FOXP3 Rs3761548 Research Articles

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients

Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated in Brazilian kidney transplant recipients within the 1-year post-transplant. Two-hundred and sixty-nine kidney transplant recipients were enrolled at a kidney transplant center in São Paulo city, Brazil, and treated with tacrolimus plus everolimus or mycophenolate sodium (clinical trial NCT01354301). Clinical and laboratory data, including renal function parameters and drug blood levels were recorded. Genomic DNA was extracted from blood samples. Polymorphisms in MTOR rs1057079 (c.4731G>A), rs1135172 (c.1437T>C), and rs1064261 (c.2997C>T); PPP3CA rs3730251 (c.249G>A); FKBP1A rs6033557 (n.259+24936T>C); FKBP2 rs2159370 (c.-2110G>T); and FOXP3 rs3761548 (c.-23+2882A>C) and rs2232365 (c.-22-902A>G) were analyzed by real-time PCR. Frequencies of gene polymorphisms did not differ among the treatment groups. Analysis of primary outcomes showed that patients carrying MTOR c.1437CC and FOXP3 c.-23+2882CC genotypes had higher serum creatinine than non-carriers (p < 0.05) at 1-year post-transplant. MTOR c.4731G allele (AG+GG genotype) was associated with increased risk for acute rejection (OR = 3.53, 95% CI = 1.09–11.48, p = 0.037). Moreover, 1-year cumulative incidence of rejection was higher in MTOR c.4731G allele carriers compared to AA genotype carriers (p = 0.027). Individually, analysis of secondary outcomes revealed that FKBP2 c.-2110GG genotype carriers had higher risk of leukopenia, FKBP1A n.259+24936C allele carriers had increased risk of constipation, and FOXP3 c.-22-902A or c.-23+2882A allele had higher risk of gastrointestinal disorders (p < 0.05). However, these results were not maintained in the multivariable analysis after p-value adjustment. In conclusion, variants in genes of mTOR and calcineurin pathways are associated with long-term impaired renal function, increased risk of acute rejection, and, individually, with adverse events in Brazilian kidney transplant recipients.

Association between Multiple Sclerosis and FOXP3 Gene Promoter Region Mutations

Regulatory T-Cells (Treg Cells), as one of the immune system components, have been highly effective in the autoimmune diseases prevention, particularly multiple sclerosis (MS). MS is a chronic inflammatory and autoimmune disease characterized by immune infiltration and inflammation in the central nervous system. Regulatory T (Treg) cells play an important role in the control of autoimmunity. Expression and action of the transcription factor FOXP3 controls the development and function of Treg cell. The aim of this study was to investigate the association between MS and FOXP3 gene promoter region polymorphisms rs2232365 (-924A/G) and rs3761548 (-3279A/C) in a Turkish population. In this case-control study we investigated these polymorphisms in 80 MS patients and 80 healthy controls using PCR-RFLP methods. Results of our study showed that while there is significant correlation between MS and FOXP3 rs3761548 polymorphism (p=0.031), FOXP3 rs2232365 polymorphism, has not been found to be associated with the disease (p=0.31). As FOXP3 gene is one of the most important genes in the regulation of the immune cells, it may be concluded that the expression of this gene is important in MS patients. As this SNP is located in the promoter region of the gene, it may affect the expression level of FOXP3 protein.

FOXP3 rs3761548 polymorphism is associated with knee osteoarthritis in a Turkish population.

Functional polymorphisms located in FOXP3 intron 1 was recently found to be associated with rheumatoid arthritis (RA). Although RA is an autoimmune disease, there is supporting evidence that activated maladaptive responses including pro-inflammatory pathways play roles in osteoarthritis (OA), similar to RA. The aim of this study was to explore the relationship between rs2232365 (-924A/G) and rs3761548 (-3279A/C) polymorphisms as well as possible changes in the 600 bp promoter region of FOXP3 and knee OA. Patients with primary knee OA (n = 300) and healthy individuals (n = 300) were examined for rs3761548 and rs2232365 FOXP3 gene polymorphisms by the polymerase chain reaction-restriction fragment-length polymorphism method. The 600 bp promoter region (between -500 and +100) of the gene was also sequenced with direct sequencing in 50 knee OA patients and 50 healthy individuals. There were no sequence variants in the promoter region tested both in OA patients and healthy controls. The SNP rs2232365 showed no association with OA susceptibility and severity and the results of other genetic models were also nonsignificant. On the other hand, rs3761548 AC (P = 0.003), AA + CC (P = 0.0014) as well as AC + AA (P = 0.40) genotypes showed association with Grade 4 knee OA patients. Our findings indicated that the association between FOXP3 rs2232365 polymorphism and knee OA tended to yield negative results but the FOXP3 rs3761548 C allele was associated with elevated risk of OA in Grade 4 knee OA patients in a Turkish population.

Functional Foxp3 polymorphisms and the susceptibility to cancer: An update meta-analysis.

Background:Forkhead box P3 (Foxp3) plays important roles in the development and pathogensis of cancer. To investigate the association of 3 polymorphisms of Foxp3 (rs3761548, rs 3761549 and rs2280883) and cancer risk, an updated meta-analysis was performed.Methods:Around 11 studies including 4344 cancer patients and 4665 healthy controls were selected for this meta-analysis. There were nine studies with 3783 cases and 4096 controls for rs3761548, 4 studies with 1669 cases and 1613 controls for rs3761549 and 4 studies with 1821 cases and 1799 controls for rs2280883. Odds radios (ORs) and 95% confidence intervals (CIs) were used to evaluate the cancer risk.Results:Meta-analysis showed that rs3761548 was associated with an increased cancer risk in the overall population under the recessive model (AA vs CA + CC: OR = 1.45, 95%CI = 1.03–2.02, P = .03). No association was found between rs3761549, rs2280883 polymorphisms, and cancer susceptibility in the overall population. Nonetheless, in the genotyping methods subgroup analysis of rs2280883, a lower risk of cancer was found in studies using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) under the allelic model (C vs T: OR = 0.70, 95%CI = 0.52–0.95, P = .02), heterozygote model (TC vs TT: OR = 0.60, 95%CI = 0.41–0.87, P = .008) and dominant model (CC + TC vs TT: OR = 0.63, 95%CI = 0.45–0.90, P = .01). In the subgroup analysis by cancer types showed C allele or TC carriers were insusceptible to cancer under 3 genetic models (C vs T: OR = 0.78, 95%CI = 0.64–0.95, P = .01; TC vs TT: OR = 0.50, 95%CI = 0.32–0.79, P = .003; CC + TC vs TT: OR = 0.64, 95%CI = 0.51–0.82, P < .001).Conclusion:Our results suggest that rs3761548 polymorphism is associated with cancer risk.

The association of IL-33 and Foxp3 gene polymorphisms with recurrent pregnancy loss in Egyptian women

Deregulated immunity is one of the most important factors implicated in recurrent pregnancy loss (RPL). The possible role of interleukin-33 (IL-33) and forkhead/winged helix transcription factor (Foxp3) in RPL have not been fully investigated. We aimed to evaluate IL-33 rs1929992 and Foxp3 rs2232365 single nucleotide polymorphisms (SNPs) and their serum levels in Egyptian RPL females.Blood samples were collected from 142 RPL patients and 123 women as healthy controls. IL-33 rs1929992 SNP was determined by polymerase chain reaction restriction fragment length polymorphism and Foxp3 rs2232365 SNP was determined using allele specific polymerase chain reaction. The serum IL-33 and Foxp3 levels were measured by enzyme linked immunosorbent assay.Foxp3 rs2232365 SNP showed statistically significant association with RPL. The risk of RPL was significantly higher in women carrying Foxp3 G allele than those carrying A allele. Lower serum levels of Foxp3 and IL-33 were observed in RPL patients than controls (P < 0.001). Foxp3 serum levels were much lower in carriers of G allele than those carrying A allele in all studied groups.Foxp3 rs2232365 SNP could be considered as a risk factor for RPL. The lowered serum levels of IL-33 and Foxp3 in RPL patients suggested that they might have an important role in the pathogenesis of the disease. Therefore, we hypothesized that Foxp3 polymorphisms may be important in RPL pathogenesis.

Relationship between forkhead/winged helix transcription factor 3 gene polymorphisms and susceptibility and phenotype of Crohn′s disease

Objective To investigate the relationship between forkhead/winged helix transcription factor (Foxp) 3 gene polymorphisms and susceptibility and phenotype of Crohn′s disease (CD) in Han nationality in Zhejiang province. Methods From January 2007 to December 2015, 268 diagnosed CD patients and 490 healthy controls were enrolled. The four single nucleotide polymorphism (SNP) of Foxp3 rs3761547, rs2232365, rs2294021 and rs3761548 were examined by a SNaPshot technique, and their relation with the efficacy of infliximab was evaluated. The linkage disequilibrium (LD) and haplotype were also analyzed. Unconditional Logistic regression analysis was performed for statistical analysis. Results There was no significant difference in the four mutant alleles and genotype frequencies between 31 patients with effective infliximab treatment and 19 patients with ineffective treatment (all P>0.05). The results of LD analysis indicated that the above four SNP were in a tight linkage. The frequency of haplotype GCGC of male CD group was 29.20% (40/137), which was higher than that of male healthy control group (19.37%, 43/222), and the difference was statistically significant (odd ratio (OR)=1.717, 95% confidence interval (CI) 1.045 to 2.820, P=0.032). The frequency of haplotype ACGA of female CD group was 13.36% (35/262), which was lower than that of female healthy control group (19.03%, 102/536), and the difference was statistically significant (OR=0.656, 95%CI 0.433 to 0.995, P=0.046). The frequency of haplotype ATAC of male colon (L2) type was 25.93% (7/27), which was lower than that of ileocecal colon (L3) type (75.38%, 49/65), and the difference was statistically significant (OR=0.114, 95%CI 0.041 to 0.320, P<0.01). The frequency of haplotype GCGC of male L2 type was 51.85% (14/27), which was higher than that of L3 type (9.23%, 6/65), and the difference was statistically significant (OR=10.590, 95%CI 3.423 to 32.758, P<0.01). The frequency of haplotype ATAC of male stenotic (B2) type was 73.21% (41/56), which was higher than that of nonstenotic and nonpenetrated (B1) type(47.30%, 35/74), and the difference was statistically significant (OR=0.328, 95%CI 0.156 to 0.693, P=0.003). The frequency of haplotype GCGC of male B2 type was 17.86% (10/56) which was lower than that of nonstenotic and nonpenetrated (B1) type (39.19%, 29/74), and the difference was statistically significant (OR=2.946, 95%CI 1.295 to 6.784, P=0.009). The frequency of haplotype ACGA of male penetrated (B3) type was 71.43% (5/7), which was higher than that of nonstenotic and nonpenetrated (B1) type (12.16%, 9/74), and the difference was statistically significant (OR=0.055, 95%CI 0.009 to 0.329, P<0.01). Conclusion Foxp3 (rs3761547, rs2232365, rs2294021, rs3761548) gene polymorphisms are associated with the susceptibility and phenotype of CD in Chinese Han patients, but not related with the efficacy of infliximab. Key words: Crohn disease; Genes; Polymorphism, single nucleotide; Forkhead/winged helix transcription factor 3

Association of Foxp3 Polymorphism With Allograft Outcome in Kidney Transplantation.

BackgroundForkhead box P3 (Foxp3) is the most reliable marker for regulatory T cells, which play an important role in maintaining renal allograft tolerance. Recently, Foxp3 polymorphisms have been reported to be associated with graft outcome in kidney transplantation. We analyzed the association of Foxp3 polymorphisms with renal allograft outcome.MethodsFoxp3 polymorphisms (rs3761548 A/C, rs2280883 C/T, rs5902434 del/ATT, and rs2232365 A/G) were tested by PCR with sequence-specific primers (PCR-SSP) in 231 adult kidney transplantation recipients from 1996-2004 at Seoul National University Hospital.ResultsPatients with the rs3761548 CC genotype showed better graft survival than those with the AC or AA genotype (log rank test, P=0.03). Patients with the rs3761548 CC genotype also showed a lower rate of recurrence of the original glomerular disease than those with the AC or AA genotype (P=0.01). The frequency of acute rejection (AR) in patients with the rs2280883 TT genotype was lower than that in patients with the rs2280883 CT or CC genotype (26.9% vs 53.3%, P=0.038). Patients with the rs2280883 TT genotype also showed better graft survival than those with the CT or CC genotype (P=0.03).ConclusionsFoxp3 rs3761548 CC and rs2280883 TT genotypes were associated with superior graft outcome of kidney transplantation. Further studies involving a larger number of patients are needed.

Pharmacogenetic markers to predict the clinical response to methotrexate in south Indian Tamil patients with psoriasis.

Despite the advent of several new systemic therapies, methotrexate remains the gold standard for the treatment of moderate to severe psoriasis. However, there exists a significant heterogeneity in individual response to methotrexate. There are no consistently reliable markers to predict methotrexate treatment response till date. We aimed to demonstrate the association of certain genetic variants in the HLA (HLA-A2, HLA-B17, and HLA-Cw6) and the non-HLA genes including T-helper (Th)-1, Th-2, Th-17 cytokine genes (IFN-γ, IL-2, IL-4, IL-10, IL-12B, and IL-23R), and T-regulatory gene (FOXP3) with the methotrexate treatment response in South Indian Tamil patients with psoriasis. Of the 360 patients recruited, 189 patients with moderate to severe psoriasis were treated with methotrexate. Of the 189 patients, 132 patients responded to methotrexate and the remaining 57 patients were non-responders. We analyzed the association of aforesaid polymorphisms with the methotrexate treatment outcome using binary logistic regression. We observed that there were significant differences between genotype frequencies of HLA-Cw6 and FOXP3 (rs3761548) among the responders compared to non-responders, with conservative estimation. We observed that pro-inflammatory cytokines such as IFN-γ, IL-2, IL-12, and IL-23 were markedly reduced with the use of methotrexate, in comparison to the baseline levels, while the plasma IL-4 levels were increased posttreatment. Our results serve as preliminary evidence for the clinical use of genetic markers as predictors of response to methotrexate in psoriasis. This might aid in the future in the development of a point-of-care testing (POCT) gene chip, to predict optimal treatment response in patients with psoriasis, based on their individual genotypic profile.

T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort

BackgroundPsoriasis is known to be associated with an up-regulation of T-helper (Th)-1 & Th-17 cytokines and a relative down-regulation of Th-2 and T-regulatory (T-reg) cytokines. Certain allelic variants of these cytokine genes may alter Th1/Th17 and Th2/T-reg balance and may be associated with the risk of psoriasis. Hence we aimed to determine the association of IL-4 (rs2243250), IL-10 (rs1800871 and rs1800896) and FOXP3 (rs3761548) gene polymorphisms with risk of psoriasis in South Indian Tamils. MethodsA total of 360 cases of psoriasis and 360 healthy controls were recruited. The polymorphism in IL-4 (rs2243250) & IL-10 (rs1800871) were typed by ARMS-PCR and IL-10 (rs1800896) & FOXP3 (rs3761548) were typed by TaqMan 5′allele discrimination assay. ResultsWe observed that IL-4 (rs2243250) had a reduced risk of psoriasis, while the IL-10 (rs1800871) conferred an increased susceptibility to psoriasis, as compared with controls. However, IL-10 (rs1800896) and FOXP3 (rs3761548) gene polymorphisms were not associated with psoriasis risk. The plasma IL-4 levels was not different between the cases and controls, however the heterozygous CT genotype demonstrated significant high IL-4 levels. Plasma IL-10 levels were significantly increased in cases compared to controls, however none of the genotypes were associated with the plasma IL-10 levels. ConclusionOur results suggest that IL-4 (rs2243250) polymorphism is protective against psoriasis, while IL-10 (rs1800871) polymorphism confers increased risk of psoriasis in South Indian Tamils. Detection of these genetic variants as predictive risk factors may lead to the selection of patient-tailored therapy to maximize the effectiveness of therapy.

Impact of FOXP3 Polymorphisms on the Blood Level of Tacrolimus in Renal Transplant Recipients.

Tacrolimus is an immunosuppressive medication for organ transplantation. FOXP3(+) T regulatory cells (Tregs) play roles in suppression of rejection and induction of graft tolerance. This study aimed to evaluate the correlation between the polymorphism of FOXP3 and the blood level of tacrolimus in renal transplant recipients. This retrospective study included 100 renal transplant recipients receiving tacrolimus treatment and 100 healthy control subjects. Genotyping for FOXP3 rs3761547 AA, AG, GG, rs3761548 AA, AC, CC and rs223236 AA, AG, GG was performed. Concentrations of tacrolimus, creatinine, and urea nitrogen levels in blood were measured. Frequencies of genotypes of FOXP3 rs3761548 AA, AC, and CC, rs3761547 AA, AG, GG and rs 223236 AA, AG, GG in renal transplant recipients were similar to those in normal people. The blood level of tacrolimus in recipients with rs3761548 CC was significantly higher than that in recipients with rs3761548 AA and AC (P< .001). No difference in the blood level of tacrolimus was found in recipients with different genotypes of rs3761547 and rs223236. Compared to rs3761548 AA and AC groups, there was no difference of Modification of Diet in Renal Disease (MDRD) glomerular filtration rate and the level of blood urea nitrogen before transplantation; however, these 2 parameters were significantly improved after transplantation in the rs3761548 CC group. The level of tacrolimus was correlated positively with MDRD glomerular filtration rate and negatively with the blood urea nitrogen level in recipients with rs3761548 CC genotype after transplantation. Our study identified a new relationship between FOXP3 rs3761548 and the blood level of tacrolimus. These results suggest that the polymorphism of FOXP3 may affect tacrolimus pharmacokinetics.

Association of functional genetic variants of transcription factor Forkhead Box P3 and Nuclear Factor-κB with end-stage renal disease and renal allograft outcome

BackgroundThe transcription factor FOXP3 and NF-κB regulates the expression of various genes that play an important role in the regulation of renal inflammation. We investigated the association of FOXP3 (rs2232365, rs3761548, rs5902434 and rs2294021) and NF-κB1 (rs28362491 and rs696) gene variants in susceptibility and prognosis of end stage renal disease (ESRD) and renal allograft outcome. MethodsWe genotyped four common polymorphisms of FOXP3 and two-tag SNPs of NF-κB1 genes in 350 ESRD cases and 350 controls. Single marker analysis and SNP–SNP interaction model (one to six way combinations) was used for determination of clinical outcome of ESRD and acute rejection episode (ARE). ResultsWe observed significantly higher occurrence of mutant genotypes of tag-SNPs of FOXP3 namely; rs2232365 and rs3761548 along with NF-kB1 namely; rs28362491 and rs696 in ESRD and ARE cases, suggested a risk association for ESRD and ARE. Interestingly, multifactor dimension reduction analysis suggested an increased risks of nearly 6-folds for ESRD and 23-folds for ARE cases under the six factors model which consists of tag-SNPs of FOXP3 (rs2232365, rs3761548, rs5902434 and rs2294021) and NF-kB1 (rs28362491 and rs696). Kaplan–Meier survival analysis showed the lowest overall survival for mutant genotypes compared with wild and heterozygous genotypes of rs2232365 and rs3761548 tag SNPs of FOXP3 as well as NF-kB1 tag-SNPs rs28362491 and rs696 in renal allograft recipients. The crude and adjusted hazard ratios in univariate and multivariate Cox regression models showed almost 2-folds to 3-folds risk for overall survival against mutant genotypes of tag-SNPs of FOXP3 (rs2232365 and rs3761548) and NF-kB1 (rs28362491 and rs696) genes. ConclusionsThese results suggest that variants of transcription factor FOXP3 and NF-kB1 might be associated with increased risk to the clinical outcome of ESRD and renal allograft survival.

Association between single-nucleotide polymorphisms of key genes in T regulatory cells signaling pathways and the efficacy of allergic rhinitis immune therapy

To investigate the genetic association pattern between single-nucleotide polymorphisms (SNP) of key genes in T regulatory cells signaling pathways and the efficacy of allergic rhinitis (AR) specific immune therapy(SIT). A population of 102 AR patients(Beijing Tongren hospital, from January to Decemeber 2012) caused by simple dust mite received standardized specific immune therapy, who lived in Beijing region was recruited. In immunotherapy before and after 1 years of treatment, the study objects were scored by nasal symptoms score, nasal signs score and total score of daily life distress three indicators to assess the efficacy. A total of 43 reprehensive marker SNP which were in FOXP3, IL-2, TGF-βand EBI3 gene regions and the upstream and downstream 1 000 kb were selected according to the Beijing people database from Hapmap website. The individual genotyping was performed by MassARRAY platform.Plink software was used for statistic analysis. Subgroup analysis for the efficacy evaluation of three indicators displayed that IL-2_rs77468365, FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the improvement of sneezing in nasal symptoms. IL-2_rs77468365, FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the improvement of runny nose in nasal symptoms. TGF-β(rs747857, rs6508975, rs2241715, rs12462166, rs12983775, rs1800470 and rs2317130)and FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of nasal obstruction in nasal symptoms. FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of nasal itching in nasal symptoms. IL-2_rs77468365 and FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the overall improvement in nasal symptoms. EBI3_rs670188 and FOXP3(rs2280883, rs2232365, rs3761549, rs3761548 and rs3761547) were associated with the improvement of inferior turbinate mucosa swelling in nasal signs. IL-2_rs77468365, EBI3_rs393581, TGF-β(rs11466359 and rs11466345), FOXP3(rs2280883, rs17847095, rs2232365 and rs3761548)were associated with the improvement of inferior turbinate mucosa color in nasal signs. EBI3(rs393581, rs4740 and rs353702), FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of water discharge in nasal signs. IL-2_rs77468365, EBI3(rs393581, rs4740 and rs353702), FOXP3( rs2280883, rs2232365 and rs3761548)were associated with the overall improvement in nasal signs. TGF-β(rs12461895, rs2241717 and rs7258445), FOXP3(rs2280883, rs2232365, rs3761549, rs3761548 and rs3761547)were associated with the improvement of life puzzle. The genetic polymorphism (SNPs) of four important functional candidate genes( FOXP3, IL-2, TGF-βand EBI3) in T regulatory cells signaling pathways were detected in significant correlation with the efficacy of allergic rhinitis specific immune therapy.

Association of FoxP3 rs3761548 polymorphism with susceptibility to colorectal cancer in the Chinese population.

The aim of the present study was to determine the association of the Forkhead box P3 (FoxP3) rs3761548 polymorphism with the risk of colorectal cancer (CRC). Polymorphism genotyping was detected with polymerase chain reaction-polyacrylamide gel electrophoresis (PCR-PAGE), and data revealed that the AA, AC, and the combined A variant genotype (AA+AC) conferred a significantly greater risk of CRC [OR (95% CI) = 2.806 (1.726-4.563), 1.54 (1.121-2.11), and 1.797 (1.344-2.404), respectively]. Moreover, the A allele of rs3761548 was observed to be associated with higher susceptibility of CRC [OR (95% CI) = 1.792 (1.424-2.254)]. Unfortunately, no significant association was observed between the two subgroups after stratification by clinical characteristics including age; gender; tumor size, growth pattern, or differentiation; lymph node metastasis; and TNM pathological stage. Thus, we concluded that the FoxP3 gene polymorphism contributes to CRC susceptibility in a Chinese population.

Association between FOXP3 promoter polymorphisms and cancer risk: A meta-analysis

Epidemiological studies have been conducted to investigate the association between the FOXP3 promoter polymorphisms, rs3761549 and rs3761548, and the risk of cancer. However, the results from these studies have been controversial. In order to obtain a more precise conclusion of this association, the present meta-analysis was performed. The odds ratio (OR) and 95% confidence interval (95% CI) values were used to assess any correlations between the data. Overall, the rs3761549 (C>T) and rs3761548 (C>A) polymorphisms of the FOXP3 gene were not associated with the cancer risk in an Asian population. In the subgroup analyses based on cancer type, no significant associations were identified between these two polymorphisms and breast cancer. However, the results altered when the analyses were restricted to hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) (for rs3761549: TT+CT vs. CC OR, 0.52, 95% CI, 0.38–0.72; TC vs. CC OR, 0.25, 95% CI, 0.16–0.39; T vs. C OR, 0.76, 95% CI, 0.59–0.97. For rs3761548: AA vs. AC+CC OR, 3.20, 95% CI 1.76–5.81; AA+AC vs. CC OR, 2.56, 95% CI, 1.75–3.76; AA vs. CC OR, 4.41, 95% CI, 2.36–8.25; AC vs. CC OR, 2.15, 95% CI, 1.42–3.25; A vs. C OR, 2.32, 95% CI, 1.74–3.10). The present meta-analysis indicates that the FOXP3 rs3761549 (C>T) and rs3761548 (C>A) polymorphisms are not associated with the risk of breast cancer, but with the risk of HCC and NSCLC. Therefore, a study with a larger sample size is required to further evaluate this association.

The serum level of transforming growth factor beta1 and its association with Foxp3 gene polymorphism in Iranian women with recurrent spontaneous abortion

The aim of the study was to determine the role of transforming growth factor-beta1 (TGF-β1) and Foxp3 (rs3761548) promoter polymorphisms in Iranian women with recurrent spontaneous abortion (RSA). Eighty women with RSA were compared with eighty in a control group. Serum levels of TGF-β1 were measured using ELISA and Foxp3 (rs3761548) promoter polymorphisms using a PCR-RFLP technique. In addition, serum levels of TGF-β1 were compared in different genotypes in the two groups. The women's ages in the two groups were similar (30.15 ± 4.42 years [RSA] vs. 29.97 ± 4.51 [control]) as were serum TGF-β1 concentrations in case and control groups (53.42 ± 2.08 ng/ml in control and 56.31 ± 2.58 ng/ml in the RSA group; p = 0.4). Furthermore, there was no significant difference in the genotype frequencies of the rs3761548 Foxp3 gene between the two groups (p = 0.3) and the levels of TGF-β1 were similar in different genotypes. In conclusion, the data indicate that serum TGF-β1 levels and Foxp3 (rs3761548) promoter polymorphism is not a risk factor for RSA and that there is no association between the polymorphism and serum TGF-β1 levels.

Association of FOXP3 gene polymorphism in Chinese women with endometriosis

To assess the association between single nucleotide polymorphisms (SNPs) of forkhead box P3 gene (FOXP3) and endometriosis in Chinese Han women from central China. MassARRAY IPLEX and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) technique was used to determine the genotypes of FOXP3 gene in 314 patients with endometriosis and 358 healthy controls. Genotypes of C/T polymorphism for the rs2280883 locus, A/C for the rs3761548 locus, and C/T for the rs3761549 locus were determined. No significant difference was detected in distribution of genotypes CC, CT and TT (P=0.770, OR=0.960; P=0.923, OR=1.013) and frequencies of C and T alleles (P=0.772, OR=0.960; P=0.925, OR=1.013) for rs2280883 and rs3761549 between the two groups. And no significant difference was detected in distribution of genotypes AA, AC and CC (P=0.762, OR=0.958) and frequencies of A and C alleles (P=0.715, OR=0.950) for rs3761548 was detected between the two groups. Based on r-AFS classification, the patients were divided into two groups (respectively with I-II stage and III-IV stage endometriosis). Again, no significant difference was detected in distribution of genotypes CC, CT and TT (P=0.454, OR=1.198, P=0.526, OR=0.909; P=0.220, OR=0.750, P=0.548, OR=1.094) and frequencies of C and T alleles (P=0.473, OR=1.215, P=0.532, OR=0.912; P=0.204, OR=0.737, P=0.558, OR=1.089) for rs22080883 and rs3761549 loci between the two patient groups. No association was found between distribution of genotypes AA, AC and CC (P=0.431, OR=1.211; P=0.508, OR=0.905) and frequencies of A and C alleles (P=0.417, OR=1.226; P=0.516, OR=0.908) for rs3761548 locus between the two patient groups. Our study has failed to found any association between FOXP3 gene polymorphisms rs2280883, rs3761548 and rs3761549 with endometriosis in Chinese Han patients.

Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients

FOXP3 gene is known to be important for regulatory T cell development and function, and is associated with the rejection of human kidney transplants. The present study was therefore conducted to determine the effect of FOXP3 polymorphisms on allograft rejection in renal transplant recipients. A total of 166 adult patients were categorized into either a Rejection group (65 patients) or a No rejection group (101 patients). Rs3761547, rs3761548 and rs2232365 variant alleles in the FOXP3 gene were genotyped using a TaqMan probe technique, and their relationships with rejection were investigated. There was no significant difference in the genotype frequencies of rs3761547 and rs2232365 variants between patients with and without rejection history (P > 0.05). Binary logistic regression analysis showed that the rs3761548 AA genotype carriers were associated with about a fourfold greater risk for rejection compared with CC genotype (5 years post-transplant: odds ratio 3.95, 95% confidence interval 1.27-12.29, P = 0.018). Kaplan-Meier analysis revealed a lower mean time to the first rejection in rs3761548 AA compared with CC genotype patients (Log rank = 4.303, P = 0.038). Multivariate Cox regression analysis indicated that rs3761548 AA genotype carriers have up to about a twofold (hazard ratio 2.37, 95% confidence interval 1.17-4.80, P = 0.017) higher risk for rejection than CC carriers. Our study suggests an association between FOXP3 rs3761548 polymorphisms and allograft rejection in renal transplantation. This association should be further proven in large prospective studies because of the small sample size and confounding factors in this retrospective study.