CTLA-4 Polymorphisms Research Articles

CTLA-4 polymorphisms: influence on transplant-related mortality and survival in children undergoing allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for a variety of hematological diseases; however, it is still associated with substantial morbidity and mortality. Transplant-related mortality (TRM) after HSCT depends mainly on the toxicity of the conditioning regimen, infections, and graft-versus-host disease. The purpose of this study was to identify the association between CTLA-4 single nucleotide polymorphisms and TRM in children undergoing allogeneic HSCT. 153 donors and 153 children with acute lymphoblastic leukemia, acute myeloid leukemia or juvenile myelomonocytic leukemia who had undergone allogeneic HSCT were genotyped of CTLA-4 gene for rs3087243 (CT60G>A), rs231775 (+ 49 A>G) and rs4553808 using TaqMan real-time polymerase chain reaction. We observed a significant association between the donor's CLTA-4 genotype of rs3087243 and TRM in children undergoing allogeneic HSCT. Genotype AG was found in 78 donors (51%), GG in 44 donors (29%) and 31 donors (20%) were homozygous for AA. 30 patients died as a result of transplant-related causes. Interestingly, we observed a significantly reduced TRM in children who were transplanted from a donor with the CTLA-4 genotype GG in comparison to genotype AG or AA (9 versus 19 versus 36%, P = 0.013). In addition, we found significant differences of event-free survival (EFS) depending on the donor's genotype. The EFS was 64, 46 or 32% if the patient was transplanted from a donor with CTLA-4 genotype GG, AG or AA, respectively (P = 0.043). In multivariate analysis, CTLA-4 genotype of rs3087243 was an independent risk factor for TRM (P = 0.011) and EFS (P = 0.035). This study provides first evidence that the CTLA-4 polymorphisms are significant risk factors for TRM and survival in children undergoing allogeneic HSCT and should be evaluated in further trials.

CTLA4 gene polymorphisms associated with insulindependent diabetes mellitus (IDDM) type I in Iraqi population

This study was correlated to evaluate polymorphisms in CTLA4 associated with insulin-dependent diabetes mellitus in a Iraqi population. Blood samples were collected from 40 patient (4-25 years) from 1/6/2010- 1/2/2011, isolation of DNA were done and PCR was performed using primer for CTLA4 gene. The result shows that 31 patients have mutation in 49 position A/G polymorphism in exon 1 of CTLA4 by using BstEII enzyme. There is a highly significant correlation between diabetes and incidence of A/G 49 position in exon 1 of CTLA4 gene (X2 = 32.1, P>0.05), the conclusion is that there is enough evidence to support the claim that diabetes is related to A/G 49 transition mutation

Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies

Background/Aims: CTLA-4 polymorphisms are associated with susceptibility to various cancers, but the results are often conflicting. Hence, we performed a comprehensive meta-analysis to quantitatively investigate the association between CTLA-4 polymorphisms (rs231775, rs4553808，rs5742909, rs3087243 or rs733618) and cancer risk. Methods: Data were collected from PubMed and Web of Science. A total of 67 case-control studies were selected for quantitative analysis. Stata (Version 12) software was used to calculate the odds ratio (OR) and 95% confidence interval (CI) to evaluate the strength of the associations. Subgroup meta-analysis was conducted based on ethnicity and cancer type. Heterogeneity tests, sensitivity analysis, and publication bias assessments were also performed. Results: rs231775, rs4553808 and rs5742909 but not rs3087243 and rs733618 were significantly related to cancer risk. In analyses stratified by ethnicity, both rs231775 and rs4553808 were significant susceptibility polymorphisms in an Asian population but not in a Caucasian population. Moreover, there were stronger associations between the rs231775 polymorphism and increased risk of bone, breast, liver, head and neck and pancreatic cancers. Additionally, rs4553808 was associated with significantly increased susceptibility to breast cancer and head and neck cancer. Conclusion: rs231775, rs4553808 and rs5742909 may be used as predictive genetic biomarkers for cancer predisposition. Combined detection of CTLA-4 SNPs could be a useful tool for prediction of cancer susceptibility in clinical practice.

CTLA-4 gene polymorphisms are associated with obesity in Turner Syndrome.

Turner syndrome (TS) is characterized by a set of clinical conditions, including autoimmune/inflammatory diseases and infectious conditions, that can compromise a patient’s quality of life. Here we assessed polymorphisms in CTLA-4 +49A/G (rs231775), PTPN22 +1858G/A (rs2476601), and MBL2 -550 (H/L) (rs11003125), -221(X/Y) (rs7096206) and exon 1 (A/O) in women from northeastern Brazil to determine whether polymorphisms within these key immune response genes confer differential susceptibility to clinical conditions in TS. A case-control genetic association study was performed, including 86 female TS patients and 179 healthy women. An association was observed for the A/G genotype of CTLA-4 +49A/G in TS patients (p=0.043, odds ratio [OR]=0.54). In addition, an association between the CTLA-4 G/G genotype and obesity was detected in TS patients (p=0.02, OR=6.04). Regarding, the -550(H/L) polymorphism in the MBL2 promoter, the frequency of the H/L genotype was significantly higher in the TS group than healthy controls (p=0.01, OR=1.96). The H/H genotype indicated a protective effect in TS patients (p=0.01, OR=0.23). No differences were observed in the distribution of -221(X/Y), MBL2 exon 1 variants, and PTPN22 +1858G/A in any assessed groups. CTLA-4 variants are potentially involved in obesity in this cohort of TS patients from northeastern Brazil.

The Influence of Genetic Variations in the CD86 Gene on the Outcome after Allogeneic Hematopoietic Stem Cell Transplantation.

CD86 molecule is the ligand for both costimulatory (CD28) and coinhibitory (CTLA-4) molecules, and it regulates immune response after allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we postulate that CD86 gene variations might influence the outcome after alloHSCT. Altogether, 295 adult patients (pts) undergoing related (105 pts) and unrelated (190 pts) donor-matched HSCT were genotyped for the following CD86 gene polymorphisms: rs1129055, rs9831894, and rs2715267. Moreover, the donors' rs1129055 polymorphism was determined. None of the investigated SNPs alone were associated with aGvHD and rate of relapse. However, we showed that rs2715267 SNP influenced overall survival (OS) after alloHSCT. The 24-month OS for the rs271526GG recipients was worse than that for the recipients possessing T allelle (TT or GT genotypes) (p = 0.009). Moreover, analysis of gene-gene interaction between CD86 and CTLA-4 showed that having both the A allele for CD86 rs1129055 and the CTLA-4 CT60GG genotype in recipients increased the risk of aGvHD about 3.5 times. Interestingly, the donors' rs1129055GG genotype and the recipients' CT60GG genotype also increased the risk of aGvHD about 2.7-fold. We postulate that recipients' CD86 gene polymorphisms influence the overall survival after alloHSCT and, together with CTLA-4 polymorphisms, might be considered a risk factor for aGvHD.

Functional Polymorphisms of CTLA4 Associated with Aggressive Periodontitis in the Chinese Han Population

Background/Aims: CTLA4 has been identified functioning as a protein receptor which functions as an immune checkpoint, downregulating the immune system. Susceptibility to aggressive periodontitis (AgP) is influenced by gene polymorphisms related to the immune response. In this study, we focused on SNPs in the 3’-UTR of CTLA4 among Chinese AgP patients, and investigated any further relationships between the SNPs and miRNAs. Methods: This case–control study included 120 AgP patients and 150 healthy controls. Genotyping was used to detect allele distribution. Cell transfection and the dual luciferase reporter assay were performed to investigate the potential functions of SNPs located in the 3’UTR of CTLA4. Results: The data show that patients with a history of smoking were more susceptible compared to controls, exhibiting deeper probing depth, greater attachment loss and more sites of bleeding on probing. The results of genotyping analysis revealed that individuals with the GA and AA genotypes, and with the A carrier had a decreased risk (P = 0.015, P = 0.03). Furthermore, patients with the G allele might be regulated by miR-105, which caused a down-regulation of CTLA4. The carriers of the GG genotype exhibited the worst results of attachment loss and bleeding on probing. Conclusion: These findings show that rs56102377 in the 3’-UTR of CTLA4 may act as a protective factor by disrupting the regulatory role of miR-105 in CTLA4 expression. Thus, our study highlighted a potential role of these polymorphisms as genetic susceptibility biomarkers of periodontitis in Chinese Han populations.

CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens.

Single-nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte antigen-4 (CTLA-4) are important risk factors associated with autoimmune diseases and malignancies. This study explored the association of CTLA-4SNPs with the development of myeloma and evaluated the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4SNPs. Peripheral blood samples from 86 patients with multiple myeloma (MM) and 154 healthy controls were obtained to investigate CTLA4 polymorphisms. Five SNP genotypes of CTLA-4, namely, -1772 (rs733618), -1661 (rs4553808), -318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were evaluated through TaqMan SNP genotyping assays (Applied Biosystems). Some of the CTLA-4 polymorphisms displayed frequencies that vary among ethnic groups. Kaplan-Meier analysis revealed that patients with rs733618 GG showed a significantly lower disease-free survival (0 vs. 57.4%, P = 0.020) and overall survival (46.3 vs. 83.3%, P = 0.026) than those with GA+AA following bortezomib-based therapy. Multivariate analyses showed that rs733618 GG was a risk factor for OS (HR = 0.012; 95% CI = 0.001-0.199; P = 0.002). The incidence of nonhematologic grade 3/4 adverse events significantly increased in the rs4553808 GG+GA group compared with that in the AA group (P = 0.036). CTLA-4 rs733618 GG reduced the progression-free survival and the overall survival of patients with MM who received bortezomib-based therapy. Information regarding CTLA-4 polymorphisms and haplotypes may be used to improve MM therapy. Future studies must determine the precise effect of CTLA-4 polymorphisms and haplotypes on MM therapy outcomes by using different cohorts with a large number of subjects.

The effect of CTLA-4 and CD28 gene variants and circulating protein levels in patients with gastric cancer

Abstract Objective Gastric cancer is one of the most common malignancies worldwide. The risk factors for gastric cancer include environmental and genetic factors. Inflammation and the immune system are known to contribute to the development of the gastric cancer. We examined the influence of critical polymorphisms of CTLA-4 and CD28 genes and circulating protein levels on the etiology of gastric cancer. Methods Genotyping of SNPs was performed in 55 gastric cancer patients and 105 healthy individuals using the PCR-RFLP method, and circulating levels of sCTLA-4 and sCD28 were measured. Results There were no significant differences in the genotype and allele distributions of the evaluated SNPs [CTLA-4-318 C>T (rs5742909), CTLA-4+49 A>G (rs231775), CD28 C>T (rs3116496)] between gastric cancer patients and controls (p=0.36, p=0.78, and p=0.80, respectively). The circulating levels of sCTLA-4 and sCD28 were significantly different between the gastric cancer group and the control group (p<0.001 and p<0.001, respectively). Conclusion The present results suggest that the CTLA-4 and CD28 gene polymorphisms that were evaluated do not play an important role in Turkish patients with gastric cancer. However, sCTLA4 and sCD28 levels were higher in cancer patients and may be useful as an auxiliary parameter in the diagnosis and monitoring of gastric cancer.

Altered vulnerability to asthma at various levels of ambient Benzo[a]Pyrene by CTLA4, STAT4 and CYP2E1 polymorphisms

BackgroundWithin fossil- and solid-fuel dependent geographic locations, mechanisms of air pollution-induced asthma remains unknown. In particular, sources of greater genetic susceptibility to airborne carcinogen, namely, benzo[a]pyrene (B[a]P) has never been investigated beyond that of a few well known genes. ObjectivesTo deepen our understanding on how the genotypic variations within the candidate genes contribute to the variability in the children's susceptibility to ambient B[a]P on doctor-diagnosed asthma. MethodsClinically confirmed asthmatic versus healthy control children (aged, 7–15) were enrolled from historically polluted and rural background regions in Czech Republic. Contemporaneous ambient B[a]P concentration was obtained from the routine monitoring network. The sputum DNA was genotyped for 95 genes. B[a]P interaction with SNPs was studied by two-stage, semi-agnostic screening of 621 SNPs. ResultsThe median B[a]P within the highly polluted urban center was 8-times higher than that in the background region (7.8 vs. 1.1 ng/m3) during the period of investigation. Within the baseline model, which considered B[a]P exposure-only, the second tertile range was associated with a significantly reduced odds (aOR = 0.28) of asthma (95% CI, 0.16 to 0.50) compared to those at the lowest range. However, the highest range of B[a]P was associated with 3.18-times greater odds of the outcome (95% CI, 1.77 to 5.71). Within the gene-environment interaction models, joint occurrence of a high B[a]P exposure range and having a high-risk genotype at CTLA4 gene (rs11571316) was associated with 9-times greater odds (95% CI, 4.56–18.36) of the asthma diagnosis. Similarly, rs11571319 at CTLA4 and a high B[a]P exposure range was associated with a 8-times greater odds (95% CI, 3.95–14.27) of asthma diagnosis. Furthermore, having TG + GG genotypes on rs1031509 near STAT4 was associated with 5-times (95% CI, 3.03–8.55) greater odds of asthma diagnosis at the highest B[a]P range, compared to the odds at the reference range. Also CYP2E1 AT + TT genotypes (rs2070673) was associated with 5-times (95% CI, 3.1–8.8) greater odds of asthma diagnosis at the highest B[a]P exposure. ConclusionsThe children, who jointly experience a high B[a]P exposure (6.3–8.5 ng/m3) as well as susceptible genotypes in CTLA4 (rs11571316 and rs11571319), STAT4 (rs1031509), and CYP2E1 (rs2070673), respectively, are associated with a significantly greater odds of having doctor-diagnosed asthma, compared to those with neither risk factors.

968 - IFN alpha modulates the response to BCG immunotherapy in bladder cancer patients with specific CTLA4 and CD28 single nucleotide polymorphisms

968 - IFN alpha modulates the response to BCG immunotherapy in bladder cancer patients with specific CTLA4 and CD28 single nucleotide polymorphisms

Is the Genetic Background of Co-Stimulatory CD28/CTLA-4 Pathway the Risk Factor for Prostate Cancer?

The impairment of immunological surveillance caused by aberrant T cell activation can lead to an inadequate anti-tumor response. Therefore, deregulation in co-stimulatory pathway might be associated with cancer susceptibility. Here we undertook a prospective study to investigate whether genetic variations in gene encoding molecule CD28 and CTLA-4 playing pivotal role in regulating adoptive immune response can influence susceptibility to prostate cancer. Single nucleotide polymorphisms (SNPs) in CTLA-4 and CD28 genes were genotyped in 301 prostate cancer (PCa) patients and 301 controls. The distributions of the genotypes and haplotypes in the CTLA-4/CD28 SNPs were similar in both studied groups. However, the overrepresentation of carriers of CTLA-4c.49A>G[A] allele and carriers of CTLA-4g.319C>T[T] allele in PCa as compared to controls was observed (p = 0.082 and p = 0.13, respectively). The risk of disease was higher (OR 1.78) for carriers of both susceptibility alleles as compared to carriers of protective genotypes (p = 0.03). The CTLA-4c.49A>G and CTLA-4g.319C>T SNPs might be considered as low risk susceptibility locus for PCa.

Polymorphisms of the Costimulatory Genes CTLA-4, CD28, PD-1, and ICOS and Outcome of Kidney Transplants in Iranian Patients.

Costimulatory molecules are important factors determining the outcome of transplant. The aim of the present study was to investigate the effect of CTLA-4, CD28, PD-1, and ICOS gene polymorphisms on the outcome of kidney transplant. A total of 172 kidney transplant recipients were included in this study. There were 45 recipients (26%) who experienced acute rejection. The CTLA-4, PD-1, ICOS, and CD28 gene polymorphisms were evaluated by polymerase chain reaction and restriction fragment length polymorphism methods. There were no differences between kidney transplant recipients with or without acute rejection in the distribution of genotypes and alleles of studied costimulatory molecules. Significant associations were observed between the AA genotype and the A allele of CTLA-4 1661 (P = .04, P = .05) and also CT and TT genotypes of PD-1.9 in the male compared with female subgroup of patients, with low frequency in the acute rejection group (P = .03; P = .04). Significant associations were observed between the AA genotype and the A allele of CTLA-4 -1661 (P = .02; P = .01) and also GA genotype of PD-1.3 (P = .03) in the male subgroup compared with female subgroup with low frequency of acute rejection. A significant association was observed between TC genotype of CD28 in the female compared with male subgroup of patients with high frequency of acute rejection (P = .05). The above results suggest that genetic polymorphisms of costimulatory molecules function as sex-dependent risk factors for development of acute rejection. Further studies are needed in different populations.

CD28, CTLA-4 and CCL5 gene polymorphisms in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint destruction caused by infiltrating leukocytes including T cells. An important role in T cell co-stimulation is played by the CD28, as a stimulatory signal transducer and the inhibitory CTLA-4. CCL5 is produced by circulating T cells and plays an active role in the chemotactic activity of T cells in RA. The aim of this study was to examine the associations between polymorphisms within CD28, CTLA-4, and CCL5 genes and RA. We examined 422 patients (340 female, 82 male, mean age 57.5±12.5years) with rheumatoid arthritis and 338 healthy subjects (261 female, 77 male). Disease activity was determined on the basis of DAS28 score. The patients with DAS28 of ≤2.5 were classified as subjects in remission of disease symptoms; the patients who had DAS28 of >2.5 were classified as subjects with active form of RA. There were no statistically significant differences in the distribution of studied genotypes and alleles between RA patients and the control group. A statistically significant difference was observed in the distribution of CTLA4 exon 1 +49A>G rs231775 genotypes between patients with DAS28 ≤2.5 and DAS28 >2.5 where the increased frequency of AA genotype among patients with DAS28 >2.5 was revealed (OR 1.55; 95% CI 1.01-2.38). The results of our study suggest no significant association between CD28 rs1980422, CCL5 rs2107538, CTLA-4 exon 1 +49A>G rs231775 and rs3087243 gene polymorphisms and RA in the Polish population. Our results indicate a possible association between CTLA-4 exon 1 +49A>G rs231775 gene polymorphism and RA activity.

Polymorphisms of CTLA-4 Are Associated with Treatment Outcome in Multiple Myeloma Patients Receiving Bortezomib-Based Regimens

Objectives: SNPs of CTLA-4 have been shown to be important risk factors associated with autoimmune disease and malignancy , the objectives of this study were to explore the association of CTLA-4 SNPs with the development of myeloma and to evaluate the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4 SNPs.Methods: Peripheral blood samples from 86 MM patients and 154 controls were obtained for the investigation of CTLA4 polymorphisms, The five SNP genotypes of CTLA-4, namely, -1772(rs733618),-1661 (rs4553808), -318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were determined by TaqMan SNP genotyping assays (Applied Biosystems) ,Results: Some of the CTLA-4 polymorphisms display frequencies that are different among the different ethnic groups. The Kaplan-Meier analysis revealed that patients with rs733618 GG showed a significantly lower DFS (0% vs. 57.4%, P = 0.020) and OS (46.3% vs. 83.3%, P = 0.026) than those with GA+AA in MM patients after Botizomib based therapy. Multivariate analyses showed that rs733618 GG were risk factor for OS (HR= 0.025; 95% CI= 0.004-0.161;P=0.000). The incidence of nonhematologic grade 3/4 adverse events was significantly increased in the rs 4553808 GA+GG group compared to AA group(P=0.036).Conclusion: In summary, CTLA-4 rs733618 GG reduced the progression-free survival and overall survival in MM patients after Botizomib based therapy,knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for MM therapy. The exact effect of the CTLA-4 polymorphism and haplotype on MM therapy outcome should be determined in different cohorts with substantially larger number of subjects.The first 2 authors contributed equally to this work. DisclosuresNo relevant conflicts of interest to declare.

CTLA-4 and IL-6 gene polymorphisms: Risk factors for recurrent pregnancy loss

The purpose of the present study was to evaluate the possible association between CTLA-4 +49A/G and IL-6 −634C/G polymorphisms, and the risk of recurrent pregnancy loss (RPL). 240 women (120 healthy controls and 120 with RPL) were enrolled in this case-control study. Genotyping was performed using a PCR-RFLP technique. In the case of polymorphic CTLA-4 +49A/G, the wild type allele G was associated with a decreased risk of RPL (OR: 0.42, 95%CI: 0.25–0.69, p=0.001). As to IL-6 −634C/G polymorphism, a highly significant difference was observed, and those women who carry at least one mutant G allele presented a probability of developing RPL about 5 times greater than controls (OR: 5.1, 95%CI: 1.04–25.3, p=0.04). The results indicate that polymorphisms of CTLA-4 and IL-6 genes may influence the risk of developing RPL among Iranian women, suggesting that more research on the immunogenetics of pregnancy should be conducted to confirm our results, and to declare the exact roles of studied molecules in RPL pathogenesis.

Role of HLA-DRB1, PTPN22, CTLA4 Gene Polymorphisms in Susceptibility to Rheumatoid Arthritis

Background and AIM: The genetic and environmental factors are believed to play an important role in the pathogenesis of rheumatoid arthritis (RA), the precise etiology is still uncertain. Regarding its genetic components, the strongest genetic association with RA is that found for certain alleles of HLA-DRB1. Recent studies have revealed that the single‐nucleotide polymorphism (SNP) of non-HLA PTPN22 and CTLA4 gene were associated with RA. The associations of HLA, PTPN22 and CTLA4 polymorphisms with RA risk have been less well replicated. Thus, the current study was undertaken to investigate the effects of HLA-DRB1, PTPN22, CTLA4 gene polymorphisms and autoantibodies in susceptibility to RA. Methods: A total of 200 patients fulfilled the criteria for RA and 200 healthy individuals were included in the study. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured by enzyme-linked immunosorbent assay (ELISA). HLA-DRB1 alleles were determined by polymerase chain reaction-sequence specific primer (PCR-SSP) method. Samples were genotyped for PTPN22 1858C/T (rs2476601) and CTLA4 CT60 (rs3087243) variants using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: In RA patients 88% and 82% were positive for anti-CCP and RF autoantibodies, respectively. A significant increase in the frequency of HLA-DRB1*01, HLA-DRB1*04, HLA-DRB1*10, HLA-DRB1*14 shared epitope (SE) alleles were identified in RA patients, whereas in healthy subjects, they were HLADRB1*03, HLA-DRB1*07, HLA-DRB1*11, HLA-DRB1*13. There was no association of the PTPN22 1858T variant with RA and it seems to be independent of MHC associations. The frequency of CTLA4 CT60 A allele carriers was significantly higher in RA patients and also it is preferentially in SE-positive RA patients. Conclusion: Our results confirmed the previously reported HLA-DRB1 SE alleles associations with RA. The CTLA4 polymorphism appears to interfere with HLA-DRB1 susceptibility to RA. On the other hand, we failed to provide evidence for the association of the PTPN22 SNP with RA.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Immune and Genetic Susceptibility in the Development of Cervical Cancer

Cervical cancer is the second most frequent cancer in women worldwide. Although 99.7% of cases are attributed to a previous infection by Human papillomavirus, a small percentage of the infected women progress to cervical cancer, suggesting the existence of different risk factors involved in the development and progression of this pathology. Genetic variability related to the host immune system could play an important role in the defense response to Human papillomavirus and therefore to the probability of developing cervical cancer. Worldwide, several international studies have reported that some genetic variations in immune system, such as polymorphisms in genes HLA, CTLA-4, MTHFR, Tp53 and receptors of natural killer cells are associated with susceptibility to cervical cancer, although these variations can also play a protective role depending on the study population. The role of the genetic factors of the host cell is an important factor in the progression of the cervical cancer.

Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.

Association of gene polymorphisms of FV, FII, MTHFR, SERPINE1, CTLA4, IL10, and TNFalpha with pre-eclampsia in Chinese women.

To investigate the association of polymorphisms in genes involved in coagulation, fibrinolysis, and inflammation with pre-eclampsia (PE) in a Chinese population. It is a case-control study of patients with PE (n=117) and controls (n=286) from the Maternal and Children's Hospital of Shenzhen City carried out between June 2014 and May 2015. The rs6025, rs6020, rs1801133, rs1799963, rs1799889, rs231775, rs1800896, rs1800629, and rs1799724 polymorphisms were analyzed using Snap Shot. Multifactor dimensionality reduction (MDR) and logistic regression analyses were carried out to assess the interactions among these SNPs. The frequencies of polymorphisms in tumor necrosis factor-α (TNF-α) (rs1800629 and rs1799724) and interleukin 10 (IL-10) (rs1800896) were significantly different between patients with PE and controls (P<0.05). The best interaction model identified a marginally significant interaction between rs1799724 and rs1800896 (P=0.05). This study suggests that polymorphisms in the TNF-α and IL-10 genes could be associated with PE, but additional studies are necessary to explore the mechanisms involving these polymorphisms and the gene-gene interactions involved in the susceptibility to PE.