Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Compelling Evidence Linking CD40 Gene With Graves' Disease in the Chinese Han Population.

ABSTRACT: 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 (P _Combined = 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.

SUBMITTER: Jiang H

PROVIDER: S-EPMC8639283 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Correlation between CTLA-4 and CD40 gene polymorphisms and their interaction in graves' disease in a Chinese Han population.

Project description:BackgroundSingle-nucleotide polymorphism (SNP) haplotype and SNP-SNP interactions of CTLA-4 and CD40 genes, with susceptibility to Graves' disease (GD), were explored in a Chinese Han population.MethodsSNP were genotyped by high resolution melting (HRM). Use the method of Pearson χ2 test and Logistic regression for the association between single SNP and Graves' disease. Using the method of χ2 test and Multifactor Dimensionality Reduction (MDR) to analysis the haplotype frequency distribution, the interaction of SNPs respectively.ResultsGenotypic and allelic frequencies of SNP rs231775, rs3087243 and rs1883832 were statistically different between controls and GD (p < 0.05). Mutant allelic frequency of G rs231775 was higher, and A and T allelic frequencies of rs3087243 and rs1883832 were lower in GD than in controls (P < 0.05). In CTLA-4 rs1024161, rs5742909, rs231775, rs231777, rs231779, rs3087243 and rs11571319 showed D' < 50% and r2 < 0.3 among each SNP. We identified six commonly found haplotypes; TCGCTGC was associated with the highest GD risk (OR = 2.565) and TCACTAC the lowest (OR = 0.096). MDR analysis indicated interactions among the rs231775 GG, rs231779 TT and rs3087243 GG genotypes in CTLA-4 might increase GD risk by 2.53-fold (OR = 2.53).ConclusionCTLA-4 and CD40 were associated with GD incidence in a Chinese Han population. The TCGCTGC and TCACTAC haplotypes in the CTLA-4 gene, were risk and protective factors for Graves'disease respectively. Interactions among the SNPs of rs231775, rs231779 and rs3087243 significantly increase the susceptibility to GD.

| S-EPMC6142355 | biostudies-literature

Association of the CTLA4 gene with Graves' disease in the Chinese Han population.

Project description:To determine whether genetic heterogeneity exists in patients with Graves' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81x10(-9), OR = 1.35, and genotype distributions p = 2.75x10(-9), OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.

| S-EPMC2843719 | biostudies-literature

Association of genetic variations in FoxP3 gene with Graves' disease in a Southwest Chinese Han population.

Project description:BackgroundGraves' disease (GD) is a T cell-mediated organ-specific autoimmune disease. Forkhead box P3 (FoxP3) is an excellent marker for the induction and development of regulatory T cells (Tregs). Recent studies showed that single-nucleotide polymorphisms (SNPs) in the FoxP3 gene were associated with the increased susceptibility to several autoimmune diseases. In the present study, we investigated the association of FoxP3 gene polymorphisms with GD in a Southwest Chinese Han population.MethodsA two-stage case-control study was performed in 890 healthy controls (male, 282; female, 608) and 503 patients with GD (male, 138; female, 365). Four SNPs (rs3761548, rs3761549, rs3761547, and rs2280883) were genotyped by the polymerase chain reaction-restriction fragment length polymorphism assay. The χ2 test was used to compare the genotype distributions and allele frequencies between GD patients and healthy controls.ResultsIn the first stage, the significantly increased frequencies of the A allele (p = .031, odds ratio [OR] = 1.635) and AA genotype (p = .023, OR = 3.257), together with a significantly decreased frequency of the C allele (p = .031, OR = 0.611) of FoxP3/rs3761548 were found in female patients with GD. None of the other FoxP3 SNPs was associated with GD susceptibility. Subsequent validation and combination of data confirmed the association between FoxP3/rs3761548 and the female patients with GD (A allele: p < .001, OR = 1.672; AA genotype: p = .005, OR = 2.488; CC genotype: p = .001, OR = 0.622; C allele: p < .001, OR = 0.615, respectively).ConclusionOur findings suggest that FoxP3/rs3761548 is significantly associated with female GD patients in a Southwest Chinese Han population.

| S-EPMC10571500 | biostudies-literature

Fine mapping of thyroglobulin gene identifies two independent risk loci for Graves' disease in Chinese Han population.

Project description:BackgroundThis study aimed to determine independent risk loci of Graves' disease (GD) in the thyroglobulin (TG) region.MethodsIn this two-staged association study, a total of 9,757 patients with GD and 10,626 sex-matched controls were recruited from Chinese Han population. Illumina Human660-Quad BeadChips in the discovery stage and TaqMan SNP Genotyping Assays in the replication stage were used for genotyping. Trend test and logistic regression analysis were performed in this association study.ResultsIn the discovery stage, rs2294025 and rs7005834 were the most highly associated susceptibility loci with GD in TG. In the replication phase, 7 SNPs, including rs2294025 and rs7005834, were selected for fine-mapping. Finally, we confirmed that rs2294025 and rs7005834 were the independent risk loci of GD in the combined populations. At the same time, there was no significant difference between the risk allele frequencies of rs2294025 and rs7005834 in different clinical phenotypes of GD.ConclusionsThe fine mapping study of thyroglobulin identified two independent SNPs (rs2294025 and rs7005834) for GD susceptibility. However, no significant differences for rs2294025 and rs7005834 were observed, between the different clinical phenotypes of GD, including gender, Graves' ophthalmopathy (GO), and serum levels of thyrotropin receptor antibody, thyroid peroxidase antibody, and thyroglobulin antibody. These results provide a deeper understanding of the association mechanism of thyroglobulin and GD risk.

| S-EPMC6803187 | biostudies-literature

Replication of association of nine susceptibility loci with Graves' disease in the Chinese Han population.

Project description:This study is to evaluate the association of 9 single nucleotide polymorphisms (SNPs) with Graves' disease (GD) in different homogenous samples of the Chinese Han population. A total of 2,865 unrelated individuals were enrolled from Linyi City, Shandong Province, China, including 1,139 patients of GD and 1,726 controls. All 9 SNPs showed significant associations with GD (P < 1.3×10(-4), Bonferroni corrected Pc < 0.001). The most significant association was detected at rs2281388 at the HLA-DPB1 locus (P=1.3×10(-21); OR=1.62, 95% CI: 1.47-1.79). After adjusting for gender and age, 7 SNPs remained significantly associated with GD (P < 3.4×10(-4), Pc < 0.003). The risk of GD caused by any of these SNPs was not significantly different between female and male participants (Phet > 0.15). Four SNPs located in MHC regions were significantly associated with GD in different ages (P < 8.4×10(-4), Pc < 0.04). The risks of any SNP leading to the development of GD did not differ significantly in different ages (P_trend > 0.02, Pc > 0.18). The rs6457617 at the HLA-DR-DQ locus was significantly correlated with gender in GD patients (P=0.004, Pc =0.04). No significant correlation was found between any SNP and age of diagnosis in GD patients (P > 0.02, Pc > 0.17). The 9 previously identified SNPs are associated with GD in the Chinese Han population. And, gender and age may not influence the associations between the 9 SNPs and GD.

| S-EPMC4276217 | biostudies-literature

Candidate gene associations reveal sex-specific Graves' disease risk alleles among Chinese Han populations.

Project description:BACKGROUND:With several susceptibility single nucleotide polymorphisms identified by case-control association studies, Graves' disease is one of the most common forms of autoimmune thyroid disease. In this study, we aimed to determine whether any observed differences in genetic associations are influenced by sex in Chinese Han populations. METHODS:A total of 8,835 patients with Graves' disease and 9,936 sex-matched healthy controls were enrolled in the study. Confirmed by a two-staged association analysis, sex-specific analyses among 20 Graves' disease susceptibility loci were conducted. RESULTS:A significant sex-gene interaction was detected primarily at rs5912838 on Xq21.1 between the GPR174 and ITM2A genes, whereby male Graves' disease patients possessed a significantly higher frequency of risk alleles than their female counterparts. Interestingly, compared to women, male patients with Graves' disease had a higher cumulative genetic risk and higher persistent thyroid stimulating hormone receptor antibody-positive rate after receiving antithyroid drug therapy for at least 1 year. CONCLUSION:The findings of this study suggest the existence of one potential sex-specific Graves' disease variant on Xq21.1. This could increase our understanding of the pivotal mechanism behind Graves' disease and ultimately aid in identifying possible therapeutic targets.

| S-EPMC7336758 | biostudies-literature

A genetic variant in the CD40 gene is related to HBV infection in the Chinese Han population.

Project description:BackgroundCD40 is an important immune costimulatory molecule that has recently been found to be associated with chronic hepatitis B. This study aims to explore the association between CD40 polymorphisms and HBV infection, as well as to investigate the impact of different rs1883832 genotypes on CD40 expression and its effect on the progression of chronic HBV infection.MethodsWe genotyped rs1883832 in 3433 individuals using MassARRAY, and quantified the CD40 expression, including CD40 mRNA, sCD40, and mCD40. The CD40 and HBV infection indicators were assessed to investigate the potential function of rs1883832 in suppressing HBV replication in HepG2.2.15 and HepAD38, CD40L in cytotoxic t lymphocytes (CTLs) and interferon-γ, TNF-α, granzyme B, and perforin were measured to elucidate the mechanism by which CD40 inhibits HBV replication.ResultsOur study revealed that the frequencies of CC genotype and C allele of rs1883832 were significantly higher in immune recovery compared to chronic hepatitis B. Individuals with CC genotype exhibited significantly elevated CD40 in serum and B cells compared to TT genotypes in chronic hepatitis B. Additionally, CD40 is capable of inhibiting HBV replication and transcription in hepatocytes by means of interaction with CD40L. A significant negative correlation was found between HBV DNA, HBeAg, and mCD40. Conversely, the expressions of ALT and mCD40 showed a positive correlation, which aligns with the trend of CD40L.Conclusionsrs1883832 C allele may have a protective role in HBV immune recovery. This protective effect could potentially be attributed to the regulation of CD40 expression. The activation of the anti-HBV immune response, which occurs through binding CD40L on CTL, can suppress HBV DNA replication and potentially facilitate immune recovery in HBV infection.

| S-EPMC10697618 | biostudies-literature

Association of CD40 Gene Polymorphisms With Systemic Lupus Erythematosus and Rheumatoid Arthritis in a Chinese Han Population.

Project description:Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases. CD40 participates in inflammatory response, and promotes fibroblast proliferation, leading to occurrence and progression of SLE, RA. This study explores CD40 gene polymorphisms in SLE and RA patients from a Chinese Han population. Two hundred SLE patients, 340 RA patients, and 900 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood, and six polymorphisms of CD40 gene (rs3765456, rs1569723, rs73115010, rs13040307, rs1883832, and rs4810485) were detected by KASP method. Frequencies of rs1569723 genotypes AA, AC, AA+AC were significantly higher in RA patients as compared to those in healthy controls (P = 0.049, P = 0.024, P = 0.022). Frequencies of genotypes CT, CC+CT of rs1883832, and GT, GG+GT of rs4810485 were significantly higher in RA patients as compared to those in healthy controls (P = 0.012, P = 0.018, P = 0.009, P = 0.015). RA patients carrying rs13040307 C allele and rs73115010 T allele showed increased number of swollen joints. Moreover, frequency of allele T of rs13040307 was lower in SLE patients with positive anti-dsDNA and hematuria as compared to that in patients without these parameters (P = 0.038, P = 0.045). There were increased frequencies of genotype TT, allele T for rs13040307 and lower frequencies of genotype TT, allele T for rs73115010 in lupus patients with myositis (all P<0.05). Interestingly, frequencies of rs1569723 A allele, rs4810485 T allele were higher in SLE patients with myositis, and frequencies of rs3765456 A allele, rs1883832 T allele were lower in SLE patients with myositis (All P<0.05). In conclusion, CD40 gene polymorphisms may associate with susceptibility to SLE and RA.

| S-EPMC8100582 | biostudies-literature

Genetic heterogeneity of susceptibility gene in different ethnic populations: refining association study of PTPN22 for Graves' disease in a Chinese Han population.

Project description:In our previous studies, we presumed subtypes of Graves' disease (GD) may be caused by different major susceptibility genes or different variants of a single susceptibility gene. However, more evidence is needed to support this hypothesis. Single-nucleotide polymorphism (SNP) rs2476601 in PTPN22 is the susceptibility loci of GD in the European population. However, this polymorphism has not been found in Asian populations. Here, we investigate whether PTPN22 is the susceptibility gene for GD in Chinese population and further determine the susceptibility variant of PTPN22 in GD. We conducted an imputation analysis based on the results of our genome-wide association study (GWAS) in 1,536 GD patients and 1,516 control subjects. Imputation revealed that 255 common SNPs on a linkage disequilibrium (LD) block containing PTPN22 were associated with GD (P<0.05). Nine tagSNPs that captured the 255 common variants were selected to be further genotyped in a large cohort including 4,368 GD patients and 4,350 matched controls. There was no significant difference between the nine tagSNPs (P>0.05) in either the genotype distribution or allelic frequencies between patients and controls in the replication study. Although the combined analysis exhibited a weak association signal (P(combined) = 0.003263 for rs3811021), the false positive report probability (FPRP) analysis indicated it was most likely a false positive finding. Our study did not support an association of common SNPs in PTPN22 LD block with GD in Chinese Han population. This suggests that GD in different ethnic population is probably caused by distinct susceptibility genes.

| S-EPMC3875558 | biostudies-literature

Precision Medicine in Graves' Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody.

Project description: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.

| S-EPMC8212124 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data