Disentangling the common genetic architecture and causality of rheumatoid arthritis and systemic lupus erythematosus with COVID‐19 outcomes: Genome‐wide cross trait analysis and bidirectional Mendelian randomization study

Yao, Minhao; Huang, Xin; Guo, Yunshan; Zhao, Jie; Z, Liu

doi:10.1002/jmv.28570

Cited by 19 publications

(11 citation statements)

References 51 publications

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“…The results of coloc can be found in Table S2 and coloc-SuSiE in Table S3. In the four analyzed tissues, we identified a total of 28 unique genes (Figure S2), among these genes, 50% (14/28) have been reported to be associated with COVID-19 ( DPP9 30,31 , WNT3 32,33 , ABO 34,35 , NAPSA , 36 GSDMB 37,38 , RAB2A 29 , OAS1 39 , OAS3 7 , LRRC37A2 40 , MAPT 32 , FUT2 41,42 , IKZF3 43 , ICAM5 41,44 , CCR9 34,45 ).…”

Section: Resultsmentioning

confidence: 99%

Integrating population-level and cell-based signatures for drug repositioning

He,

Xu,

Zhou

et al. 2023

Preprint

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Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Furthermore, drugs with genetic evidence are more likely to progress successfully through clinical trials towards FDA approval. Exploiting these developments, single gene-based drug repositioning methods have been implemented, but approaches leveraging the entire spectrum of molecular signatures are critically underexplored. Most multi-gene-based approaches rely on differential gene expression (DGE) analysis, which is prone to identify the molecular consequence of disease and renders causal inference challenging. We propose a framework TReD (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based drug-induced transcriptome response profiles. TReD embeds the disease signature and drug profile in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell screen assay. The robustness is ensured by evaluation in additional cell screens. For an application, we implement the framework to identify potential drugs against COVID-19. Taking transcriptome-wide association study (TWAS) results from four relevant tissues and three DGE results as disease features, we identify 37 drugs showing potential reversal roles in at least four of the seven disease signatures. Notably, over 70% (27/37) of the drugs have been linked to COVID-19 from other studies, and among them, eight drugs are supported by ongoing/completed clinical trials. For example, TReD identifies the well-studied JAK1/JAK2 inhibitor baricitinib, the first FDA-approved immunomodulatory treatment for COVID-19. Novel potential candidates, including enzastaurin, a selective inhibitor of PKC-beta which can be activated by SARS-CoV-2, are also identified. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screens that can accelerate the search for new therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Integrating population-level and cell-based signatures for drug repositioning

He,

Xu,

Zhou

et al. 2023

Preprint

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“…The impact of obesity on the development and progression of autoimmune diseases has been established in prior research 43,44 . Additionally, RA, as an autoimmune disease, often cooccurs with SLE 45 . Given multiple exposures and effectors, to further ascertain the causal relationship between SLE and HBV, we included BMI and RA in a multivariable MR analysis.…”

Section: Discussionmentioning

confidence: 99%

“…43,44 Additionally, RA, as an autoimmune disease, often cooccurs with SLE. 45 Given multiple exposures and effectors, to further ascertain the causal relationship between SLE and HBV, we included BMI and RA in a multivariable MR analysis. Notably, our findings suggest that the association between SLE and a reduced risk of HBV remained significant even after accounting for BMI.…”

Section: Reverse Mr and Multivariable Mrmentioning

confidence: 99%

Systemic lupus erythematosus is associated with lower risk of hepatitis B virus infection: A multivariable Mendelian randomization study in East Asian population

Li,

Zhang,

Ren

et al. 2023

Journal of Medical Virology

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The relationship between systemic lupus erythematosus (SLE) and hepatitis B virus (HBV) infection is still unclear. We conducted a two‐sample Mendelian randomization (MR) analysis using summary statistics from genome‐wide association studies for SLE and HBV infection in individuals of East Asian ancestry. The inverse‐variance weighted (IVW) method, weighted median (WM) method, and MR‐Egger method were used to estimate the causal effect of SLE on HBV infection. Additionally, we performed a multivariable MR analysis adjusting for the effects of body mass index and rheumatoid arthritis. This MR study included a total of 225 106 individuals of East Asian ancestry, comprising 5616 cases and 219 490 controls. The IVW method (OR: 0.79, p = 3.34E−08) and the WM method (OR: 0.79, p = 9.09E−06) revealed a causal relationship between genetically predicted SLE and a low risk of HBV infection. The multivariable MR analysis still suggested a low risk of HBV infection associated with SLE (OR: 0.83, p = 2.89E−06). Our MR analysis supports a causal relationship between SLE and a low risk of HBV infection in individuals of East Asian ancestry.

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“…A genome‐wide cross trait analysis and bidirectional Mendelian randomization study showed that a higher genetic vulnerability to RA is associated with hospitalization in SARS‐CoV‐2 infection, but there was no association in the opposite direction 22 . Previous studies showed that the over‐presentation of the missense mutation MICB*004 is the possible association between COVID‐19 and RA 23,24 .…”

Section: The Impact Of Genetic Factors On Covid‐19 Patientsmentioning

confidence: 99%

Illuminating the connection: Unearthing the mechanisms linking COVID‐19 and rheumatoid arthritis

Feng,

Kuo,

Shih

et al. 2023

Int J of Rheum Dis

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Disentangling the common genetic architecture and causality of rheumatoid arthritis and systemic lupus erythematosus with COVID‐19 outcomes: Genome‐wide cross trait analysis and bidirectional Mendelian randomization study

Cited by 19 publications

References 51 publications

Integrating population-level and cell-based signatures for drug repositioning

Integrating population-level and cell-based signatures for drug repositioning

Systemic lupus erythematosus is associated with lower risk of hepatitis B virus infection: A multivariable Mendelian randomization study in East Asian population

Illuminating the connection: Unearthing the mechanisms linking COVID‐19 and rheumatoid arthritis

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