FOXP3 Rs3761548 Research Articles

Effect of immunogenetics polymorphism and expression on direct-acting antiviral drug response in chronic hepatitis C

The prevalence of HCV infection in Egypt has decreased following the introduction of direct-acting antiviral therapy. However, treatment response is influenced by various factors, particularly host immunogenetics such as IL-28B and FOXP3 polymorphisms. The current study examined the impact of SNPs in the FOXP3 gene promoter region on HCV-infected Egyptian patients, along with SNPs in the IL28B gene.This study involved 99 HCV patients who achieved SVR12 after a 12 week DAA treatment while 63 HCV patients experienced treatment failure. IL28B rs12979860 SNP was identified using real-time PCR, while IL28B rs8099917, FOXP3 rs3761548, and rs2232365 SNPs were analyzed using RFLP-PCR. Serum levels of IL28B and FOXP3 were quantified using ELISA technique in representative samples from both groups. The IL28B rs12979860 T > C (P = 0.013) and FOXP3 rs2232365 A > G polymorphisms (P = 0.008) were found to significantly increase the risk of non-response. Responders had higher IL28B serum levels (P = 0.046) and lower FOXP3 levels (P < 0.001) compared to non-responders. Regression analysis showed an association between IL28B rs12979860 and FOXP3 rs2232365 with treatment response, independent of age and gender. A predictive model was developed with 76.2% sensitivity and 91.9% specificity for estimating DAAs response in HCV patients.Our findings confirmed the IL28B rs12979860 T > C and FOXP3 rs2232365 A > G polymorphisms significantly affect DAA treatment response in HCV Egyptian patients. Lower levels of IL-28B along with higher levels of FOXP3 are linked to poor response. Our results may lead to new insights into DAA responsiveness contributing to personalized medicine and improving therapeutic decision-making for HCV patients.Graphical abstract

FOXP3 (rs 3761548) and BRAF (V600E) gene polymorphism among Egyptians with hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is a universal problem. The risk factors for HCC could either be environmental or host-genetic-related. The polymorphism of both FOXP3 (rs3761548) and BRAF (V600E) genotypes and alleles was studied in 104 Egyptian HCC patients and 90 healthy subjects. There is a significant increase in the frequency of AC genotype in HCC group, while there is a significant decrease in the frequency of AA genotype in the patient’s group, compared to controls. The CC genotype is completely absent in the control group, while its frequency is 2 (1.92%) in the patient’s group. The C allele frequency is significantly increased in HCC patients (93 = 44.7%) while it is 39 (22.4%) in the control group. However, there is a significant decrease in the A allele frequency in HCC patients (115 = 55.3%) in comparison with controls (135 = 77.6%). The M allele in the BRAF gene (V600E) is significantly increased in HCC patients (90 = 43.69%) while it is 41 (22.78%) in controls. However, there is a significant decrease in the N allele frequency in HCC patients (116 = 56.31%) compared to controls (139 = 77.22%). FOXP3 (rs3761548) and BRAF (V600E) gene polymorphisms could be considered independent risk factors for HCC incidence.

The impact of FOXP3 polymorphisms on oral cancer progression and clinicopathological characteristics.

Oral cancer is the sixth leading cause of cancer mortality worldwide. Genetic, epigenetic, and epidemiological risk factors were suggested to be correlated with the carcinogenesis of oral cancer. In this study, we focused on the correlations of FOXP3 single-nucleotide polymorphisms (SNPs) to oral cancer susceptibility and clinicopathological characteristics. The FOXP3 SNPs rs3761547, rs3761548, rs3761549, and rs2232365 in 1053 controls and 1175 male patients with oral cancer were analyzed with real-time polymerase chain reaction. The results showed that the betel quid chewer who carried the FOXP3 rs3761548 polymorphic variant "T" were significantly associated with lower risk to develop oral cancer [AOR (95% CI) = 0.649 (0.437-0.964); p = 0.032]. The betel quid chewers with genotypic variant "T" of FOXP3 rs3761548 in male oral cancer patients were associated with lower risk of cell differentiated grade [AOR (95% CI) = 0.592 (0.377-0.930); p = 0.023]. The carriers of FOXP3 rs3761548 polymorphic variant "T" in male oral cancer patients with alcohol consumption were associated with lower risk to develop greater tumor [AOR (95% CI) = 0.609 (0.378-0.983); p = 0.042] and lower risk of cell differentiated grade [AOR (95% CI) = 0.440 (0.248-0.779); p = 0.005]. In conclusion, our results have revealed that the FOXP3 rs3761548 polymorphic variant "T" was associated with lower risk of oral cancer susceptibility, greater tumor size, and cell differentiated grade among betel quid chewers. The FOXP3 rs3761548 polymorphisms may play a role as pivotal biomarkers to predict oral cancer disease development and prognosis.

Upregulation of FOXP3 may act on immunological misbalance in Turner syndrome

AbstractTurner syndrome (TS) presents a characteristic immune imbalance among patients. As the X chromosome‐linked FOXP3 gene is a powerful immune regulator, in this work we investigated a possible relationship between FOXP3 and TS. We evaluated 117 TS patients to investigate whether genetic associations within polymorphisms in FOXP3 (rs3761548, rs3761549) were associated with immune conditions. TaqMan Assays genotyping probes were employed in a real‐time PCR‐based method. Subsequently, we compared FOXP3 mRNA expression levels in TS patients and healthy females (control group), using fluorogenic probes through qPCR assay. We detected that the T allele from rs3761549 FOXP3 SNP was significantly associated with chronic inflammatory diseases in TS patients (P = 0.008, OR = 0.17, CI = 0.02‐0.71). Further, we observed an upregulation of FOXP3 mRNA levels in the TS group compared to the HC group (+9.21 FC; P = 2.541 × 10−7). In conclusion, our results demonstrated a differential distribution of the T rs3761549 allele in chronic inflammatory diseases among TS patients, as well as that FOXP3 upregulation may influence appropriate immune or inflammatory regulation in these patients.

DNA Polymorphisms in Pregnant Women with Sticky Platelet Syndrome.

Sticky platelet syndrome (SPS) is a thrombophilia caused by the increased aggregability of platelets in response to the addition of low concentrations of epinephrine (EPI) and/or adenosine diphosphate (ADP). Some of the single nucleotide polymorphisms (SNP), alleles and haplotypes of platelet glycoprotein receptors were proved to have a role in the etiology of thrombotic episodes When comparing SPS and the control group, in VEGFA rs3025039, the p value for both CC vs. TT and CT vs. TT analyses was &lt;0.001. Interestingly, no minor TT genotype was present in the SPS group, suggesting the thrombotic pathogenesis of recurrent spontaneous abortions (RSA) in these patients. Moreover, we found a significant difference in the presence of AT containing a risky A allele and TT genotype of ALPP rs13026692 (p = 0.034) in SPS patients when compared with the controls. Additionally, we detected a decreased frequency of the GG (CC) genotype of FOXP3 rs3761548 in patients with SPS and RSA when compared with the control group (p value for the CC (GG) vs. AA (TT) 0.021). This might indicate an evolutionary protective mechanism of the A (T) allele in the SPS group against thrombotic complications in pregnancy. These results can be used for antithrombotic management in such pregnant patients.

Association between FOXP3 (rs3761548) promoter polymorphism with vitiligo patients, their clinical data and response to phototherapy: A study from Egypt

Association between FOXP3 (rs3761548) promoter polymorphism with vitiligo patients, their clinical data and response to phototherapy: A study from Egypt

Associations of FOXP3 gene polymorphisms with susceptibility and severity of preeclampsia: A meta‐analysis

AbstractObjectiveFOXP3 single nucleotide polymorphisms (SNPs) were recently elucidated to influence the development of preeclampsia (PE), but the results on this issue still remained controversial. Thus, a meta‐analysis was implemented to systematically investigate the roles of FOXP3 SNPs in PE.MethodsEligible publications were identified by retrieving relevant electronic databases. Meanwhile, the association intensity was estimated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) in various genetic models.ResultsTotally eight investigations involving 3446 subjects were enrolled in the final meta‐analysis. The AC and AC + CC genotypes of FOXP3 rs3761548 were related to the susceptibility of PE in over‐dominant (OR = 1.19, 95%CI = 1.02‐1.38, P = 0.03) and recessive (OR = 0.59, 95% CI: 0.36‐0.97, P = 0.04) models. Furthermore, correlation between rs2232365 and PE was observed in recessive model (GG vs. GA + AA) (OR = 0.79, 95%CI: 0.65‐0.97, P = 0.03). Moreover, rs2232365 GA and GG + GA genotypes were associated with the severity of PE. However, rs4824747, rs3761547 and rs2280883 polymorphisms had no significant impact on PE susceptibility.ConclusionsFOXP3 rs3761548 and rs2232365 SNPs influenced the PE susceptibility and therefore may be potential biomarkers for prediction of PE risk.

Investigation of possible associations between tryptophan/kynurenine status and FOXP3 expression in colorectal cancer

Tryptophan metabolism in the tumor microenvironment exerts immunosuppressive effects by affecting the anti-tumor functions of immune cells. The immunosuppressive roles of tryptophan and tryptophan metabolites and their effects on the FOXP3 gene, highly expressed in regulatory T cells (Tregs), are remarkable. Our study aimed to investigate the relation between tryptophan metabolism and the transcription factor FOXP3 gene in colorectal cancer (CRC). Patients with CRC (n = 159) and controls (n = 112) were included in the study. The FOXP3 rs3761548 variant genotyping from the isolated genomic DNA was performed by PCR-RFLP. FOXP3 gene expression was determined by Q-PCR in RNAs isolated from resected tissues at the same time. Serum tryptophan, kynurenine, kynurenic acid levels of the cases were determined by HPLC. In serum samples with CRC, tryptophan level was 14.32 ± 1.09 μmol/L, kynurenine level was 1.33 ± 0.02 μmol/L, and the kynurenic acid level was 0.01 ± 0.001 μmol/L. The level of tryptophan was found to be low in CRC compared to control (p < .001). In cases with CRC, CC genotype (p = .048) and C allele (p = .012) frequency for FOXP3 rs3761548 were higher than the control group. It was found that the expression level of the FOXP3 gene was approximately 44 times higher in the advanced tumor stage (T3 + T4) than in the early tumor stage (T1 + T2) (p = .021). We suggest that there may be a possible relationship among serum TRP, TRP metabolites (KYN, KYNA) levels, FOXP3 gene expression, and FOXP3 gene variants in CRC pathogenesis.

Gene polymorphism associated with FOXP3, CTLA-4 and susceptibility to pre-eclampsia: a meta-analysis and trial sequential analysis

Previous studies have detected the correlation of polymorphisms in regulatory T cells associated genes FOXP3 and CTLA-4 with pre-eclampsia (PE) risk, but the results are inconsistent among studies. Eligible studies were retrieved in several database. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilised to evaluate the relationship between FOXP3 rs3761548, FOXP3 rs2232365, CTLA-4 rs231775 polymorphisms, and PE susceptibility in the genetic models. The subgroup analysis and trial sequential analysis were performed. Twelve studies with a total of 4658 participants were included. There was a statistically significant association between FOXP3 rs3761548 polymorphism and PE within the recessive model in Asian (OR = 0.54, 95% CI = 0.34–0.86). Trial sequential analysis indicated sufficient proof of such association in the Asian population. This meta-analysis provides sufficient statistical evidence indicating an association between FOXP3 rs3761548 polymorphism and PE risk in Asian. IMPACT STATEMENT What is already known on this subject? FOXP3 and CTLA4 are markers of regulatory T cells which play a crucial role during a preeclamptic pregnancy. What do the results of this study add? Eleven studies with a total of 4658 participants were included. There was a statistically significant association between FOXP3 rs3761548 polymorphism and pre-eclampsia (PE) within the recessive model in Asian (OR = 0.54, 95% CI = 0.34–0.86). Trial sequential analysis indicated sufficient proof of such association in the Asian population. However, there was no enough evidence could proof significant association between FOXP3 rs2232365 or CTLA-4 rs231775 polymorphism and PE. What are the implications of these findings for clinical practice and/or further research? This meta-analysis provides sufficient statistical evidence indicating an association between FOXP3 rs3761548 polymorphism and PE risk in Asian. The findings in this study may provide a basis for the further study on FOXP3 rs3761548 polymorphism in future research.

Association of IL4 rs2070874, FoxP3 rs3761548 Polymorphisms with Keratoconus in Algeria.

Purpose The aim of this case–control study was to determine the impact of environmental factors on the predisposition to develop keratoconus in a sample of Western Algerian population. Subsequently, we were interested in the implication of two single nucleotide polymorphisms (SNPs) IL4 rs2070874 and FOXP3 rs3761548, previously described as contributing to the occurrence of allergy, in the development of keratoconus.MethodsThe study included 70 unrelated KC cases and 70 controls originating from Western Algeria. DNA genotyping was done using predesigned probe-based allelic discrimination TaqManⓇ assays. Allele and genotype frequencies were compared between the cases and controls by Chi-square test and odds ratios with 95% confidence intervals.ResultsA significant association between risk factors such as family history, atopy, eye rubbing, and the development of keratoconus was found in our sample. Smoking would provide a protective effect against the pathology. No statistically significant differences were found in the allele and genotype frequencies between cases and controls neither for IL4 rs2070874 nor for FOXP3 rs3761548.ConclusionOur study provides, for the first time, a clear demonstration of the absence of association of the allergy-associated IL4 and FOXP3 polymorphisms with KC in a sample from Western Algerian population.

FOXP3 and GATA3 Polymorphisms, Vitamin D3 and Multiple Sclerosis.

Background: Regulatory T cells (Tregs) alterations have been implicated in the pathogenesis of Multiple Sclerosis (MS). Recently, a crucial role of the X-Linked Forkhead Box P3 (FoxP3) for the development and the stability of Tregs has emerged, and FOXP3 gene polymorphisms have been associated with the susceptibility to autoimmune diseases. The expression of Foxp3 in Tregs is regulated by the transcription factor GATA binding-protein 3 (GATA3) and vitamin D3. The aim of this retrospective case-control study was to investigate the potential association between FOXP3 and GATA3 genetic variants, Vitamin D3, and MS risk. Methods: We analyzed two polymorphisms in the FOXP3 gene (rs3761547 and rs3761548) and a polymorphism in the GATA3 gene (rs3824662) in 106 MS patients and 113 healthy controls. Serum 25(OH)D3 was also measured in all participants. Results: No statistically significant genotypic and allelic differences were found in the distribution of FOXP3 rs3761547 and rs3761548, or GATA3 rs3824662 in the MS patients, compared with controls. Patients that were homozygous for rs3761547 had lower 25(OH)D3 levels. Conclusions: Our findings did not show any association among FOXP3 and GATA3 SNPs, vitamin D3, and MS susceptibility.

The role of FOXP3 rs3761548 and rs2294021 polymorphisms in pediatrics acute lymphoblastic leukemia: association with risk and response to therapy.

FOXP3 X-linked gene has crucial roles in the development and function of regulatory T cells. We investigated the association of FOXP3 rs3761548, rs3761549 and rs2294021 single nucleotide polymorphisms (SNPs) with acute lymphoblastic leukemia (ALL) susceptibility and response to therapy. Genotyping was performed in 247 patients and 210 healthy subjects. We observed a higher frequency of rs3761548 A carriers and rs2294021 C carriers (p < 0.04) in male patients, and lower frequencies of rs3761548 AC genotype (p = 0.04) and rs2294021 CT genotype (p = 0.01) in female patients compared to controls. ACC (p = 0.04) and ATC haplotypes (p = 0.002) were associated with susceptibility to ALL. There was a significant correlation between the genotypes of rs3761548 and rs2294021 SNPs with event-free survival (EFS) and overall survival (OS). The rs3761548 A genotype in male patients was associated with increased risk of relapse (p < 0.0001), shorter EFS, increased death rate (p = 0.002) and shorter OS compared to C genotype (p = 0.001). Similar significant results were observed for the relation of rs2294021 C genotype with response to therapy in male patients. In females, patients with rs3761548 AC genotype had longer EFS (p = 0.02) and those with rs2294021 CT had longer EFS and OS (p < 0.005). According to haplotype analysis, patients carrying ACC or ATC haplotypes had the highest number of WBCs and shorter EFS or OS, and patients with CCT haplotype had the lowest number of WBCs and longer EFS or OS. These results provided evidence for the impact of these polymorphisms on susceptibility and response to therapy in children with ALL.

Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients

T regulatory cells (Tregs) and related-cytokines are effectively engaged in the process of tumor immune escape and functionally inhibit immune response against the tumor. This study aimed to investigate the association of Foxp3 gene single nucleotide polymorphism (SNP) (rs3761548) with serum IL-35, IL-10, and TGF-β levels in gastric adenocarcinoma (GA) patients. The blood samples were obtained from 150 GA patients and 166 control subjects. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was done to genotyping of Foxp3 gene polymorphism (rs3761548). The serum cytokines levels were measured using the ELISA method. According to genotyping, the AA, and AC genotypes and A allele demonstrated significantly greater risk of GA. Considering the Lauren classification, our results revealed a greater risk of GA progression in patients with AC + AA genotype compared to CC genotype. Moreover, significantly increased levels of IL-10, IL-35, and TGF-β were observed in GA patients compared to controls and also in diffuse-type compared to the intestinal type of GA patients. The IL-35, IL-10 concentrations in GA patients displayed significant differences between the participants with CC, AC and AA genotypes. Further analysis indicated the prognostic role of serum IL-35, IL-10, and TGF-β levels in GA patients. Our results confirmed that the Foxp3 polymorphism (rs3761548) could influence the predisposition to GA and the serum IL-10, IL-35, and TGF-β levels. Thus, this polymorphism might be involved in the GA progression through influencing Tregs function and the secretion of immunomodulatory cytokines.

FOXP3rs3761548 gene variant and interleukin-35 serum levels as biomarkers in patients with multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Aberrant expression of transcription factor forkhead box P3 (FoxP3) has been suggested to underlie different immunological disorders as FOXP3 expression is essential for T regulatory cells (Tregs) to maintain their suppressive and anti-inflammatory functions and exert immunologic self-tolerance. Interleukin-35 (IL-35) is an important immunosuppressive cytokine that is produced mainly by CD4+ FOXP3+ Tregs. To assess the possible role of the FOXP3 rs3761548 (C/A) single-nucleotide variation (SNV) in relapsing-remitting multiple sclerosis (RRMS). Also, measurement of the serum IL-35 concentration and study its relation to different genotypes and the degree of disease-related disability. A total of 100 RRMS patients and 90 healthy control subjects were subjected to genotyping for the FOXP3 (rs3761548) variant by TaqMan real-time PCR, and measurement of the IL-35 level in their sera by Elisa. The frequencies of the AA genotype and A allele were significantly higher in the MS patients than in the healthy controls (P=0.008, OR=2.53, 95% CI=1.27-5.04; P=0.001, OR=1.98, 95% CI=1.31-3.00, respectively). There was a significant association between FOXP3 rs3761548 variant and female MS patients. The serum IL-35 level was significantly higher in MS patients (1372 [575-2192] pg/mL) compared to healthy controls (604 [454-696] pg/mL) (P<0.0001). No significant differences were found between the different FOXP3 genotypes and EDSS score (P=0.730). The FOXP3rs3761548 gene variant may influence the genetic susceptibility to MS rather than affecting its course, severity or progression. The serum IL-35 level might have a role in the development of the disease, however its role in disease-related disability is questionable.

Polymorphisms in the TGFB1 and FOXP3 genes are associated with the presence of antinuclear antibodies in chronic hepatitis C

Chronic infection with Hepacivirus C (HCV) can lead to the occurrence of antinuclear antibodies (ANAs) and changes in cytokine profiles that can be similar to autoimmune diseases. The aim of the study was to identify polymorphisms in important mediators of the immune response in association with ANAs, which could contribute to the development of autoimmunity in hepatitis C. The study included 87 patients with chronic hepatitis C who were evaluated for the presence of ANA (indirect immunofluorescence) and for polymorphisms in the FOXP3, IFNG, IL6, IL8, IL10, MBL2, CRP, TGFΒ1 and TNFA genes (real-time PCR). Of the patients evaluated, 17 (19.54%) had ANA reactivity. The G allele of the FOXP3 rs2232365 polymorphism was more frequent in ANA-positive women (p = 0.0231; OR = 3,285). The C allele of the TGFΒ1 rs1800469 polymorphism was associated with ANA production (p = 0.0169; OR = 2.88). The results suggest that polymorphisms in genes related to immunological regulation may be associated with mechanisms that lead to the emergence of autoantibodies in the context of chronic Hepacivirus C infection.

The association between IL18, FOXP3 and IL13 genes polymorphisms and risk of allergic rhinitis: a meta-analysis.

Allergic rhinitis (AR) is a chronic inflammatory disease of nasal mucosa. Loss of function of Th17 cells and regulatory T (Treg) cells plays a role in the pathogenesis of AR. IL18, FOXP3, and IL13 are key genes in the development of AR. However, the genetic associations between IL18, FOXP3 and IL13 genes polymorphisms and AR risk were inconclusive yet. A meta-analysis was performed by searching through Pubmed, EMBASE, web of science and CNKI databases. The ORs and 95%CIs were used to assess the genetic association between the allelic, dominant and recessive models of IL18, FOXP3 and IL13 genes polymorphisms and AR risk. A total of 15 articles (6 for FOXP3, 5 for IL18, and 5 for IL13) were enrolled in the present study. No association was detected between the IL18 rs187238, rs1946518, rs360721, FOXP3 rs2232365, rs3761548 and IL13 rs1800925 polymorphisms and AR risk (p > 0.05). Significant associations were observed between the allelic (p = 0.001, OR 1.32, 95% CI 1.12-1.56), dominant (p = 0.005, OR 1.43, 95% CI 1.11-1.83) and recessive models (p = 0.01, OR 1.64, 95% CI 1.13, 2.40) of IL13 rs20541 and AR risk. Subgroup analysis based on ethnicity revealed that the IL13 rs20541 was significantly associated with AR risk in Asian population (allelic model: p = 0.009, OR 1.36, 95% CI 1.13-1.63, dominant model: p = 0.005, OR 1.43, 95% CI 1.11-1.83; recessive model: p = 0.01, OR 1.64, 95% CI 1.13-2.40). IL13 rs20541 may contribute to the risk of AR in Asian population. To confirm these results, larger number of case-control study with more subjects is necessary in the future.

The role of two common FOXP3 gene promoter polymorphisms in preeclampsia in a Turkish population: a case–control study

Preeclampsia (PE), which occurs in approximately 5% of pregnancies worldwide and constitutes clinically serious complications in 2–3%, is one of the leading causes of maternal and prenatal morbidity and mortality. Recent studies report that regulatory T (Treg) cells, which act as immunosuppressant, are associated with PE. It is clearly defined that FOXP3/Scurfin (Forkhead Box P3) is involved in the development and function of Tregs. However, there are different conclusions regarding the relationship between PE and FOXP3 gene polymorphisms for different populations. For this reason, in this study we investigate the association between FOXP3 gene promoter region polymorphisms and PE in a Turkish population 500 PE patients and 500 healthy pregnant women. Blood samples taken from pregnant women were studied by PCR-RFLP method. As a result, rs2232365 polymorphism was significantly associated with disease (p < .0001) while no significant association was found between rs3761548 polymorphism and the disease (p = .17). Based on these results, it is though that FOXP3 rs2232365 polymorphism may be predisposed to PE development in terms of Turkish population. However, further and functional studies are needed in terms of other polymorphisms and mutations.IMPACT STATEMENTWhat is already known on this subject? A number of recent publications suggest that Tregs may play a role in the pathogenesis of PE. It is known that a stable and high FOXP3 expression is required to maintain the suppressive T cell function of Tregs. Down regulation of FOXP3 in PE has been reported in many previous studies, but the mechanism is still uncertain.What do the results of this study add? Our study has examined two FOXP3 promoter region polymorphisms in terms of Turkish population for the first time. Rs2232365 polymorphism associated with the disease in heterozygous genotype.What are the implications of these findings for clinical practice and/or further research? It has been shown that FOXP3 gene promoter region polymorphisms may be associated with PE for Turkish population. Our results can be a guide for more detailed statistical evaluations and functional studies.

Association of Foxp3 and TGF-β1 Polymorphisms with Pre-Eclampsia Risk in Chinese Women.

The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes that encode forkhead box p3 (Foxp3) (rs3761549 C>T, rs2280883T>C, rs2232365 A>G and rs3761548 C>A) and transforming growth factor (TGF)-β1 (rs11466359 C>T, rs11466345 A>G and rs1800469 T>C) are associated with pre-eclampsia (PE) risk in Chinese women. SNPs were identified by polymerase chain reaction and ligase detection reaction. Allelic variant and genotype frequencies for Foxp3 and TGF-β1 were compared between PE women (n = 203) and healthy pregnant (HP) controls (n = 243). The TGF-β1 rs1800469 TT genotype was found more frequently in PE patients than in HP controls [CC vs. CT+TT: odds ratio (OR) = 1.71; 95% confidence interval (CI): 1.04-2.81; p = 0.033], indicating that the T allele of rs1800469 confers a risk for PE [OR = 1.46; 95% CI: 1.12-1.92; p = 0.006]. The Foxp3 rs2232365 A allele was associated with severe PE specifically [OR = 1.70; 95% CI: 1.12-2.58; p = 0.01], compared with mild PE. There were no haplotype associations with PE. These findings indicate that allelic variants of TGF-β1 rs1800469 T influence PE risk in Chinese women. Pregnant Han Chinese women carrying the rs1800469 TT genotype were at increased risk of PE.

Association of Crohn's disease with Foxp3 gene polymorphisms and its colonic expression in Chinese patients.

BackgroundFork head/winged helix transcription factor (Foxp3) plays a pivotal role in regulatory T (Treg) cells. The present study aimed to assess the association of Crohn's disease (CD) with Foxp3 polymorphisms and its colonic expression in Chinese patients.MethodsThe Foxp3 polymorphisms, rs3761547, rs2232365, rs2294021, and rs3761548, were examined by SNaPshot in 268 CD patients and 490 controls. The colonic expression levels of Foxp3, IL‐2, and IL‐4 were detected in 31 CD patients and 31 controls using real‐time quantitative polymerase chain reaction, immunohistochemistry, and enzyme‐linked immunosorbent assay.ResultsCompared to male controls, the proportion of variant allele of rs3761547 was increased in male patients. The variant alleles of rs3761547, rs2232365, and rs2294021 were less in male patients with stricturing CD compared to those with non‐stricturing, non‐penetrating CD; however, these variants were frequently detected in male patients with colonic CD than in those with ileocolonic CD. The variant allele of rs3761548 was increased in male patients with penetrating CD compared to those with non‐stricturing, non‐penetrating CD. The colonic expression of Foxp3 was higher in CD patients than in controls (both males and females). Compared to male patients carrying wild‐type alleles, the colonic expression of Foxp3 was downregulated in male patients with variant alleles, rs3761547, rs2232365, rs2294021, and rs3761548, respectively. However, the Foxp3 polymorphisms were not significantly related with the colonic expression levels of IL‐2 and IL‐4 in CD patients (both males and females).Conclusion Foxp3 polymorphisms might increase the CD susceptibility by reducing the colonic expression of Foxp3 in male patients.

FOXP3 GENE POLYMORPHISM IS ASSOCIATED WITH BREAST CANCER IN IRANIAN PATIENTS

Breast cancer (BC) is one of the leading causes of cancer death among women. Recent studies have characterized FoxP3 as a marker of regulatory T cells and an X-linked tumor suppressor gene, which is involved in the pathogenesis of BC. Therefore, we investigated the potential influence of three single-nucleotide polymorphisms (SNPs) of FoxP3 gene on the development of BC in Iranian women. The association between FoxP3 rs2232365, rs3761548 and rs4824747 polymorphisms and BC risk was assessed in 124 BC patients and 198 healthy controls using sequence-specific primers. We identified significant difference of rs3761548 in both allele and genotype frequencies between cases and control groups. Our results showed that individuals carrying FoxP3 rs3761548 AA genotype had about 4.3-fold increased risk of BC compared with CC carriers. No significant association was found between rs3761548C>A polymorphism and clinical outcome parameters (age of onset, tumor size, lymph nodes metastasis, tumor stage, progesterone receptor status, estrogen receptor status, Ki-67 status, HER-2 status and duration of disease). This study has provided the first genetic data on the FoxP3 gene polymorphism in south of Iran and proposes the rs3761548 polymorphism of FoxP3 gene as a risk factor, but not a prognostic marker in the development of BC in Iranian population.