Programmed Cell Death-1 Gene Research Articles

Association of programmed death-1 gene polymorphisms with the risk of basal cell carcinoma.

Environmental and genetic factors play a fundamental role in the pathogenesis of basal cell carcinoma (BCC) defined as the most common cancer of skin. Programmed death-1 (PD-1), encoded by programmed cell death-1 (PDCD1) gene, serves as an inhibitory molecule in the suppression of immune responses and a risk factor in the development of different cancers. In this study, we investigated the role of two single nucleotide polymorphisms (SNPs) within PDCD1 gene, and haplotypes defined by these SNPs, in the development of BCC in an Iranian population. Whole blood samples were obtained from 210 BCC and 320 healthy subjects. Genomic DNA was extracted from whole blood samples, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype determinations of PD1.3 (rs11568821) and PD1.5 (rs2227981) SNPs, and 4 haplotypes were constructed by PDCD1 SNPs. The frequency of G allele of PD1.3 was significantly higher in BCC patients than healthy subjects (p<0.02), while these significant differences were not observed in the frequencies of PD1.5 alleles between BCC and healthy subjects. Moreover, we found that there were no statistically significant differences in PD1.3 and PD1.5 genotypes between BCC and control groups. Of all estimated haplotypes for PDCD1, only AC haplotype was associated with BCC (OR=0.22, 95% CI=0.06-0.79, p<0.01). These findings suggest that PD1.3G allele and AC haplotype of PDCD1 contribute to BCC in the Iranian population. However, further studies in different populations with larger sample size are required to confirm this study.

Synergistic Antitumor Effect on Bladder Cancer by Rational Combination of Programmed Cell Death 1 Blockade and CRISPR-Cas9-Mediated Long Non-Coding RNA Urothelial Carcinoma Associated 1 Knockout.

Targeted therapy produces objective responses in bladder cancer patients, although the responses can be short. Meanwhile, response rates to immune therapy are lower, but the effects are more durable. Based on these findings, it was hypothesized that urothelial carcinoma associated 1 (UCA1)-targeted therapy could synergize with programmed cell death 1 (PD-1) blockade to enhance antitumor activity. To test this hypothesis, the effects of CRISPR-Cas9 targeting of UCA1 and PD-1 were assessed in vitro and in vivo. It was found that gRNA/cas9-targeted UCA1 induced apoptosis of 5637 bladder cancer cells, whereas PD-1 gene knockout could be achieved by electroporation of gRNA/cas9 targeting PD-1, as detected by polymerase chain reaction. In 5637 cell-xenografted humanized SCID mice, stimulation with CRISPR-Cas9 systems, immune phenotypes, and cytokine expression of human dendritic cells (DCs) was detected by flow cytometry, and polymerase chain reaction, respectively. The results of these assays suggested that the gRNA/cas9 treatment upregulated expression of CD80, CD83, and CD86 and significantly increased interleukin (IL)-6, IL-12, and IL-23 and tumor necrosis factor alpha mRNA levels. Co-administration of anti-PD-1 and anti-UCA1 treatment suppressed tumor growth and markedly improved survival of 5637 xenografted mice. Additionally, the combination treatment increased interferon gamma production by T cells that subsequently enhanced the expression of Th1-associated immune-stimulating genes to reduce transcription of regulatory/suppressive immune genes and reshape the tumor microenvironment from an immunosuppressive to a stimulatory state. Finally, anti-UCA1 treatment was shown to induce interferon gamma-dependent programmed cell death ligand 1 expression within 5637 xenograft tumors in vivo. Together, these results demonstrate potent synergistic effects of a combination therapy using LncRNA UCA1-targeted therapy and immune checkpoint blockade of PD-1, thus supporting the translational potential of this combination strategy for clinical treatment of bladder cancer.

PD-1 Haplotype Combinations and Susceptibility of Patients to Squamous Cell Carcinomas of Head and Neck

ABSTRACTIntroduction: Head and neck squamous cell carcinomas (HNSCCs) are the most common cancers of head and neck and the sixth most common malignancy worldwide. Programmed cell death 1 (PD-1) is an immune inhibitory molecule which through interaction with its ligands recruits protein phosphatase resulting in immune response inhibition. Expression of PD-1 ligands on tumor cells is considered as one of the crucial immune evasion mechanisms. This study aimed to investigate the association of PD-1 gene polymorphisms at positions PD1.3 (rs11568821), PD1.5 (rs2227981) and PD1.9 (rs2227982) with susceptibility to HNSCCs.Subjects and methods: 150 patients pathologically confirmed to suffer from HNSCCs and 150 age-sex matched healthy controls were recruited in this study. Genomic DNA was extracted from white blood cells of all participants. Restricted fragment length polymorphisms (RFLP)-PCR was performed using site specific primers to determine the genotypes in each position.Results: Statistical analyses indicated no significant differences in the frequencies of genotypes, alleles as well as haplotypes between patients and controls (P > 0.05), however, haplotype combination differed significantly between two groups. GCC/GCT, GCC/GCC and GCT/GCC were higher in the HNSCC patients than the control group (P < 0.05). On the other hand, in the controls, GCT/GCT, GCT/ACC, GCT/ACT and ACC/GCT were more frequent. No significant association was found with various HNSCC clinicopathological characteristics.Discussion: Our results suggested that although PD-1 gene polymorphisms at three investigated positions are not solely associated with susceptibility to HNSCCs, haplotype combinations emerged from these three loci may render susceptibility.

Safety and activity of programmed cell death-1 gene knockout engineered t cells in patients with previously treated advanced esophageal squamous cell carcinoma: An open-label, single-arm phase I study.

3054Background: We designed the clinical trial to investigate the safety and activity of Programmed death-1 (PD-1) knockout engineered T cell in patients with advanced esophageal squamous cell carc...

Programmed cell death 1 gene polymorphism association with activity and severity of systemic lupus erythematosus and rheumatoid arthritis in Egyptian patients

Background Programmed cell death 1 (PD-1) is an inhibitory regulator molecule of T cells and B cells. The PD-1 gene polymorphism was reported to be associated with autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), with conflicting results in different studies. Aim The aim was to investigate the potential association of PD-1.3 (rs11568821) polymorphism with SLE and RA in Egyptian patients and its relationship to the disease activity and severity. Patients and methods A total of 88 Egyptian patients with RA and 95 Egyptian patients with SLE as well as 85 healthy Egyptian controls were included in this study. PD1.3G/A (rs11568821) polymorphism was performed by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) technique. Results There was a significant difference in the distribution of A allele of PD-1.3 between RA, SLE, and control groups (38, 40, and 16%, respectively). Patients carrying A allele had high risk for RA and SLE in comparison with healthy control. Patients with RA with AA genotype had a significantly higher levels of C-reactive protein, erythrocyte sedimentation rate, anticyclic citrullinated peptide positivity, disease activity index 28, and modified Sharp score compared with those with GG and GA genotypes. Moreover, in SLE, AA genotype was significantly correlated with low C3 and C4, high proteinuria, positive anti-dsDNA antibody production, and damage index. Conclusion PD1.3G/A (rs11568821) polymorphism was associated with an increased risk of RA and SLE in Egyptian patients, so it could be a reasonable genetic risk factor for both diseases. Moreover, patients with RA and SLE who are homozygous for A allele are susceptible to have increased disease activity and severity.

Case-control Association Study of Autoimmunity Associated Variants in PDCD1 and Juvenile Idiopathic Arthritis.

Purpose: Variants in the gene encoding Programmed Cell Death-1 (PDCD1) have been associated with susceptibility to Systemic Lupus Erythematosus and other autoimmune diseases. Giv-en that clinically distinct autoimmune phenotypes share common genetic susceptibility factors, vari-ants in PDCD-1 were tested for a possible association with Juvenile Idiopathic Arthritis (JIA).Methods: Four Single Nucleotide Polymorphisms (SNPS) in the PDCD1 gene were genotyped and analyzed: rs7421861, rs11568821, rs10204525, and rs7568402 in 834 cases and 855 controls of Northern European ancestry. Each variant was examined for possible associations with JIA and then analyzed for association with JIA categories.Results:PDCD1 variants showed no association with JIA in the cohort overall (rs7421861 p=0.63, rs11568821 p=0.13, rs10204525 p=0.31, and rs7568402 p=0.45). Stratification by JIA categories indicated a significant association between systemic JIA and PDCD1 rs7568402 (OR=0.53, p=0.0027), which remained significant after 10,000 permutations, but was not replicated in an inde-pendent multi-ethnic systemic JIA cohort. A nominal association between enthesitis-related arthritis and rs115668821 was also observed (OR=0.22, p=0.012).Conclusion: Unlike other multiple autoimmune disease associated genetic variants, there was no as-sociation between PDCD1 variants and JIA or JIA categories.

Are programmed cell death 1 gene polymorphisms correlated with susceptibility to rheumatoid arthritis?

Background:Several studies investigated the relationship between programmed cell death 1 (PDCD1) gene polymorphisms and rheumatoid arthritis (RA) risk, but the results were controversial. To explore whether PDCD1 gene polymorphisms have an effect on RA risk, we conducted this meta-analysis to investigate the relationships between PDCD1 polymorphisms (rs36084323 [PD-1.1 G/A], rs11568821 [PD-1.3 G/A] and rs2227981 [PD-1.5 C/T]) and RA risk under 4 genetic models.Methods:PubMed, EMBASE, Web of Science, Cochrane Library China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBLM) were systematically searched for all eligible case-control studies. The last search was updated on September 10, 2016. Studies were accessed using Newcastle-Ottawa Scale case control study (NOS), and the combined effect size was calculated using STATA software, version 12.0. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the association. Heterogeneity analysis and subgroup analysis were also performed. Sensitivity analysis and publication bias were also performed if necessary.Results:This meta-analysis included 6 studies. The result demonstrated null association between rs36084323 (PD-1.1 G/A) polymorphism and RA susceptibility in all 4 genetic models. With regard to rs11568821 (PD-1.3 G/A), statistically significant association with RA risk was observed under allele model in Caucasians (allele model A vs G, OR = 1.19, 95% CI = 1.03–1.41). There was no significant association between rs2227981 (PD-1.5 C/T) polymorphism and RA risk.Conclusion:The present study suggests that mutant A allele in rs11568821 (PD-1.3 G/A) might increase the susceptibility to RA in Caucasians.

Programmed death-1 polymorphisms is associated with risk of esophagogastric junction adenocarcinoma in the Chinese Han population: A case-control study involving 2,740 subjects.

Single nucleotide polymorphisms (SNPs) in Programmed cell death 1 (PD-1) gene may contribute to the development of cancer. In this study, we selected PD-1 rs10204525 T>C, rs2227982 A>G, rs36084323 T>C and rs7421861 A>G polymorphisms and designed a hospital-based case-control study to determine the potential relationship between these functional SNPs in PD-1 gene and esophagogastric junction adenocarcinoma (EGJA) risk. A total of 1,063 EGJA patients and 1,677 controls were enrolled from Eastern Chinese Han population. SNPscanTMgenotyping assay was used to analyze the genotyping of PD-1 polymorphisms. We found that PD-1 rs7421861 A>G polymorphism was associated with the development of EGJA. However, PD-1 rs2227982 A>G polymorphism was a protective factor for EGJA. In addition, PD-1 rs36084323 CC homozygote genotype might be associated with a borderline decreased risk of EGJA. In a subgroup analysis, a decreased risk of EGJA in never drinking and never smoking groups was identified. Haplotype comparison analysis suggested that PD-1 Trs10204525Grs2227982C36084323Ars7421861 haplotype significantly decreased the risk of EGJA. However, Trs10204525Grs2227982C36084323Grs7421861 haplotype in PD-1 gene may confer risk to EGJA. In conclusion, our study highlights rs2227982 A>G, rs36084323 T>C and rs7421861 A>G polymorphisms and haplotypes in PD-1 gene, especially within the intron region, are significantly associated with the risk of EGJA. Further case-control studies with larger sample size and detailed gene-environmental data to replicate these findings in different populations are needed to validate our conclusion.

Association of programmed cell death-1 gene polymorphisms with chronic hepatitis C virus infection and antiviral effect

Association of programmed cell death-1 gene polymorphisms with chronic hepatitis C virus infection and antiviral effect

Pathogenicinflammation in the CNS of mice carrying humanPLP1mutations

Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated the disease progression in mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of multiple sclerosis. These mouse models show loss-of-function of PLP1 associated with neuroinflammation; the latter leading to clinically relevant axonal degeneration, neuronal loss and brain atrophy as demonstrated by inactivation of the recombination activating gene 1. Moreover, these pathological hallmarks were substantially amplified when we attenuated immune regulation by inactivation of the programmed cell death-1 gene. Our observations support the view that primary oligodendroglial abnormalities can evoke pathogenically relevant neuroinflammation that drives neurodegeneration, as observed in some forms of multiple sclerosis but also in other, genetically-mediated neurodegenerative disorders of the human nervous system. As many potent immunomodulatory drugs have emerged during the last years, it is tempting to consider immunomodulation as a treatment option not only for multiple sclerosis, but also for so far non-treatable, genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.

Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush

Programmed cell death-1 (PD-1) is a key negative receptor inducibly expressed on T cells, B cells and dendritic cells. It was discovered on T cells undergoing classical programmed cell death. Studies showed that PD-1 ligation promotes retinal ganglion cell (RGC) death during retinal development. The purpose of this present study is to characterize PD-1 regulation in the retina after optic nerve crush (ONC). C57BL/6 mice were subjected to ONC and RGC loss was monitored by immunolabelling with RNA-binding protein with multiple splicing (Rbpms). Time course of PD-1 mRNA expression was determined by real-time PCR. PD-1 expression was detected with anti-PD-1 antibody on whole mount retinas. PD-1 staining intensity was quantitated. Colocalization of PD-1 and cleaved-caspase-3 after ONC was analyzed. Real-time PCR results demonstrated that PD-1 gene expression was significantly upregulated at day 1, 3, 7, 10 and 14 after ONC. Immunofluorescent staining revealed a dramatic increase of PD-1 expression following ONC. In both control and injured retinas, PD-1 tended to be up-expressed in a subtype of RGCs, whose somata size were significantly larger than others. Compared to control, PD-1 intensity in large RGCs was increased by 82% in the injured retina. None of the large RGCs expressed cleaved-caspase-3 at day 5 after ONC. Our work presents the first evidence of PD-1 induction in RGCs after ONC. This observation supports further investigation into the role of PD-1 expression during RGC death or survival following injury.

Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma

Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9-84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFα, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500-2,000-fold in vitro. Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted.

NF-κB regulates PD-1 expression in macrophages.

Programmed cell death-1 (PD-1) is responsible for T cell exhaustion during chronic viral infections and is expressed on a variety of immune cells following activation. Despite its importance, the mechanisms that regulate PD-1 in cell types other than CD8 T cells are poorly defined. In this study, the molecular mechanisms for inducing PD-1 expression in CD4 T cells, macrophages, and B cells were explored. In CD4 T cells, PD-1 induction following TCR stimulation required NFAT, as the calcineurin/NFAT pathway inhibitor cyclosporin A was able to block PD-1 induction in a manner similar to that seen in CD8 T cells. In contrast, LPS but not PMA and ionomycin stimulation was able to induce PD-1 expression in macrophages in a manner insensitive to cyclosporin A-mediated inhibition. B cells could use both pathways, although the levels of PD-1 expression were highest with PMA and ionomycin. An NF-κB binding site located upstream of the gene in conserved region C was required for NF-κB-dependent PD-1 gene activation in macrophages. Chromatin immunoprecipitation showed NF-κB p65 binding to this region following stimulation of macrophages with LPS. PD-1 induction was associated with histone modifications characteristic of accessible chromatin; however, in contrast to CD8 T cells, conserved region B in macrophages did not lose CpG methylation upon stimulation and PD-1 expression. The linkage of TLR/NF-κB signaling to the induction of PD-1 suggests the possibility of an opportunistic advantage to microbial infections in manipulating immune inhibitory responses.

Association between PDCD1 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus in Three Main Ethnic Groups of the Malaysian Population.

The programmed cell death 1 (PDCD1) gene encodes for the PD-1 (programmed death 1) molecule, which negatively regulates self-reactive T- and B-cells in the maintenance of peripheral tolerance. A previous report had shown the development of lupus-like phenotypes in PD-1-deficient C57BL/6 mice, was suggestive to the role of PDCD1 in predisposing to systemic lupus erythematosus (SLE). Hence, we aimed to investigate the association between PDCD1 and SLE susceptibility in the Malaysian population. A TaqMan-based real-time PCR was employed to screen for PD1.1, PD1.3, PD1.5 and PD1.6 in both SLE and healthy control groups of 200 samples each. The observed frequency for PD1.5C/C genotype was significantly higher in Indian SLE patients and Malay controls (p < 0.01). On the other hand, the PD1.5C/T genotype might predispose the Malays to SLE, but confer a protective effect among the Indians (p < 0.01). The PD1.1, PD1.3 and PD1.6 were, however, not correlated to genetic predisposition of SLE in our Malaysian population. In conclusion, PD1.5 variant was significantly associated to SLE susceptibility in our Malaysian cohort. Our failure in replicating the association between other investigated PDCD1 variants and risk of getting SLE might due to ethnic and geographic variations in the distribution of these genetic variants.

Relationship between programmed cell death-1 polymorphisms and clearance of hepatitis B virus.

Programmed cell death-1 (PD-1) plays a critical role in regulating T-cell function during hepatitis B virus (HBV) infection. This study investigated the relationship between the polymorphisms of PD-1 gene and the susceptibility to HBV infection. Single nucleotide polymorphisms (SNPs) in PD-1 gene at positions +7146 G>A (guanine to adenine substitution) and +7209 C>T (cytosine to thymine substitution) were analysed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 220 subjects with chronic hepatitis B infection and 165 spontaneous clearance of HBV subjects. However, no statistically significant differences were found in the genotype distributions of the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms among chronic hepatitis B and spontaneous clearance subjects. According to stratified analyses, borderline significance was observed between PD-1 +7146 GA genotype and risk of HBV chronicity in the subgroup of male gender (OR = 1.88, 95% 0.95-3.71; P = 0.07). Our findings demonstrate for the first time that the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms have not been any major role in genetic susceptibility to chronicity of HBV infection, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.

Clinical scale zinc finger nuclease (ZFN)-driven gene-editing of PD-1 in tumor infiltrating lymphocytes (TIL) for the potential treatment of metastatic melanoma

Multiple inhibitory pathways exist to block the immune response to cancer potentially limiting the effectiveness of adoptive cell transfer (ACT). Programmed cell death-1 (PD-1) is a member of the CD28 superfamily and is expressed on activated T cells. Its ligands, PDL-1 and PDL-2 are expressed on a variety of tumor cells, including melanoma. The binding of PD-1 to PDL-1 inhibits T cell effector function, and represents an important mechanism for PDL-1 expressing tumors to evade the host immune response to cancer. PD-1 thus represents an attractive target for gene-editing of tumor-targeted T cells prior to ACT. To this end, our aim was to eliminate PD-1 expression in tumor infiltrating lymphocytes (TIL) by genome-editing using zinc finger nucleases (ZFNs) directed against the PD-1 gene at a scale sufficient for patient treatment. Using the MaxCyte GT Flow Transfection System to deliver mRNA encoding the PD-1 ZFNs, we show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9 - 84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Importantly, the PD-1 gene-edited TIL product displayed an effector memory phenotype and expanded approximately 500 - 2000 fold during a rapid cell expansion in vitro while retaining T cell effector function. Thus further study to determine the safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted.

The programmed cell death 1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T and PD 1.9 C/T) and susceptibility to ankylosing spondylitis: a meta-analysis.

The objective is to integrate all the eligible studies and investigate whether the programmed cell death 1 (PDCD-1) gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T, and PD 1.9 C/T polymorphism) are correlated with ankylosing spondylitis risk (AS). Ankylosing spondylitis is a chronic inflammatory disease, and several genetic and environmental factors play an important role in the development and progression of AS. Significant associations between PDCD-1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T or PD 1.9 C/T) and AS risk have been reported; however, some of these results are controversial. A systematic online search was performed using PubMed, EMBASE, Web of Science, and the Cochrane Library to identify case-control studies investigating the relationship between PD 1.3 G/A, PD 1.5 C/T, and PD 1.9 C/T polymorphisms and the susceptibility of AS. The pooled odds ratio (OR) with 95 % confidence interval (CI; 95 %) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study populations. Five studies involving 909 cases and 982 controls met the inclusion criteria after assessment by two reviewers. Overall, there were no significant associations between PD 1.3 G/A and PD 1.5 C/T polymorphisms and AS risk. With regard to PD 1.9 C/T polymorphism, a significant association was found under the allele contrast model (T vs. C: OR 1.74, 95 % CI 1.48-2.06, P < 0.001), heterozygote model (CT vs. CC: OR 2.43, 95 % CI 1.65-3.59, P < 0.001), homozygote model (TT vs. CC: OR 1.87, 95 % CI 1.30-2.71, P = 0.001), and dominant model (CT/TT vs. CC: OR 2.29, 95 % CI 1.65-3.18, P < 0.001). In the subgroup analysis of ethnicity, no significant associations were found between PD 1.3 G/A, PD 1.5 C/T polymorphisms, and AS risk in either Asian or Caucasian populations. However, our study suggested that PD 1.9 C/T polymorphism was significantly associated with AS in Asian populations (T vs. C: OR 1.72, 95 % CI 1.46-2.04, P < 0.001; CT vs. CC: OR 2.44, 95 % CI 1.56-3.82, P < 0.001; TT vs. CC: OR 1.88, 95 % CI 1.30-2.73, P = 0.001; and CT/TT vs. CC: OR 2.29, 95 % CI 1.58-3.32, P < 0.001) but not in Caucasian populations. The PD 1.9 C/T polymorphism may be involved in susceptibility to AS, particular in Asian populations; however, no significant associations were found between PD 1.3 G/A, PD 1.5 C/T polymorphisms, and AS risk in either Asians or Caucasians.

Association of the costimulatory molecule gene polymorphisms and active cytomegalovirus infection in hematopoietic stem cell transplant patients

Determinative associations may exist between costimulatory molecule gene polymorphisms with a variety of post hematopoietic stem cell transplantation (HSCT) viral related clinical outcomes especially acute graft versus host disease (aGVHD). Therefore in this study the associations between costimulatory molecule gene polymorphisms including: cytotoxic T-lymphocyte antigen-4 (CTLA4), programmed cell death-1 (PD-1), inducible T cell costimulator (ICOS), and cluster differentiation 28 (CD28) with active cytomegalovirus (CMV) infection were evaluated in HSCT patients. The 72 allogeneic HSCT patients with and without aGVHD were enrolled in this cross sectional study between years: 2004-2011. The single nucleotide polymorphisms in loci of the costimulatory molecules including: CTLA4 gene (-318 C/T, 1722 T/C, 1661 A/G, +49 A/G), PD-1 gene (PD-1.3 A/G, PD-1.9 C/T), ICOS gene (1720 C/T), and CD28 gene (+17 C/T) were analyzed in studied HSCT patients by PCR-RFLP methods. The active CMV infection was evaluated in fresh EDTA-treated blood samples of each allogeneic HSCT patients by CMV antigenemia kit according to manufacturer's instruction. Active CMV infection was found in 11 of 72 (15.27 %) of allogeneic HSCT patients. The T allele and TT genotype of the CD28 +17 C/T were significantly higher frequency in active CMV infected allogeneic HSCT patients experienced aGVHD. The G allele and GG genotype of the CTLA4 -1661 A/G were significantly higher frequent in active CMV infected allogeneic HSCT patients experienced low grade of aGVHD. Finally, finding of significant associations between CD28 +17 C/T and CTLA4 -1661 A/G genotypes with CMV active infection in allogeneic HSCT patients experienced aGVHD emphasize on the importance of the genetic pattern of costimulatory genes in outcomes of active CMV infection in HSCT patients needs completed studies.

An exon polymorphism of programmed cell death 1 gene is associated with both the susceptibility and thoracolumbar kyphosis severity of ankylosing spondylitis in a Chinese Han population

BackgroundAlthough human leukocyte antigen (HLA)-B27 gene is the major susceptible gene associated with ankylosing spondylitis (AS), it has been recognized that non-HLA-B27 genes also play key roles in the development of AS. The purpose of this study is to investigate whether a single nucleotide polymorphism (SNP) in the exon region of the programmed cell death 1 (PDCD-1) gene is associated with the susceptibility or the thoracolumbar kyphosis severity of AS in a Chinese Han population. MethodsA total of 255 AS patients between January 2008 and October 2012 were recruited in this study. Two hundred and three healthy patients were recruited as normal controls. According to the severity of thoracolumbar kyphosis, the AS patients were further divided into group A (patients with kyphosis <70°, n=135) and group B (patients with kyphosis ≥70°, n=120). One exon polymorphism, rs2227982 (C/T) of PDCD-1 gene, was selected for analysis. Genotyping was performed by TaqMan probe assays in all the subjects. ResultsThere were significant differences of genotype distributions of rs2227982 between AS patients and normal controls. The frequency of the T allele was significantly higher in AS patients when compared with normal controls. The frequency of the T allele in group B was significantly higher than that in group A. Carriage of the TT genotype increased the risk of severe thoracolumbar kyphosis 1.9-fold in AS patients. ConclusionsOur study confirms a significant association between the SNP rs2227982 of PDCD-1 gene and the susceptibility of AS in a Chinese Han population. Moreover, the TT genotype is suggested to be associated with the severity of thoracolumbar kyphosis secondary to AS.

Lack of association between CTLA-4 and PDCD1 polymorphisms and acute rejection in German liver transplant recipients

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that are involved in regulation transplant rejection and tolerance induction. Thus, CTLA-4 and PDCD1 may be good candidate genes to evaluate in liver transplant rejection. In this retrospective study, we investigated whether four functional single nucleotide polymorphisms (SNP) of the CTLA-4 gene and PDCD1 gene were associated with susceptibility to liver transplant rejection. The SNPs -1772T>C (rs733618), -1661A>G (rs4553808) of the CTLA-4 gene, and the SNPs 7146G>A (rs11568821), 7209C>T (rs41386349) of the PDCD1 gene were genotyped by polymerase chain reaction allele specific restriction enzyme analysis (PCR-ASRA) in 100 liver recipients with acute rejection, 104 liver transplant recipients without acute rejection and 100 healthy control individuals. For the selected SNPs we did not detect any significant difference in genotypic and allelic frequencies between liver transplant recipients with and without acute rejection. In conclusion, our results suggest that the tested SNPs may not be associated with susceptibility to acute liver transplant rejection in a Caucasian population.