymorphisms at position +801 of CXCL12. We also showed an elevated level of CXCL12 circulating level in Iranian asthma patients. Conclusion. Our findings suggest that SDF-1α3′A (CXCL12) polymorphism plays a role in pathogenesis of asthma. It can also be concluded that circulatory level of CXCL12 presumably can be used as one of the pivotal biological markers in diagnosis of asthma.

SNP rs1801157 significantly correlates with distant metastasis in CXCL12 expressing esophagogastric cancer

We performed this study in order to evaluate the impact of the chemokine CXCL12 and its single-nucleotide polymorphism (SNP) rs1801157 on clinicopathological parameters and survival in patients undergoing surgery for esophagogastric cancer. The expression pattern of CXCL12 and its polymorphisms were analyzed by RT-PCR and PCR-RFLP in 69 consecutive fresh-frozen samples of human esophagogastric junction and gastric adenocarcinomas and statistically analyzed. Expression of the CXCL12 (SNP rs1801157) polymorphisms GA/AA significantly correlated with distant metastasis (P=0.026), but not with prognosis. However, CXCL12 expression was not significantly associated with the tumor infiltration depth, lymphatic metastasis and grading. As CXCL12 polymorphisms mediate tumor cell dissemination in esophagogastric cancer, they could represent a marker indicating advanced disease. Antagonists targeting the CXCL12/ CXCR4 axis may be a novel therapeutic option in this entity.

Haplotype analysis of chemokine CXCL12 polymorphisms and susceptibility to premature ovarian failure in Chinese women

BACKGROUND Chemokine (C-X-C motif) ligand 12 (CXCL12/stromal cell-derived factor 1) has been suggested to play an essential role in primordial germ cell migration, colonization and survival, and in the primordial to primary follicle transition. This study was performed to investigate an association of polymorphisms in CXCL12 with the risk of premature ovarian failure (POF) in Chinese patients. METHODS Tagging single nucleotide polymorphisms (SNPs) were selected using the Chinese HapMap database. Five SNPs (rs4948878, rs1801157, rs266087, rs266093 and rs1029153) were genotyped by direct sequencing in 111 patients with POF and 183 healthy controls recruited from the First Affiliated Hospital, Anhui Medical University, China. RESULTS Compared with controls, there were significantly higher frequencies of the rs1801157 A allele and haplotype C-T-A-T-T in cases with POF [P = 6.38E-07, odds ratio (OR) = 3.10, 95% confidence interval (CI) 1.955-4.890 by allele; P = 7.0E-04, OR = 2.39, 95% CI 1.43-3.97 by haplotype]. No differences were observed for the other four SNPs between POF cases and controls. CONCLUSIONS A strong association between a CXCL12 polymorphism and POF was established in Chinese patients, suggesting that CXCL12 might be a new candidate gene involved in POF. The A allele of CXCL12 polymorphism rs1801157 is a possible risk factor for developing POF. However, further independent studies are necessary to confirm our findings.

Polymorphism and circulating levels of the chemokine CXCL12 in colorectal cancer patients

The chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is a small protein that regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. CXCL12 as ligand and its receptor CXCR4 have been implicated in colorectal cancer (CRC) progression including angiogenesis and metastasis. A CXCL12 gene variant CXCL12-A (CXCL12-G801A, a single nucleotide polymorphism in the 3' untranslated region) is associated with increased susceptibility to breast cancer. Based on the suggested role of CXCL12 in the pathogenesis of cancer we examined the association of the gene variant CXCL12-A with CRC. The polymorphism was analysed with PCR and RFLP methods. Furthermore, the plasma CXCL12 levels from patients with CRC were also examined. There was no significant difference in genotype distribution and allelic frequencies between CRC patients (n=151) and controls (n=141). On the other hand, we found that the carrying rate of allele CXCL12-A was higher in colon cancer patients compared with rectal cancer patients (P=0.017). Analyses by ELISA showed that CRC patients (n=63) had a lower CXCL12 plasma level compared with controls (P<0.0001). Moreover, patients with tumours classified as Dukes' stage B and C revealed lower levels than patients with tumours in Dukes' stage A. Further studies with larger samples of patients are necessary to determine whether the CXCL12 polymorphism and plasma level reflect the clinical outcome of CRC and have an impact on CRC progression.