CTLA4 Single Nucleotide Polymorphisms Research Articles

Genetic Polymorphisms in Follicular Helper T Cell–Related Molecules Predispose Patients to De Novo Donor-Specific Antibody Formation After Kidney Transplantation

Risk prediction of de novo donor-specific antibody (dnDSA) formation is crucial for understanding the long-term prognostic impact of kidney transplantation (KT). Recently, follicular helper T (Tfh) cells, a subtype of CD4+ T cells, have been reported to play an important role in dnDSA formation after solid organ transplantation. Given the growing recognition of the importance of Tfh cells in generating a strong humoral immune response, we examined whether polymorphisms in Tfh cell-related molecules were associated with dnDSA formation after KT. Eighty-three patients who underwent living-donor KT between January 2013 and February 2020 at Hiroshima University Hospital were included in the study. Six Tfh cell-related molecules (BCL6, CXCR5, CXCL13, ICOS, CD40L, and IL21) that are important for Tfh cell differentiation and maturation in secondary lymphoid tissues were investigated. CTLA4, which is important for Tfh-cell activation, was also investigated. Single nucleotide polymorphisms (SNPs) in the genes for these molecules were detected using Taq Man SNP genotyping and evaluated for their association with dnDSA formation after KT. Of the 83 KT recipients, 8 developed dnDSAs during the observation period. No statistically significant differences were observed in the baseline characteristics between patients with and without dnDSA formation, except for donor age. Among the 7 Tfh cell-related molecules, the incidence of dnDSA formation was associated with CXCR5 and CTLA4 SNPs. Furthermore, combining these 2 SNPs enabled more significant stratification of dnDSA formation. Our findings indicate that genetic polymorphisms in Tfh cell-related molecules are predisposing factors for dnDSA formation after KT.

Association of CTLA-4 Single Nucleotide Polymorphisms with Autoimmune Hypothyroidism in Iraqi Patients

Genetic and environmental factors are believed to have a key role in the development and pathogenesis of autoimmune thyroid diseases (AITD). This study aimed to investigate the association between two CTLA-4 gene single nucleotide polymorphisms (SNPs) CT60/rs3087243 and CT61/rs11571319 with autoimmune thyroiditis in a sample of Iraqi patients. Seventy-five patients (67 females, 8 males) and eighty-eight subjects (79 females and 9 males) matched in age, gender, and ethnicity as a control group. Thyroid autoantibodies were present in females more than in males with a total positivity of anti-TPO of 92% and anti-TG positivity of57.3 %. Thyroid evaluation tests including T3, T4, and TSH were abnormal only in patients not receiving L-thyroxine treatment for autoimmune hypothyroidism, while patients on L-treatment and control subjects had normal results of these tests. CTLA-4 genotype frequencies were consistent with Hardy-Weinberg equilibrium (HWE) with no significant differences (p > 0.05) between the genotypes of patients and the control group. Analysis of CTLA-4 genotype and allele frequencies in patients and controls indicated the lack of significant differences among these frequencies except for allele G of rs3087243 which was associated significantly (P= 0.032) with the disease with OR of 1.62, while allele A can have a protective effect with OR of 0.66. Alleles of rs11571319 showed no significant ifferences despite the decreased frequency of G allele (83.33vs.87.5 %) and increased frequency of A allele (16.66vs.12.5%) in patients compared to controls. In conclusion, G allele of rs3087243 can be considered a risk factor for autoimmune hypothyroidism while noassociation was found regarding rs11571319 in the Iraqi population.

PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors.

To investigate the role of CTLA-4, PD-1 (programmed death-1), and PD-L1 (programmed death-ligand 1) single nucleotide polymorphisms (SNPs) in predicting clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). A total of 166 consecutive patients were included. We correlated SNPs with clinical benefit, progression-free survival, time to treatment failure, and overall survival and evaluated the incidence of SNPs in nonresponder and long clinical benefit groups. Considering the entire cohort, no correlation was found between SNPs and clinical outcome; however, PD-L1 rs4143815 SNP and the long clinical benefit group showed a statistically significant association (p = 0.02). The nonresponder cohort displayed distinctive PD-L1 haplotype (p = 0.05). PD-L1 SNPs seem to be marginally involved in predicting clinical outcome of NSCLC treated with ICI, but further investigations are required.

Impact of Single-Nucleotide Polymorphisms of CTLA-4, CD80 and CD86 on the Effectiveness of Abatacept in Patients with Rheumatoid Arthritis.

Abatacept (ABA) is used as a first-line treatment in patients diagnosed with moderate and severe rheumatoid arthritis (RA). The interindividual response to ABA therapy is very variable in these patients. The objective of our study was therefore to investigate the role of polymorphisms of the CTLA-4, CD80 and CD86 genes, as well as that of clinical factors of the disease, in the response to ABA in patients with RA. A retrospective cohort study was carried out in 109 patients receiving treatment with ABA and diagnosed with RA. The genetic variables were analyzed using real-time PCR with TaqMan® probes. The patients were classified according to the European League Against Rheumatism (EULAR) criteria at 6 and 12 months from start of treatment. The independent variables associated with higher EULAR response were lower duration of previous biologic disease-modifying anti-rheumatic drugs and lower baseline values of the disease activity score 28 after 6 months of ABA treatment; and lower baseline patient’s visual analogue scale (PVAS) after 12 months. In addition, a significant association was found between duration of ABA treatment, non-administration of concomitant glucocorticoids and lower baseline values of the number of inflamed joints and erythrocyte sedimentation rate clinical variables, with remission of the disease after 6 months’ treatment with ABA. Finally, remission of the disease after 12 months’ treatment with ABA was associated with earlier age at start of ABA therapy and lower number of previous biologic therapies (BTs). The CTLA-4 rs5742909-T allele and the CTLA-4 rs231775-G allele were found to be associated with satisfactory EULAR response and low disease activity (LDA) after 12 months’ treatment with ABA (CTLA-4 rs5742909 T vs. CC; OR = 5.88; CI95% = 1.48–23.29 and OR = 4.75; CI95% = 1.35–17.94, respectively, and CTLA-4 rs231775 G vs. AA, OR = 3.48; CI95% = 1.20–10.09 and OR = 4.68; CI95% = 1.49–17.94, respectively). In conclusion, patients with RA treated with ABA showed better EULAR response and LDA rate when they had the CTLA-4 rs5742909-T or CTLA-4 rs231775-G polymorphisms; furthermore, this remission rate increased in patients that began ABA treatment earlier, those with a lower number of previous BTs and those with a lower PVAS value.

A sequencing study of CTLA4 in Pakistani rheumatoid arthritis cases.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease. The interaction of genetic and environmental factors is likely necessary for RA. Among potential genetic factors, many major histocompatibility complex (MHC) and non-MHC variants may be involved in RA susceptibility. CTLA4 is involved in the regulation of T-cell response during an immune reaction, and multiple CTLA4 single nucleotide polymorphisms (SNPs) have been associated with numerous autoimmune diseases, including RA. To our knowledge, the genetic association of CTLA4 with RA risk has not been examined previously in the Pakistani population. In this study, we sequenced the entire CTLA4 gene and flanking regions in 95 Pakistani RA cases followed the screening of identified variants in Study 1 sample consisting of 350 RA cases and controls. Four common significant variants identified in Study 1 sample were further examined in a larger Study 2 replication sample comprising 1,678 independent RA cases and controls. We report significant associations of three variants from the combined analysis: rs3087243 (OR = 1.26, p = 4.47E-03), rs5742909 (OR = 1.78, p = 4.60E-03), and rs11571319 (OR = 1.48, p = 6.64E-03); the latter is a novel association in the Pakistani sample.

Th2 cell regulatory and effector molecules single nucleotide polymorphisms and periodontitis

To investigate the association between T helper 2 (Th2) cell regulatory and effector molecules' genetic polymorphisms and periodontitis. Single nucleotide polymorphisms (SNPs) of 11 Th2 cell regulatory or effector molecules genes (CD28, CTLA4, IL4, IL5, IL6, IL9, IL10, IL13, IL4R, GATA3, STAT6, and rs1537415; total 130SNPs) were studied in Chinese nonsmokers (163 periodontitis-free controls, 141 periodontitis patients) using Sequenom iPlex assays. SNPs potentially associated with periodontitis (adjusted allelic P<0.1) in this cross-sectional study were further investigated via meta-analysis. Allele G of rs4553808 in promoter of CTLA4 was more frequently detected in periodontitis than controls (P<0.005), but did not remain significant after age and gender adjustment. Haplotype (GTT) in a block of three CTLA4 SNPs (rs4553808, rs16840252, rs5742909) was significantly associated with periodontitis. Meta-analysis of SNPs identified indicated allele T of CTLA4 rs5742909 (3 studies; 461 control, 369 periodontitis) and allele G of IL6 rs1800796 (18 studies; 2760 control, 2442 periodontitis) were significantly associated with periodontitis (OR=1.44 and OR=1.30, respectively). Within limitations of this study, a haplotype of CTLA4 concerning Th2 cell regulation, may be associated with periodontitis in Chinese nonsmokers followed. Meta-analysis indicated rs5742909 of CTLA4 and rs1800796 of IL6 appeared significantly associated with periodontitis.

Investigation of the Correlation between Graves' Ophthalmopathy and CTLA4 Gene Polymorphism.

Graves’ disease (GD) is an autoimmune inflammatory disease, and Graves’ ophthalmopathy (GO) occurs in 25–50% of patients with GD. Several susceptible genes were identified to be associated with GO in some genetic analysis studies, including the immune regulatory gene CTLA4. We aimed to find out the correlation of CTLA4 gene polymorphism and GO. A total of 42 participants were enrolled in this study, consisting of 22 patients with GO and 20 healthy controls. Chi-square or Fisher’s exact test were used to appraise the association between Graves’ ophthalmopathy and CTLA4 single nucleotide polymorphisms (SNPs). All regions of CTLA4 including promoter, exon and 3’UTR were investigated. There was no nucleotide substitution in exon 2 and exon 3 of CTLA4 region, and the allele frequencies of CTLA4 polymorphisms had no significant difference between patients with GO and controls. However, the genotype frequency of “TT” genotype in rs733618 significantly differed between patients with GO and healthy controls (OR = 0.421, 95%CI: 0.290–0.611, p = 0.043), and the “CC” and “CT” genotype in rs16840252 were nearly significantly differed in genotype frequency (p = 0.052). Haplotype analysis showed that CTLA4 Crs733618Crs16840252 might increase the risk of GO (OR = 2.375, 95%CI: 1.636–3.448, p = 0.043). In conclusion, CTLA4 Crs733618Crs16840252 was found to be a potential marker for GO, and these haplotypes would be ethnicity-specific. Clinical application of CTLA4 Crs733618Crs16840252 in predicting GO in GD patients may be beneficial.

Single Nucleotide Polymorphisms of Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) and Susceptibility to Chronic Viral Hepatitis B and C Infections

The cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is a negative regulator of T lymphocyte activation and proliferation. Single nucleotide polymorphisms (SNPs) occurring on the CTLA-4 gene can modify the ability to control the proliferation of T lymphocytes, thereby impacting the clearance of hepatitis B (HBV) and hepatitis C (HCV) virus infections. The -319C/T and +49A/G SNPs of CTLA-4 gene have been associated with autoimmune disorders and liver infections. Studies show that the +49G allele confers susceptibility to HBV and HCV infection in chronic disease (without cirrhosis), associates with the risk of chronic HCV infection in males, confers protective effect against the development of hepatocellular carcinoma, and favors viral elimination. Furthermore, the +49G allele alone or in haplotype with the -319C favors chronic infection with genotype 3 HCV; has an inverse association with HCV genotype 1; and decreases viral load in chronic hepatitis C associated with sustained viral response (SVR). These findings support an important role of the SNPs of CTLA-4 gene in viral hepatitis; however, the mechanisms by which they influence immune response against viral infections is not fully understood. This review gives an overview of the current understanding of the association between CTLA4 SNPs and HBV/HCV infections.

PDCD1 and CTLA4 polymorphisms affect the susceptibility to, and clinical features of, chronic immune thrombocytopenia.

Programmed death-1 (PD-1, PDCD1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CTLA4) play central roles in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PDCD1 and CTLA4 have been reported to be associated with susceptibility to some autoimmune diseases. However, the potential association between SNPs in these immune checkpoint genes and risk of chronic immune thrombocytopenia (cITP) remain controversial and obscure. The aims of this study were to clarify the influence of PDCD1 and CTLA4 SNPs on the risk of developing cITP and its clinical features. We obtained genomic DNA from 119 patients with cITP and 223 healthy controls; their genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients with cITP had a significantly higher frequency of the PDCD1 +7209 TT genotype compared with healthy controls. The CTLA4 -1577 GG genotype and CT60 GG genotype showed higher frequencies of platelet count <5×109 /l at diagnosis, minimum platelet count <5×109 /l, and bleeding symptoms. Moreover, the PDCD1 -606 AA genotype and +63379 TT genotype were significantly associated with a lower number of patients who achieved a complete response to prednisolone treatment. Our results suggest that the immune checkpoint polymorphisms may affect the susceptibility to the clinical features of cITP, and treatment response of the affected patients.

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.

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

Associations of single nucleotide polymorphisms of PTPN22 and Ctla4 genes with the risk of allergic rhinitis in a Chinese Han population

BackgroundAllergic rhinitis (AR) is an inflammatory disorder of the upper airway. Protein tyrosine phosphatase non-receptor 22 encoded by PTPN22 gene and cytotoxic T-lymphocyte associated 4 encoded by Ctla4 gene are associated with autoimmune diseases. PurposeThis study was performed to evaluate the potential association of PTPN22 and Ctla4 single nucleotide polymorphisms (SNPs) with AR in a Chinese Han population. MethodsA case-control study was performed in 783 Chinese AR patients and 811 healthy controls. Three SNPs in PTPN22 gene (rs2488457, rs1310182, and rs3789604) and 6 SNPs in Ctla4 gene (rs3087243, rs231779, rs11571302, rs11571315, rs231725, and rs35219727) were detected using a polymerase chain reaction–restriction fragment length polymorphism assay (PCR-RFLP). ResultsFor PTPN22 gene, a significantly decreased prevalence of the rs2488457 CC genotype and C allele was found in AR patients. The frequencies of the rs1310182 CC genotype, CT genotype, and C allele were significantly associated with the risk of AR. For Ctla4 gene, a significantly increased prevalence of the rs11571302 AA genotype, CA genotype and A allele was noted in AR patients. ConclusionSNPs of PTPN22 and Ctla4 genes are significantly associated with the risk of AR in the Chinese Han population.

Effect of CTLA-4 gene polymorphisms on long-term kidney allograft function in Han Chinese recipients.

Single nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte associated antigen-4 gene (CTLA-4) have been associated with graft rejection and long-term clinical outcome after organ transplantation. Our aim was to examine the association between CTLA-4 SNPs (rs733618, rs4553808, rs5742909, rs231775, rs3087243) and long-term allograft function in Chinese renal transplant recipients. Genotyping of CTLA-4 SNPs was performed in 292 renal transplantation recipients. To assess long-term allograft function, the estimated glomerular filtration rate (eGFR) was determined 1, 3, 6, 12, 24, 36, 48 and 60 months after renal transplantation. CTLA-4 rs733618 and rs3087243 alleles and genotypes as well as the rs5742909 and rs231775 genotypes were significantly associated with long-term allograft function after transplantation (P<0.05). Patients with favorable genotypes had higher allograft function during the 60 months after transplantation. The TACGG, CACAG and CGTAA haplotypes were also associated with long-term kidney function after renal transplantation (P<0.05 or P<0.01). In sum, the favorable CTLA-4 rs5742909TT genotype, CTLA-4 rs733618C and rs3087243A alleles, and CACAG and CGTAA haplotypes, as well as the unfavorable rs733618TT, rs3087243GG and rs231775GG genotypes and TACGG haplotype could potentially serve as effective indicators of long-term allograft function in Chinese renal transplantation recipients.

Mo1002 CTLA4, FOXP3 and ICOS Single Nucleotide Polymorphisms (SNP's) in Patients With PBC and PSC: Relation to Expression and Clinic

Mo1002 CTLA4, FOXP3 and ICOS Single Nucleotide Polymorphisms (SNP's) in Patients With PBC and PSC: Relation to Expression and Clinic

A novel multiplex pyrosequencing assay for genotyping functionally relevant CTLA-4 polymorphisms: Potential applications in autoimmunity and cancer

CTLA-4 expression/function can be affected by single nucleotide polymorphisms (SNPs) of CTLA-4 gene, which have been widely associated with susceptibility or progression to autoimmune diseases and cancer development.In this study, we analyzed six CTLA-4 SNPs (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, CT60G>A) in 197 DNA samples from 43 B-lymphoblastoid cell lines (B-LCLs), 40 systemic sclerosis (SSc) patients, 14 pre-analyzed melanoma patients and 100 Italian healthy subjects.Genotyping of −1661A>G, −1577G>A, −658C>T and CT60G>A was performed by newly developed multiplex pyrosequencing (PSQ) assays, whereas −319C>T and +49A>G by T-ARMS PCR and direct sequencing. Genotype/allele frequency were analyzed using χ2 or Fisher exact test.Our study provides the first multiplex PSQ method that allows simultaneous genotyping of two CTLA-4 SNP pairs (i.e. −1661A>G/−658C>T and −1577G>A/CT60G>A) by two multiplex PSQ reactions. Herein, we show the CTLA-4 genotype distribution in the B-LCLs providing the first and best characterized cell line panel typed for functionally relevant CTLA-4 SNPs.We also report the significant association of the −1661A/G genotype, −1661 & −319 AC-GT diplotype and −319 & CT60 TG haplotype with susceptibility to SSc without Hashimoto’s thyroiditis occurrence. Furthermore, we confirmed previous genotyping data referred to melanoma patients and provided new genotyping data for Italian healthy subjects.

OP0023 CTLA4 single nucleotide polymorphisms correlate with response to BCG immunotherapy

Background Although BCG is the gold standard for non-muscle invasive bladder cancer, there is a significant non-responder rate. The reasons for this are not known, although single nucleotide polymorphisms (SNPs) in some genes correlate with response to therapy. Bladder cancer patients who were treated with anti-CTLA4 antibodies had increased CD4 + ICOS hi IFN γ expressing T cells over Treg cell numbers in the bladder and peripheral blood. Therefore seven SNPs in the CTLA4 gene (rs733618, rs4553808, rs5742909, rs231775, rs3087243, rs7565213, rs960792) that regulate protein expression and function were chosen for analysis. Methods Institutional review board approval was obtained for this project. SNPs in 138 bladder cancer patients, who had previously been treated with BCG and for whom long-term follow-up data were available, and 146 healthy controls were analysed. Genomic DNA was extracted and subjected to PCR followed by high resolution melt (HRM) analysis and sequence analyses. Findings There were no differences in the incidence of SNPs between healthy controls and patients. By Kaplan–Meier analysis, GA at rs4553808 (148 months) and CT at rs5742909 (167 months) correlated with longer time to recurrence. By Cox regression analysis, CT at rs5742909; AA at rs3087243; AA and AG at rs7565213 and TT at rs960792 were significantly correlated with reduced risk of recurrence ( p p p p Interpretation rs231775 GG is associated with significantly increased T-cell activation. Here, rs231775 GA was associated with increased risk of disease progression, but not AA, which is expressed at a lower level in our population. These results indicate that CTLA4 blockade could be a beneficial co-therapy for some bladder cancer patients.

MP34-08 CTLA4 SINGLE NUCLEOTIDE POLYMORPHISMS CORRELATE WITH RESPONSE TO BCG IMMUNOTHERAPY

MP34-08 CTLA4 SINGLE NUCLEOTIDE POLYMORPHISMS CORRELATE WITH RESPONSE TO BCG IMMUNOTHERAPY

CTLA4 Gene Polymorphisms Influence the Incidence of Infection after Renal Transplantation in Chinese Recipients

BackgroundImmunosuppressive therapy is usually administered following renal transplantation to protect the graft from rejection. However, this often causes complications such as infections to occur. Single nucleotide polymorphisms (SNPs) within the CTLA4 gene, such as −1772T/C (rs733618), +49A/G (rs231775) and +6230 G/A (rs3087243), can affect graft rejection and the long-term clinical outcome of organ transplantation. The role of CTLA4 SNPs in T cell-mediated immunity in renal transplantation and association with infection after transplantation is unknown.MethodsIn this study, the risk of infection according to CTLA4 SNPs was investigated in 304 patients who received kidney graft transplants between 2008 and 2012.ResultsThe frequency of the rs4553808 GG genotype was significantly higher in recipients with viral infection (14.89%) than in those without infections (3.50%) (Bonferroni-adjusted p = 0.005). A significant difference (p = 0.001) in patients with the rs4553808 GG genotype from those with the AA+AG genotypes was found in the viral cohort using the log-rank test. A significant association was found between the rs4553808 genotype and onset of viral infection in transplant recipients (p = 0.001). The frequencies of the CGTAG and CGCAG haplotypes were significantly higher in the viral infection group (9.6% and 5.3%) than in the non-viral infection group (3.8% and 1.4%) (p = 0.0149 and p = 0.0111). No association between any CTLA4 SNP and bacterial infection was found. Multivariate analyses revealed that one risk factor, the use of antibody induction therapy (p = 0.007), was associated with bacterial infection, and two risk factors, antibody use (p = 0.015) and recipient rs4553808 genotype (p = 0.001), were associated with viral infection.ConclusionsThe rs4553808 GG genotype may be a risk factor for viral infection in kidney transplantation. The CTLA4 haplotypes CGTAG and CGCAG were partially associated with the development of viral infection in Chinese kidney transplant recipients.

Association of CTLA-4 Polymorphisms with Improved Overall Survival in Melanoma Patients Treated with CTLA-4 Blockade: A Pilot Study

CTLA-4 blockade with monoclonal antibodies can lead to cancer regression in patients with metastatic melanoma (MM). CTLA-4 gene polymorphisms may influence the response to anti-CTLA-4 antibodies although few data are available regarding this issue. We analyzed six CTLA-4 single nucleotide polymorphisms (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, and CT60G>A) in 14 Italian MM patients and 45 healthy subjects. We found a significant association between the −1577G/A and CT60G/A genotypes and improved overall survival (Pc < 0.006, Bonferroni corrected), further confirmed by the diplotype analysis (−1577&CT60 GG-AA diplotype, p < 0.001). A positive trend toward an association between these genotypes and response to therapy was also observed.

Genotypes in relation to phenotypic appearance and exposure to environmental factors in Graves' hyperthyroidism

Genetic polymorphisms and environmental factors are both involved in the pathogenesis of Graves' disease, but their interaction and effect on Graves' phenotypes have scarcely been investigated. To test the hypothesis that subjects with susceptibility genotypes develop more severe Graves' hyperthyroidism at a younger age and after less exposure to environmental factors, with attention to gender differences. A prospective observational multicenter study in 205 adult Caucasian patients with untreated first episode of Graves' hyperthyroidism. Evaluation of genotypes (HLA DRB1*03, DQA1*05, DQB1*02; CTLA4 49A/G, CT60 A/G; PTPN22 C/T) in relation to phenotypes (age, sex, severity (clinical, biochemical, and immunological)) of hyperthyroidism and environmental factors (smoking, stress questionnaires). G-alleles in CTLA4 single nucleotide polymorphisms were dose-dependently associated with younger age at the time of diagnosis and less exposure to daily hassles. In gender-specific analysis, this association is enhanced in men and attenuated in women. Males (but not females) in HLA linkage disequilibrium had more severe (biochemical and immunological) hyperthyroidism and a tendency to younger age at diagnosis, compared with those not in linkage disequilibrium. Graves' hyperthyroidism occurs at a younger age with less exposure to environmental factors in subjects carrying susceptibility genotypes. The impact of genotypes seems to be greater in males than in females.