The Shared Mechanism and Candidate Drugs of Multiple Sclerosis and Sjögren’s Syndrome Analyzed by Bioinformatics Based on GWAS and Transcriptome Data

Hong, Xiangxiang; Wang, Xin; Rang, Xinming; Yin, Xinyue; Zhang, Xuemei; Wang, Rui; Wang, Duo; Zhao, Tingting; Fu, Jin

doi:10.3389/fimmu.2022.857014

Cited by 14 publications

(5 citation statements)

References 54 publications

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“…Our MR analysis identi ed a positive correlation between IL-10RB and SS risk. Given the reported close relationship between JAK-STAT and SS development (49,50), the potential role of abnormal IL-10RB expression and mediation of JAK-STAT pathway activation in SS pathogenesis merits in-depth exploration.…”

Section: Discussionmentioning

confidence: 99%

Association between cytokine cycling levels and Sjogren's syndrome: genetic correlation and bidirectional Mendelian randomization study

Jiang,

Cai,

yao

et al. 2024

Preprint

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Background Sjogren's syndrome (SS) is a complex autoimmune disease influenced by genetics, yet its genetic underpinnings remain elusive. This study investigates the genetic correlation and potential causative link between cytokine cycling levels and SS. Methods Genome-wide association studies (GWAS) were conducted with 8,293 and 14,824 European participants to identify cytokines. The GWAS dataset for SS, comprising 368,028 individuals of European ancestry (2,495 cases and 365,533 controls), was sourced from the Finnish biological sample library. Single nucleotide polymorphisms (SNPs) associated with SS were identified using Linkage disequilibrium score (LDSC) regression for Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was the primary analytical approach. Additional methods including MR Egger, Weighted median, and Weighted mode were employed for robustness assessment. Heterogeneity testing, horizontal pleiotropy testing, and Steiger testing were conducted for sensitivity analysis. Reverse MR analysis was performed to assess the potential for a reverse causal relationship between SS and cytokines. Results LDSC regression analysis identified 46 cytokines for bidirectional MR analysis with SS. The IVW method revealed significant associations of genetically predicted cytokines IL10RB (P = 0.019, OR = 1.138, 95% CI: 1.021–1.267) and CXCL11 (P = 0.015, OR = 1.269, 95% CI: 1.048–1.537) with increased SS risk. The absence of heterogeneity and horizontal pleiotropy in sensitivity analysis underscores the robustness of these findings. Conclusion The study suggests a potential causal relationship between genetically predicted cytokines and SS, particularly through IL10RB and CXCL11 cycles. Further research is warranted to elucidate the biological mechanisms by which cytokine cycling levels influence SS.

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Section: Discussionmentioning

confidence: 99%

Association between cytokine cycling levels and Sjogren's syndrome: genetic correlation and bidirectional Mendelian randomization study

Jiang,

Cai,

yao

et al. 2024

Preprint

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“…Previous studies have also shown a significant reduction in arthritis severity and migration of Th17 cells to joints following the use of monoclonal antibodies against CCR6 [ 55 ]. HLA-DPA1 was identified as a common drug target for both Sjogren's syndrome and multiple sclerosis in a previous study [ 56 ], while another study more directly by weighted gene co-expression network (WGCNA) and linkage map (CMap) of illustrating HLA-DPA1 as a drug target for RA [ 57 ]. HLA-DRB1 is a recognised susceptibility-associated gene [ 58 ] with the strongest association with autoantibody-positive RA [ 59 , 60 ] and the HLA-DRB1*13 allele was found to confer strong protection against RA [ 61 ], which is consistent with the results of this study.IFNGR2 is a known causally associated gene for RA [ 62 ] and has also been identified as a potential target for the autoimmune disease, psoriasis [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of potential drug targets for rheumatoid arthritis from genetic insights: a Mendelian randomization study

Cao,

Yang,

et al. 2023

J Transl Med

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Introduction Rheumatoid arthritis (RA) is a chronic inflammatory illness that mostly affects the joints of the hands and feet and can reduce life expectancy by an average of 3 to 10 years. Although tremendous progress has been achieved in the treatment of RA, a large minority of patients continue to respond poorly to existing medications, owing in part to a lack of appropriate therapeutic targets. Methods To find therapeutic targets for RA, a Mendelian randomization (MR) was performed. Cis-expression quantitative trait loci (cis-eQTL, exposure) data were obtained from the eQTLGen Consortium (sample size 31,684). Summary statistics for RA (outcome) were obtained from two largest independent cohorts: sample sizes of 97,173 (22,350 cases and 74,823 controls) and 269,377 (8279 cases and 261,098), respectively. Colocalisation analysis was used to test whether RA risk and gene expression were driven by common SNPs. Drug prediction and molecular docking was further used to validate the medicinal value of drug targets. Results Seven drug targets were significant in both cohorts in MR analysis and supported by localization. PheWAS at the gene level showed only ATP2A1 associated with other traits. These genes are strongly associated with immune function in terms of biological significance. Molecular docking showed excellent binding for drugs and proteins with available structural data. Conclusion This study identifies seven potential drug targets for RA. Drugs designed to target these genes have a higher chance of success in clinical trials and is expected to help prioritise RA drug development and save on drug development costs.

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“…In this respect, it is interesting to note that despite sicca symptoms being rare at the beginning, almost all of our CNS patients had serological and histological evidence of an inflammatory affection of salivary glands typical of pSS. Therefore, at least an accompanying pSS is to be assumed, and data from genome-wide association studies suggest at least a genetic overlap ( 32 ). Given that the diagnosis of MS can only be made when there is no better explanation ( 10 ), there were also hints calling even the diagnosis of MS into question.…”

Section: Discussionmentioning

confidence: 99%

CNS demyelinating events in primary Sjögren's syndrome: A single-center case series on the clinical phenotype

et al. 2023

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ObjectiveThe study aimed to assess the prevalence, clinical characteristics, and therapeutic outcomes of the central nervous system (CNS) demyelinating disease in a large cohort of primary Sjögren's syndrome (pSS).MethodsThis is an explorative cross-sectional study of patients with pSS seen in the departments of rheumatology, otorhinolaryngology, or neurology of a tertiary university center between January 2015 and September 2021.ResultsIn a cohort of 194 pSS patients, 22 patients had a CNS manifestation. In this CNS group, 19 patients had a lesion pattern suggestive of demyelination. While there were no obvious differences in the patients' epidemiological disposition or rate of other extraglandular manifestations, the CNS group differed from the remaining patients with pSS by having less glandular manifestations but a higher seroprevalence for anti-SSA/Ro antibodies. Notably, patients with CNS manifestations were often diagnosed with multiple sclerosis (MS) and treated as such, although age and disease course were atypical of MS. Many first-line MS agents were ineffective in these “MS look-alikes”; however, the disease course was benign with B-cell-depleting agents.ConclusionNeurological symptoms of pSS are common and clinically manifest mainly as myelitis or optic neuritis. Notably, in the CNS, the pSS phenotype can overlap with MS. The prevailing disease is crucial since it has a major impact on the long-term clinical outcome and the choice of disease-modifying agents. Although our observations neither confirm pSS as a more appropriate diagnosis nor rule out simple comorbidity, physicians should consider pSS in the extended diagnostic workup of CNS autoimmune diseases.

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The Shared Mechanism and Candidate Drugs of Multiple Sclerosis and Sjögren’s Syndrome Analyzed by Bioinformatics Based on GWAS and Transcriptome Data

Cited by 14 publications

References 54 publications

Association between cytokine cycling levels and Sjogren's syndrome: genetic correlation and bidirectional Mendelian randomization study

Association between cytokine cycling levels and Sjogren's syndrome: genetic correlation and bidirectional Mendelian randomization study

Identification of potential drug targets for rheumatoid arthritis from genetic insights: a Mendelian randomization study

CNS demyelinating events in primary Sjögren's syndrome: A single-center case series on the clinical phenotype

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