scholarly journals Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

2021 ◽  
Vol 12 ◽  
Author(s):  
Larissa C. Faustino ◽  
George J. Kahaly ◽  
Lara Frommer ◽  
Erlinda Concepcion ◽  
Mihaela Stefan-Lifshitz ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Precision Medicine ◽  
Clinical Response ◽  
Whole Blood ◽  
Graves Disease ◽  
Mrna Levels ◽  
Gene Drive ◽  
Single Nucleotide ◽  
Expression Levels ◽  
Cd40 Gene

BackgroundCD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.MethodsWe extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients’ CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab.ResultsThree common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab.ConclusionOur data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD.

scholarly journals A Graves’ Disease-Associated Kozak Sequence Single-Nucleotide Polymorphism Enhances the Efficiency of CD40 Gene Translation: A Case for Translational Pathophysiology

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2684-2691 ◽  
Author(s):  
Eric M. Jacobson ◽  
Erlinda Concepcion ◽  
Taiji Oashi ◽  
Yaron Tomer
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Translation System ◽  
Graves Disease ◽  
Mrna Levels ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Kozak Sequence ◽  
Cd40 Gene ◽  
Cd40 Expression

Abstract We analyzed the mechanism by which a Graves’ disease-associated C/T polymorphism in the Kozak sequence of CD40 affects CD40 expression. CD40 expression levels on B cells in individuals with CT and TT genotypes were decreased by 13.3 and 39.4%, respectively, compared with the levels in CC genotypes (P = 0.012). Similarly, Rat-2 fibroblasts transfected with T-allele cDNA expressed 32.2% less CD40 compared with their C-allele-transfected counterparts (P = 0.004). Additionally, an in vitro transcription/translation system showed that the T-allele makes 15.5% less CD40 than the C-allele (P < 0.001), demonstrating that the effect of the single-nucleotide polymorphism (SNP) on CD40 expression is at the level of translation. However, the SNP did not affect transcription, because the mRNA levels of CD40, as measured by quantitative RT-PCR, were independent of genotype. Therefore, our results may suggest that the C allele of the CD40 Kozak SNP, which is associated with Graves’ disease, could predispose to disease by increasing the efficiency of translation of CD40 mRNA.

A single nucleotide polymorphism in the CD40 gene on chromosome 20q (GD-2) provides no evidence for susceptibility to Graves' disease in UK Caucasians

2004 ◽  
Vol 61 (2) ◽  
pp. 269-272 ◽  
Author(s):  
Joanne M. Heward ◽  
Matthew J. Simmonds ◽  
Jackie Carr-Smith ◽  
Helen Foxall ◽  
Jayne A. Franklyn ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Graves Disease ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Cd40 Gene

scholarly journals Compelling Evidence Linking CD40 Gene With Graves’ Disease in the Chinese Han Population

2021 ◽  
Vol 12 ◽  
Author(s):  
He Jiang ◽  
Fei-Fei Yuan ◽  
Hai-Ning Wang ◽  
Wei Liu ◽  
Xiao-Ping Ye ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Graves Disease ◽  
Nucleotide Polymorphism ◽  
Rt Pcr ◽  
Chinese Han ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Cd40 Gene ◽  
Trait Locus ◽  
Robust Evidence

Mutations in CD40 have been widely reported to be risk factors for Graves’ disease (GD). The gene, along with its cognate ligand CD40L, may regulate pro-inflammatory and immune responses. Rs1883832, located at the -1 position of the Kozak sequence, is the most well-studied single nucleotide polymorphism (SNP) of CD40, and has been confirmed to predispose those with the alteration to GD, regardless of ethnicity. Our genome-wide association study (GWAS) indicated that several SNPs, including rs1883832 located within the vicinity of CD40 were associated with GD in the Han Chinese population. Aiming at identifying the most consequential SNP and its underlying pathogenic mechanism, we performed a two-stage refined study on 8,171 patients with GD and 7,906 controls, and found rs1883832 was the most significantly GD-associated SNP in the CD40 gene region (PCombined = 9.17×10-11, OR = 1.18). Through searching the cis-expression quantitative trait locus database and using quantitative RT-PCR, we further discovered that the rs1883832 genotype can influence CD40 gene transcription. Furthermore, we demonstrated that rs1883832 is a susceptibility locus for pTRAb+ GD patients. In conclusion, the current study provides robust evidence that rs1883832 can regulate CD40 gene expression and affect serum TRAb levels, which ultimately contributes to the development of GD.

scholarly journals Bone marrow stromal antigen 2 (BST-2) genetic variants influence expression levels and disease outcome in HIV-1 chronically infected patients

2021 ◽  
Author(s):  
Hlelolwenkosi Mlimi ◽  
Kewreshini K. Naidoo ◽  
Jenniffer Mabuka ◽  
Thumbi Ndung’u ◽  
Paradise Madlala
Keyword(s):  
Viral Load ◽  
Mrna Expression ◽  
Genetic Variants ◽  
Disease Outcome ◽  
Mrna Levels ◽  
Single Nucleotide ◽  
Cd4 Counts ◽  
Expression Levels ◽  
Hiv 1 ◽  
Mrna Expression Levels

Abstract BackgroundBone marrow stromal antigen 2 (BST-2) also known as Tetherin (CD317/HM1.24), is a host restriction factor that blocks the release of HIV-1 virions from infected cells. Previous studies reported that BST-2 genetic variants or single nucleotide polymorphims (SNPs) have a preventative role during HIV-1 infection. However, the influence of BST-2 SNPs on expression levels remains unknown. In this study, we investigated the inffluence of BST-2 SNPs on expression levels and disease outcome in HIV-1 subtype C chronically infected antiretroviral therapy naïve individuals.ResultsWe quantified BST-2 mRNA levels in peripheral blood mononuclear cells (PBMCs), determined BST-2 protein expression on the surface of CD4 + T cells using flow cytometry and genotyped single nucleotide polymorphisms (SNPs) rs919267, rs919266 and rs9576 using TaqMan assays from HIV-1 uninfected and infected participants. Determined the ability of plasma antibody levels to meadiate andibodydependenet cellular phagocytosis (ADCP) using gp120 consensus C and p24 subtype B/C protein. Fc receptor-mediated NK cell degranulation was evaluated as a surrogate for ADCC activity using plasma from HIV-1 positive participants. BST-2 mRNA expression levels in PBMCs and protein levels on CD4 + T cells were lower in HIV-1 infected compared to uninfected participants (p=0.075 and p=0.005, respectively). rs919267CT (p=0.042) and rs919267TT (p=0.045) were associated with lower BST-2 mRNA expression levels compared to rs919267CC in HIV-1 uninfected participants. In HIV-1 infected participants, rs919267CT associated with lower CD4 count, (p=0.003), gp120-IgG1 (p=0.040), gp120-IgG3 (p=0.016) levels and but higher viral load (p=0.001) while rs919267TT was associated with lower BST-2 mRNA levels (p=0.046), CD4 counts (p=0.001), gp120-IgG1 levels (p=0.033) but higher plasma viral load (p=0.007). Conversely, rs9576CA was associated with higher BST-2 mRNA expression levels (p=0.027), CD4 counts (p=0.079), gp120-IgG1 (p=0.009), -IgG3 (p=0.039) levels and but with lower viral load (p=0.037). However, there was not correlation between BST-2 SNPs, p24-IgG subclass, ADCC and ADCP activity. ConclusionOur findings show that bst- 2 SNPs mediate BST-2 expression and disease outcome, correlate with gp120-IgG1, gp120-IgG3 levels but p24-IgG levels, ADCC and ADCP activity. Future studies should investigate the role of BST-2 polymorphic variants on improving myeloid dentritic cell (DC) activation and MHC class II antigene presentation.

Association of a C/T Single-Nucleotide Polymorphism in the 5' Untranslated Region of the CD40 Gene with Graves' Disease in Japanese

Thyroid ◽  
2006 ◽  
Vol 16 (5) ◽  
pp. 443-446 ◽  
Author(s):  
Yoshiyuki Ban ◽  
Teruaki Tozaki ◽  
Matsuo Taniyama ◽  
Motowo Tomita ◽  
Yoshio Ban
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Untranslated Region ◽  
Graves Disease ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Cd40 Gene

scholarly journals Methylobacterium oryzae Influences Isoepoxydon Dehydrogenase Gene Expression and Patulin Production by Penicillium expansum

Water ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1427
Author(s):  
Tiago Barros Afonso ◽  
Lúcia Chaves Simões ◽  
Nelson Lima
Keyword(s):  
Gene Expression ◽  
Distribution Systems ◽  
Water Distribution ◽  
Penicillium Expansum ◽  
Transcriptional Level ◽  
Positive Trend ◽  
Mrna Levels ◽  
Expression Levels ◽  
Production Values ◽  
Methylobacterium Oryzae

Biofilms can be considered the main source of microorganisms in drinking water distribution systems (DWDS). The ecology of a biofilm is dependent on a variety of factors, including the presence of microbial metabolites excreted by its inhabitants. This study reports the effect of the Gram-negative bacteria Methylobacterium oryzae on the idh gene expression levels and patulin production of Penicillium expansum mature biofilms. For this purpose, a RT-qPCR method to quantify idh mRNA levels was applied. In addition, the idh expression levels were compared with the patulin production. The results obtained revealed that the effect of the bacterium on pre-established P. expansum biofilms is dependent on the time of interaction. More mature P. expansum biofilms appear to be more resistant to the inhibitory effect that M. oryzae causes towards idh gene expression and patulin production. A positive trend was observed between the idh expression and patulin production values. The results indicate that M. oryzae affects patulin production by acting at the transcriptional level of the idh gene.

Hypoxemia regulates effect of lipopolysaccharide on polymorphonuclear leukocyte CD11b/CD18 expression

1994 ◽  
Vol 76 (4) ◽  
pp. 1657-1663 ◽  
Author(s):  
H. H. Simms ◽  
R. D′Amico
Keyword(s):  
Monoclonal Antibody ◽  
Polymorphonuclear Leukocyte ◽  
Whole Blood ◽  
Lipid A ◽  
Cytochalasin B ◽  
Actinomycin D ◽  
H2o2 Production ◽  
Functional Capability ◽  
Receptor Shedding ◽  
Do So

Expression of the receptor CD11b/CD18 on the polymorphonuclear leukocyte (PMN) surface is important for several aspects of PMN function during endotoxemia. The mechanisms underlying regulation of CD11b/CD18 expression during hypoxemia and endotoxemia, however, are less clear. We investigated the effects of exposure of whole blood PMNs to lipopolysaccharide (LPS) during hypoxemia. During hypoxemia (10–30% O2 saturation), LPS reduced CD11b/CD18 expression. Both kinetic assays and experiments with microfilament stabilizers (phalloidin, cytochalasin B) demonstrated that this was most likely due to receptor shedding. Incubation of whole blood PMNs with an anti-CD14 monoclonal antibody (MEM18) largely prevented the LPS-induced reduction of CD11b/CD18 expression. Decreased CD11b/CD18 expression reduced PMN functional capability, as the binding of its ligand (erythrocytes opsonized with the 3rd component of complement Cbi) and intracellular H2O2 production were reduced. After exposure to LPS, N-formyl-methionyl-leucyl-phenylalanine could rapidly induce new CD11b/CD18 receptors to the cell surface, and this was not inhibited by actinomycin D or cycloheximide. After reoxygenation (> 90% O2 saturation), CD11b/CD18 expression was restored, and this was abrogated by exposure to cytochalasin B. Lipid A was able to reproduce the effects of LPS during hypoxemia and hypoxemia-reoxygenation but required a 10-fold greater concentration to do so. These results demonstrate that during hypoxemia an important pathophysiological property of LPS is to reduce CD11b/CD18 expression. This results in diminished PMN functional capability, which would contribute to the pathogenicity of LPS during acute infectious states.

scholarly journals Thyroid papillary carcinoma: preliminary evidence for a germ-line single nucleotide polymorphism in the Fas gene

2004 ◽  
Vol 182 (3) ◽  
pp. 479-484 ◽  
Author(s):  
F Basolo ◽  
R Giannini ◽  
P Faviana ◽  
G Fontanini ◽  
A Patricelli Malizia ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Germ Line ◽  
Thyroid Tissue ◽  
Preliminary Evidence ◽  
Graves Disease ◽  
Nucleotide Polymorphism ◽  
Single Strand Conformational Polymorphism ◽  
Single Nucleotide ◽  
N 93 ◽  
Immunohistochemical Studies

The expression of Fas in thyroid tumours and Graves' disease was analysed by mRNA transcript expression. As compared with unaffected thyroid tissue, Fas expression was enhanced in Graves' disease, adenomas, and papillary and follicular carcinomas. This pattern was also reflected in immunohistochemical studies. The PCR single-strand conformational polymorphism (SSCP) method and DNA sequencing were used to analyse Fas exons 1-9. The study was carried out on five different histotypes of thyroid tumours (n=93) and tissue from Graves' disease patients. As compared with a group of healthy blood donors (n=64), a significant association (P=0.006) emerged between papillary thyroid carcinoma and a silent single nucleotide polymorphism (SNP, 988C-->T) in exon 7 of the Fas gene. Other forms of thyroid pathology were not associated with the above polymorphism. Patients with neoplasia showed the same SNP in tumour tissue, in the unaffected contralateral thyroid lobe, and in peripheral blood cells. Thus, the 988C-->T polymorphism appeared to be of germ-line origin.

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