CTLA-4 Polymorphisms Research Articles

The impact of CTLA-4 gene polymorphism on the content of organ-specific antibodies in patients with autoimmune thyroiditis among the population of Azerbaijan

BACKGROUND: The risk of developing immune tolerance to self-antigens in autoimmune thyroiditis is largely associated with a mutation in the CTLA-4 gene, the product of which negatively regulates T-cell activity. AIM: To study the A49G (rs231775) CTLA-4 polymorphism in patients with autoimmune thyroiditis in a sample of Azerbaijani residents and the effect of the frequency of identified alleles and genotypes on the level of antibodies to thyroid peroxidase and thyroglobulin. MATERIAL AND METHODS: A study was conducted in 2021–2023 involving 170 patients with autoimmune thyroiditis and 65 individuals without thyroid pathology or other autoimmune diseases, who formed a comparison group. The groups were matched by gender and age. Based on the patient history, thyroid status study results, thyroid ultrasound data, and organ-specific antibody assessment, the patients were diagnosed with autoimmune thyroiditis. The routine thyroid status study results in the comparison group were within normal limits. Genotyping of the A49G (rs231775) polymorphism was performed using polymerase chain reaction followed by digestion of the reaction product with PspEI restriction endonuclease. The results of the quantitative studies were presented as the median (Me) and interquartile range (25th quartile; 75th quartile). The correspondence of genotype frequencies to the Hardy–Weinberg equilibrium was assessed using the χ2 criterion. RESULTS: The results revealed a statistically significant increase in the frequency of the G allele (48%) compared to the control group [33.8%; p=0.039, χ2=4.27, odds ratio (OR) 1.865, 95% confidence interval (CI) 1.028–3.382] and a decrease in the frequency of the A allele (51.2%) relative to the control group (66.1%; p=0.0389, χ2=4.27, OR=0.536, CI=0.296–0.973). In 22.4% of patients with the GG genotype (p=0.005, χ2=7.86, OR=0.237, 95% CI=0.088–0.635) and 55.6% of patients with the G allele (p=0.0012, χ2=10.43, OR=0.360, 95%, CI=0.192–0.674), thyroglobulin antibody titers were more than 100 IU/ml. Thyroid peroxidase antibody levels of 100 IU/ml or more were recorded in 22.7% of study participants with the GG genotype (p=0.030) and 50.0% with the G allele (p=0.048). CONCLUSION: Elevated titers of antibodies to thyroid peroxidase and thyroglobulin were detected in patients from the population of Azerbaijan with the G allele and homozygous genotype GG of the +49A/G polymorphism of the CTLA-4 gene.

CCR5 Δ32 and CTLA-4 +49 A/G Gene Polymorphisms and Interferon-β Treatment Response in Croatian and Slovenian Multiple Sclerosis Patients.

The aim of the present study was to investigate the impact of CCR5 Δ32 and CTLA-4 polymorphisms on the response to IFN-β treatment in our cohort of MS patients from Croatia and Slovenia. Genomic DNA was obtained from 295 MS patients (230 female; 65 male) classified as responders (n = 173) and non-responders (n = 122) based on clinical criteria for treatment efficacy. Genotyping was performed via PCR/PCR-RFLP. No significant differences in the genotype/allele frequencies of CCR5Δ32 and CTLA-4 +49 A/G were detected between male responders and non-responders. A significantly higher prevalence (p = 0.039) of the CTLA-4 +49 AA genotype was found in female responders (42.1%) compared to non-responders (28.9%). Using multiple forward regression analysis, the CTLA-4 +49 AA genotype significantly predicted a positive response to IFN-β therapy in females (p = 0.011) and contributed to 4.5% of response variability. Furthermore, the combined presence of the CCR5Δ32 wtwt/CTLA-4 +49 AA genotype significantly predicted a positive response to treatment in females (p = 0.025). The age at disease onset, pretreatment relapse rate, and baseline EDSS score were not reliable predictors of treatment response in MS patients. Our results indicate that the presence of the CCR5Δ32 polymorphism was not associated with the response to IFN-β treatment, whereas the CTLA-4 +49 polymorphism showed a positive correlation with an optimal response in female patients.

Relationship Between Cytotoxic T-Lymphocyte-associated Antigen-4: Programmed Death-1 Genes Polymorphisms and Susceptibility to Pediatric B-Cell Acute Lymphoblastic Leukemia.

Programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have a vital role in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PD1 and CTLA4 have been reported to be associated with susceptibility to certain autoimmune diseases and cancers. The potential association between SNPs in these immune checkpoint genes and risk of acute lymphoblastic leukemia (ALL) still unclear. The aim of this study is to clarify the effect of PD1 and CTLA4 SNPs on the risk of developing ALL and the prognosis of the disease. The study was performed on 100 pediatric B-ALL patients and 100 controls. The PD1 and CTLA4 SNPs were examined by RFLP technique. The study revealed that CTLA4 (rs11571316) was associated with high risk of B-ALL developments OR 1.492 (CI: 1157 to 1924) ( P =0.002). PD1 (rs36084323) GA genotype was significantly associated with protective effect against nonremission ( P =0.007). PD1 (rs36084323) A allele were associated with protective effect against relapse ( P =0.008). CTLA4 and PD1 genotypes did not have significant impact on B-ALL patients outcome. The current study displayed for the first time that genetic variations of the CTLA-4, was associated with susceptibility to B-ALL and that PD1 (rs36084323) GA genotype was significantly associated with protective effect against nonremission, while PD1 (rs36084323) A allele was associated with protective effect against relapse.

Association of tuberculosis risk with genetic polymorphisms of the immune checkpoint genes PDCD1, CTLA-4, and TIM3.

The immune checkpoint proteins were reported to involve to host resistance to Mycobacteria tuberculosis (Mtb). Here, we evaluated 11 single nucleotide polymorphisms (SNPs) in PDCD1, CTLA4, and HAVCR2 genes between participants with and without TB infection. Genomic DNA isolated from 285 patients with TB and 270 controls without TB infection were used to perform the genotyping assay. Odds ratios were used to characterize the association of 11 SNPs with TB risk. In this study, the various genotypes of the 11 SNPs did not differ significantly in frequency between the non-TB and TB groups. When patients were stratified by sex, however, men differed significantly from women in genotype frequencies at HAVCR2 rs13170556. Odds ratios indicated that rs2227982, rs13170556, rs231775, and rs231779 were sex-specifically associated with TB risk. In addition, the combinations of rs2227982/rs13170556 GA/TC in men and the A-C-C haplotype of rs231775-rs231777-rs231779 in women were significantly associated with TB risk. Our results indicate that rs2227982 in PDCD1 and rs13170556 in HAVCR2 are associated with increased TB susceptibility in men and that the CTLA4 haplotype appears protective against TB in women.

Genetic biomarkers for diagnosis and treatment of spondyloarthropathies in Moroccan population

BackgroundThe spondyloarthropathies (SpA) are inflammatory rheumatologic diseases whose pathogenesis comes from interaction between genetic and environmental factors. MethodsThis is a case-control analysis that aims to explore in Moroccan population the relationship of some allelic polymorphisms of the CTLA-4 CT60, FCGR3A-158G/T SNPs and HLA-B locus with SpA disease. Eighty-four Spa patients grouped according to pain site and 95 healthy individuals from Morocco were typed by sequence-based-typing methods. ResultsThe CTLA-4 CT60 investigation showed a significantly increased frequency of rs11571319 A allele in male patients with sacroiliitis (pcorr.=0.048, OR=2.756) and a protective role of A/G genotype in SPA patients with thoracic spine (pcorr.=0.016, OR=0.055) and peripheral joints pain (pcorr.=0.036 OR=0.068), compared to controls. Furthermore, a significant increase of A/A in rs3087243 was shown in male patients with peripheral joints pain (p = 0.035 OR = 4.45). Data from FCGR3A-158 analysis evidenced a reduction of T/T (F/F) genotype in patients with thoracic spine pain (p = 0.030, OR = 0.09) and a higher frequency of G/T (F/V) (p = 0.038 OR = 5.045) towards controls. With regard to HLA-B locus, we noticed a protective role of HLA-B*45:01 (pcorr. = 0.033,OR = 0.041) and an increased frequency of HLA-B*51 alleles (51:01, 51:02, 51:08, 51:09, 51:29) and B*52:01:01 (p = 0.041,OR = 2.714), in addition to HLA-B*27 alleles (p = 0.028, OR = 2.593) commonly associated with AS pathologies. ConclusionsOur data suggest the role of some additional CTLA-4, FCGR3A and HLA-B gene polymorphisms in SPA pathogenesis of Moroccan population, useful as new diagnostic biomarkers and targets for immunotherapy.

Impact of CD 28, CD86, CTLA-4 and PD-1 genes polymorphisms on acute renal allograft rejection and graft survival among Egyptian recipients

To study the impact of four gene polymorphisms on acute renal allograft rejection (AR) and graft survival among Egyptian population. These 4 gene polymorphisms include: (1) CD 28 (rs3116496), (2) CD86 (rs1129055), (3) CTLA-4 (rs3087243), (4) PD-1 (rs2227982). This is a non-concurrent cohort study including 50 kidney transplant recipients diagnosed histopathologically as (AR) [study group] and another 50 matched allograft recipients without AR [control group]. Blood samples were taken from both groups and subjected to genotyping for the selected four genetic polymorphisms by TaqMan genotyping assay. The difference in genotypic distribution of CD 28: rs3116496 and CD86: rs1129055 wasn't statistically significant between the study and control groups (P = 0.22 and 0.33 respectively) and also both polymorphisms had no effect on graft survival (P = 0.36 and 0.74 respectively) while the addition of C allele to IVS3 +17T/C polymorphism in CD28 gene showed a protective effect against AR (P = 0.03). CTLA-4: rs3087243 AG genotype showed a protective effect against AR as it was more frequent in no rejection group compared to those with AR (P = 0.001) with a statistically significant impact on graft survival (P < 0.001), while PD-1: rs2227982 AG genotype was equally distributed between both groups (variant of unknown significance). There was no detected association between CD86 polymorphism: rs1129055 and CD 28 polymorphism: rs3116496 with the development of AR. However, C allele of CD 28 IVS3 +17T/C polymorphism and CTLA-4 polymorphism: rs3087243AG genotype both demonstrated a protective effect against AR.

Correlation of LaboratoryParameters Between Subgroups of "Wild Type", Mutated, Heterozygous Patients Based on the Presence of Rs231775 CTLA-4 Gene Polymorphisms in Pluriglandular Autoimmune Syndrome (PAS III)

Background: Autoimmune thyroid disease and diabetes mellitus type 1 are multifactorial diseases, in which there are several common, suspect genes, as well as environmental factors that contribute to the etiology of the disease. These genes were nominated as common susceptibility genes for PAS-III. Family and population studies have shown that PAS IIIA has a strong genetic background. Objective: In this work, gene polymorphisms were examined in 50 patients with PAS-IIIA. It is about polymorphism CTLA-4 gene polymorphism: rs231775. Rs231775, also known as + 49 A/G (or CTLA-4 A49G), is a common nonsynonymous CTLA-4 polymorphism. So far, it has been linked to several autoimmune diseases, especially autoimmune thyroiditis, as well as several other disorders. Methods: Peripheral blood of 50 patients was used as clinical material for the study. DNA was isolated from the collected peripheral blood samples using the Qiamp DNA mini kit, using the attached protocol and manufacturer's instructions. We also performed laboratory blood tests: Hba1c values as a parameter of glycoregulation in the last 3 months, fasting and 2-hour glycemia values, total cholesterol and triglyceride values, anti-TPO and anti-Tg thyroid antibodies. We were interested in the difference in laboratory tests in subgroups GWT, GM and GH. Results: Using the chi-square test, the association between the rs231775 polymorphism and PAS-III was proven. The values of GUK, HbA1C, cholesterol, triglycerides, antibodies to thyroglobulin and antibodies to thyroperoxidase were not statistically significantly different in all three subgroups of patients suffering from PAS III. Conclusion: It has been previously shown that people with a mutation in one allele of CTLA-4 are highly susceptible to autoimmunity, which raises the possibility that more subtle variations in the level of CTLA-4 in the general population can influence the response to therapy. Non-pathogenic polymorphisms in CTLA-4 that alter CTLA-4 expression may affect an individual's lifetime risk for the development of autoimmune and malignant disorders..

Impact of single nucleotide polymorphisms of immune checkpoint CTLA-4 (SNP rs231775 and rs5742909) in susceptibility to Hashimoto's thyroiditis patients

Background: Hashimoto thyroiditis is an autoimmune disorder causing thyroid cell destruction. This research aimed to evaluate CTLA-4 expression levels in patients with Hashimoto's thyroiditis, biochemical parameters. As well as understand the risk and protective effects of two CTLA-4 SNPs polymorphisms (rs231775 and rs5742909) in Iraqi patients. Methods: A case control study was conducted on 50 HT patients (5 men and 45 females) were assembled from Baghdad teaching hospital, Baghdad, Iraq. The relative Gene expression method was used to measure the gene expression of CTLA-4 using qRT-PCR. The single nucleotide polymorphisms of (318C/T (rs231775) and +49A/G (rs5742909) were sequenced for data analysis. Results: There was significant increase of serum CTLA-4 levels, similarity fold change of CTLA-4 was significant upregulated in HT patients compared to controls. The allele and genotypes frequencies according to HWB equilibrium showed significant differences in HT patients 318C/T (rs231775) AA genotypes, while no significant differences in the AG, GG genotypes, respectively compared to controls (p&lt;0.05), There were also no significant differences in the CTLA-4 SNP +49A/G (rs5742909), (CC, CT, TT) genotype, respectively. (p&gt;0.05). Both studied SNPs recoded higher upregulation of soluble and fold change of the immune check point (CTLA-4), respectively. Conclusion: The study reveals that CTLA-4 gene SNPs rs231775 and rs5742909 significantly influence soluble and the expression of CTLA-4 levels in HT patients, potentially causing Hashimoto disease and HT incidence and development.

Factors affecting HBV DNA suppression in chronic hepatitis B patients treated with tenofovir disoproxil fumarate.

Background: This study aims to determine the factors affecting HBV DNA suppression in chronic hepatitis B patients with tenofovir disoproxil fumarate (TDF). Methods: A case-control was carried out from October 2021 to August 2022 on 182 chronic hepatitis B patients who had TDF therapy regularly for 24 weeks at H. Adam Malik and USU Hospitals in Medan, Indonesia. The history of the samples was obtained, followed by physical examination, and blood collection. CTLA-4 polymorphism examination was carried out using real-time PCR, while the serum CTLA-4 levels were assessed with ELISA. Results:The CTLA-4 -1661G>A polymorphism, genotype GG+AG, increased 1.52 times risk of not achieving HBV DNA suppression to TDF compared to genotype AA (p=0.041). High CTLA-4 levels increased 2.28 times risk, high HBV DNA levels increased 2.09 times risk, low ALT levels increased 1.95 times risk of not achieving HBV DNA suppression (p= 0.009, 0.026, 0.036, respectively). There was no relationship between gender, age, ethnicity, obesity, baseline AST, HBeAg, genotype, liver fibrosis and HBV DNA suppression after 24 weeks of treatment (p>0.05). Conclusions: The levels of CTLA-4, HBV DNA, ALT, and CTLA-4 -1661G>A polymorphism have a potential relationship with the suppression of HBV DNA in chronic hepatitis B patients with TDF.

Genetic variants of CTLA4 are associated with clinical outcome of patients with multiple myeloma.

Immune dysfunction in patients with multiple myeloma (MM) affects both the innate and adaptive immune system. Molecules involved in the immune checkpoint pathways are essential to determine the ability of cancer cells to escape from the immune system surveillance. However, few data are available concerning the role of these molecules in predicting the kinetics of progression of MM. We retrospectively analysed polymorphisms of CTLA4 (rs231775 and rs733618), BTLA (rs9288953), CD28 (rs3116496), PD-1 (rs36084323 and rs11568821) and LAG-3 (rs870849) genes in 239 patients with newly diagnosed MM. Patients with a CTLA4 rs231775 AA/AG genotype showed a median progression-free survival (PFS) significantly lower than those with GG genotype (32.3 months versus 96.8 months respectively; p: 0.008). The 5-year PFS rate was 25% for patients with grouped AA and AG genotype vs 55.4% for patients with GG genotype. Multivariate analysis confirmed the CTLA4 rs231775 genotype as an independent risk factor for PFS (Hazard Ratio (HR): 2.05; 95% CI: 1.0-6.2; p: 0.047). Our results suggest that the CTLA4 genotype may identify patients with earlier progression of MM. This polymorphism could potentially be used as a prognostic biomarker.

Gene variations related to the hepatocellular carcinoma: Results from a field synopsis and Bayesian revaluation

Hepatocellular carcinoma (HCC) is considered as the second cause of cancer-related deaths worldwide. Genetic variations are associated with HCC risk, an issue that has been the subject of several meta-analyses. However, meta-analyses have an important limitation on the likelihood of false positive data. Henceforth, this study aimed to assess the level of noteworthiness in the meta-analyses by means of a Bayesian approach. A systematic search was performed for meta-analyses with associations between gene polymorphisms and HCC. The calculations for the False-Positive Rate Probability (FPRP) and the Bayesian False Discovery Probability (BFDP) were performed to assess the noteworthiness with a statistical power of 1.2 and 1.5 of Odds Ratio at a prior probability of 10−3 and 10−5. The quality of studies was evaluated by the Venice criteria. As additional analyses, the gene-gene and protein–protein networks were designed for these genes and products. As results, we found 33 meta-analytic studies on 45 polymorphisms occurring in 35 genes. A total of 1,280 values for FPRP and BFDP were obtained. Seventy-five for FPRP (5.86%) and 95 for BFDP (14.79%) were noteworthy. In conclusion, the polymorphisms in CCND1, CTLA4, EGF, IL6, IL12A, KIF1B, MDM2, MICA, miR-499, MTHFR, PNPLA3, STAT4, TM6SF2, and XPD genes were considered as noteworthy biomarkers for HCC risk.

Association of cytotoxic T-lymphocyte-associated protein 4 polymorphisms with recurrent pregnancy loss: A case-control study.

A large proportion of cases of recurrent pregnancy loss (RPL) are associated with immunological factors. This study investigated the association between single nucleotide polymorphisms of cytotoxic T-lymphocyte-associated protein (CTLA)-4 gene in women with a history of RPL compared to healthy women. A case-control study was performed on 2 groups consisting of 120 healthy women with no history of abortion and at least one delivery (control) and 120 women with a history of 2 or more primary RPLs (case). In addition, 5 mL of peripheral blood sample was taken from all subjects. The frequencies of CTLA-4 rs3087243 and rs231775 polymorphisms were assayed by restriction fragment length polymorphism polymerase chain reaction and rs5742909 using the high-resolution melting real-time polymerase chain reaction method. The mean age of the women in the control and RPL groups were 30.03 4.23 (range 21-37), and 28.64 3.61 yr (range 20-35), respectively. Pregnancy loss numbers ranged between 2-6 in women with a history of RPL, and between 1 and 4 in the successful pregnancy group. Statistical analysis showed a significant difference between the genotypes of GG and AG in the 2 groups in rs3087243 polymorphism (OR 1.00 for GG genotype and OR 2.87 for AG genotype, p = 0.0043). No significant difference was observed in the genotype frequencies of rs231775 and rs5742909 polymorphisms, of the 2 groups (p = 0.37, and p = 0.095), respectively. Our findings indicated that CTLA-4 polymorphism, rs3087243, might be associated with a risk of RPL in Iranian women.

Are the Costimulatory Molecule Gene Polymorphisms (CTLA-4) Associated With Infection in Organ Transplantation? A Meta-Analysis

Organ transplantation has been linked to certain gene polymorphisms. The effect of gene polymorphisms–associated organ transplantation gene on infection, on the other hand, is yet unknown. The research studying the link between the CTLA-4 rs5742909, rs733618, rs4553808, rs231775, and polymorphisms of the organ transplantation gene and infection were found in PubMed, Web of Science, Scopus, and Embase, and the published articles from 2012 to 2020 were gathered. For the best estimation of the intended results, a random-effects model was used in this meta-analysis. In this study, 1,567 studies were initially included and 9 eligible studies were eligible for further analyses. A significant correlation between CTLA4+49 [A/G-231775 odds ratio (OR) = 077, 0.59–0.95] and CTLA4 [rs5742909TT OR: 0.09, 0.27–0.45] gene polymorphism with infection in organ transplantation was observed. Also, no significant association was found between other CTLA4 gene polymorphisms with infection in organ transplantation. Further studies involving gene–gene and gene–diet interactions should be conducted to investigate this association with infection.

Relationship between CTLA4, TNF-α and PTPN22 gene polymorphism and the serum levels of antithyroglobulin and antiperoxidase antibodies in autoimmune thyroiditis

&lt;abstract&gt; &lt;p&gt;Autoimmune thyroiditis (AIT) is a chronic inflammatory that involves hyperactivation of the immune system against the thyroid gland, recognizing it as "nonself”. The aim of this research was to identify the relationships between genetic polymorphism in &lt;italic&gt;CTLA4&lt;/italic&gt;, &lt;italic&gt;TNF-α&lt;/italic&gt; and &lt;italic&gt;PTPN22&lt;/italic&gt; genes and the manifestation of AIT and levels of antithyroglobulin antibody (anti-TG Ab) and thyroid peroxidase antibody (anti-TPO Ab). The study was conducted during 2014–2020 and included 64 men and 106 women aged between 18 and 64 years with AIT. The control group consisted of 65 people (26 men, 39 women, aged between 20 and 65 years) without any thyroid pathologies or other autoimmune diseases. For molecular genetic analysis, real-time quantitative RT-PCR was used with fluorescently labeled FAM probes on a detection system CFX96 (BioRad). The results demonstrated that patients with the GG genotype and the G allele of the +49A/G polymorphism in the &lt;italic&gt;CTLA4&lt;/italic&gt; gene have significantly higher titers of anti-TG Ab. High titers of anti-TG Ab were detected in 22.4% of patients with the GG genotype (p = 0.005, χ2 = 7.86, OR = 0.237, 95% CI = 0.088–0.635), and in 55.6% of patients with the G allele (p = 0.0012, χ2 = 10.43, OR = 0.360, 95%, СI = 0.192–0.674). At the same time, the A allele of the +49A/G polymorphism is significantly more common in patients with normal anti-TG Ab values—in 68.1% of individuals (p = 0.0012, χ2 = 10.43, OR= 2.78, 95%, CI = 1.484–5.207). The results of the study indicate the prognostic significance of the G allele and the GG genotype of the +49A/G polymorphism of the &lt;italic&gt;CTLA4&lt;/italic&gt; gene predicting the probability of occurrence of anti-TG and anti-TPO antibodies.&lt;/p&gt; &lt;/abstract&gt;

Factors affecting HBV DNA suppression in chronic hepatitis B patients treated with tenofovir disoproxil fumarate

Background: This study aims to determine the factors affecting HBV DNA suppression in chronic hepatitis B patients with tenofovir disoproxil fumarate (TDF). Methods: A case-control was carried out from October 2021 to August 2022 on 182 chronic hepatitis B patients who had TDF therapy regularly for 24 weeks at H. Adam Malik and USU Hospitals in Medan, Indonesia. The history of the samples was obtained, followed by physical examination, and blood collection. CTLA-4 polymorphism examination was carried out using real-time PCR, while the serum CTLA-4 levels were assessed with ELISA. Results: The results showed that CTLA-4, HBV DNA, ALT, and CTLA-4 -1661G&gt;A polymorphisms have a relationship with HBV DNA suppression in chronic hepatitis B patients with TDF. Conclusions: The levels of CTLA-4, HBV DNA, ALT, and CTLA-4 -1661G&gt;A polymorphism have a potential relationship with the suppression of HBV DNA in chronic hepatitis B patients with TDF.

When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease

Immune checkpoint inhibitors are increasingly used as adjuvant therapy in oncology; however, they have short and long-term side effects. A major one is the surge in autoimmune diseases. The number of those conditions is continuously increasing, and recently, celiac disease was added to the list. Since celiac disease is associated with CTLA-4 polymorphism and since the disease is underdiagnosed and since the patient is at risk for various cancers, upon anti-CTRA-4 immune therapy, the loss of function of the CTLA-4 protein can predispose them to overt celiac disease. The present review highlights some potential mechanisms for CTLA-4 dysfunction, putting the patients at risk of celiac disease induction.

Association of CLTA-4 Gene Polymorphisms with Diabetes Mellitus: A Study Based on the Han Population of Northern China.

ObjectiveThis study aimed to investigate the association of CLTA-4 gene polymorphism with Type 1 and 2 diabetes mellitus (DM) (T1DM and T2DM) in the Han population of northern China.MethodsA total of 234 Chinese Han DM patients and 187 non-diabetic subjects were included in the study. Two gene polymorphisms of the CLTA-4, including CTLA-4+49A/G (rs231775) and CTLA4-318C/T (rs5742909), were studied using polymerase chain reaction-restriction endonuclease fragment length polymorphism (PCR-RFLP) analysis. Chi-square analysis and Student’s t-test were performed to determine the distribution of the gene polymorphism and alleles at the locus of CTLA4-318C/T and CTLA4+49A/G among T1DM and T2DM patients with or without diabetic ketosis (DK), diabetic nephropathy (DN) or autoantibodies (Ab).ResultsOur results indicated that the distribution frequencies of genotypes and alleles at the CTLA-4+49A/G and CTLA4-318C/T loci of T1DM patients were not significantly different from those of the controls. However, the distribution frequencies of genotypes and alleles at the CTLA-4+49A/G loci of T2DM patients were significantly different from the controls (P=0.024 for genotypes and P=0.004 for A and G alleles). Besides, the A and G alleles at the CTLA4-318C/T loci of T2DM DK+ patients showed significantly different distribution frequencies compared to those of the T2DM DK patients (P=0.001).ConclusionOur data suggest that the gene polymorphisms of CTLA-4, including CTLA-4+49A/G and CTLA4-318C/T, are important predictors of DM. CTLA-4 may be a susceptibility gene for T2DM. Patients with T2DM carrying the T allele at the CTLA4-318 C/T locus are more predisposed to diabetic ketosis.

Role of Polymorphisms on the Recurrent Pregnancy Loss: A Systematic Review, Meta-analysis and Bioinformatic Analysis

Recurrent miscarriage (RM) is a major reproductive health issue. RM is a multi-factorial disease, and is affected by environmental, genetic, and epigenetic factors. Genetics has a common role in recurrent miscarriage occurrence. It seems that molecular genetics has a great role in RSA incidence. So, in these years, RM has become for a major subject of genetics research. There are many genes that are involved in each phase for successful reproduction. This research aimed to evaluate the effect of all studied polymorphisms in studies on RSA that have not been included in any meta-analysis. PubMed, Scopus, and Web of Science databases were recruited to investigate the related articles. The systematic review results identified 143 studies worldwide. Thirteen genes have been included in assessing the case-control studies. Sixty-four SNPs were recruited to assess the association between genetic factors and RSA susceptibility. Ninety-two studies containing twenty-two SNPs (from 10 genes) were included in the quantitative analysis. Bioinformatic analysis indicated that rs12722482 showed “Damaging Status” by double servers, and rs315952 and rs854560 had “Possibly damaging” status in the PolyPhen-2 server. MethPrimer server indicated that there is “CpG Island” in the rs10895068, rs1130355, and rs41557518 variants, and rs10895068-G allele makes a CpG dinucleotide which can change the gene methylation and result in altering the gene expression. So, further studies on rs12722482 and rs10895068 can demonstrate valuable results. To the best of our knowledge, this systematic review has covered the all studied polymorphisms of HLA-C, HLA-G, PON1, AGTR1, TAFI, FAS, FAS-L, ESR1, PGR, CTLA-4, MMP-2, MMP-3, MMP-9, and IL1RN for the first time. Also, we did a novel meta-analysis for AGTR1 rs5186, TAFI rs1926447, rs3742264, HLA-G rs1063320, rs1233334, rs1736936, rs2249863, PON1 rs662, rs854560, FAS rs2234767, rs1800682, FAS-L rs763110, ESR1, rs9340799, rs3798759, PGR rs1042838, CTLA4 rs4553808, rs5742909, rs231775, rs3087243, and MMP-2 rs243865 and updated statistical finding for rs2234693 and rs371194629. Rs2234693, rs9340799, rs231775, and rs371194629 demonstrated a significant association with RSA risk. Some variations showed significant association, while further studies are suggested to confirm the results. Finally, Rs4553808 and rs5742909 revealed no significant deviation in the results. It is suggested that these SNPs may be excluded from subsequent case-control studies or other analyses.

Association of CTLA-4 and IL-4 polymorphisms in viral induced liver cancer

BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent types of cancer and is responsible for close to one million annual deaths globally. In Pakistan, HCC accounts for 10.7% of cancer incidence. Prior studies indicated an association between interleukin 4 (IL-4) and cytotoxic T lymphocyte protein 4 (CTLA-4) gene polymorphisms in many types of cancers, including HCC that are either hepatitis B virus (HBV)- or hepatitis C Virus (HCV)-induced. The association of IL-4 and CTLA-4 genetic polymorphisms with HCV-induced HCC is not yet determined in the Pakistani population. Therefore, this research is designed to investigate the implication of IL-4 and CTLA-4 gene polymorphisms by determining the association of IL-4 -590 C/T (rs2243250) and CTLA-4 + 49 A/G (rs231775) with HCC in Pakistan.MethodsDifferent bioinformatics tools were employed to determine the pathogenicity of these polymorphisms. Samples were collected from HCV-induced HCC patients, followed by DNA extraction and ARMS-PCR analysis.ResultsThe SNP analysis results indicated a positive association of IL-4 -590C/T and CTLA-4 + 49A/G gene polymorphisms with HCV-induced HCC in Pakistan. The CTLA-4 polymorphism might enhance therapeutic efficiency of HCC chemotherapy medicines. The IL-4 polymorphism might introduce new transcription factor binding site in IL-4 promoter region.ConclusionThis study delineated risk factor alleles in CTLA-4 and IL-4 genes associated with HCV-mediated HCC among Pakistani patients that may have application to serve as genetic markers for pre- and early diagnosis and prognosis of HCC in HCV patients.

Association between CTLA-4 Gene Polymorphism and Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients

Introduction: &#x0D; Hepatocellular carcinoma (HCC) is the most common form of liver cancer; most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV. The HBV-related incidence of HCC is projected to increase for several decades, because of the high prevalence of chronic HBV infection and prolonged latency to HCC development. As of late, studies concerning the connection between CTLA-4 polymorphisms and a few infections definitely stand out. Associaton CTLA-4- 1661G&gt; A had ever been reported in autoimun cases. But the association of CTLA-4-1661G&gt;A polymorphism with HCC and Chronic Hepatitis B risk is hardly reported.&#x0D; Method:&#x0D; The study was conducted in May – November 2020 at Haji Adam Malik General Hospital, Medan, Indonesia. A total of 80 individual were analyzed with case control study. The data analysis was performed with SPSS 18.0 software. Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of CTLA-4 polymorphism with the risk of HCC and Chronic hepatitis B, which was calculated by chi-squared independent test. The examination of CTLA-4 -1661G&gt; polymorphism with real time PCR method. Genomic DNA was extracted from 5 ml frozen whole blood using the DNA Extraction Kit (Qiagen, Germany) according to the manufacturer's protocol.&#x0D; Result:&#x0D; The distribution of the characteristics of patients with Hepatocellular Carcinoma(HCC) with a mean age (56.98 ± 12,05) and Hepatitis B (45,95 ± 11,02) with the most orientation for HCC was male(77,5%) and for Chronic Hepatitis B was female (47,5%).The most common BCLC stage in HCC is stage D ( 45%). The result demonstrated that frequencies of hemozyous genotype GG,allele and G were remarkably higher in Hepatocellular Carcinoma Group than Chronic Hepatitis B Group (30% vs 2,5%, 70% vs 97,5%,55% vs 33,75%) while hemozyous genotype GA+AA, allele A were remarkably higher in Chronic Hepatitis B Group than Hepatocellular Carcinoma Group ( 97,5% vs 70%, 66,25% 45%).&#x0D; Conclusion:&#x0D; In this study, The CTLA4-1661G&gt;A polymorphism is associated with the incidence of Hepatocellular Carcinoma in chronic hepatitis B patients.