Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis

Xiang, Bingyu; Deng, Chunyu; Qiu, Fei; Li, Jingjing; Li, Shanshan; Zhang, Huifang; Lin, Xiuli; Huang, Yen-Yu; Zhou, Yijun; Su, Jianzhong; Lu, Mingqin; Ma, Yunlong

doi:10.1186/s12951-021-01154-2

Cited by 21 publications

(21 citation statements)

References 94 publications

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“…The power of this study is limited by the lack of matched genetic data and scRNA-seq data in each sample for uncovering the genetic effects on immune cells for severe COVID-19. To reduce the influence of this limitation, we adopted a widely used approach by integrating a large-scale GWAS summary statistics with an enormous amount of single-cell sequencing data, as referenced in previous studies [ 49 , 89 , 90 ]. As referenced to previous studies [ 91 – 94 ], we excluded the major histocompatibility complex (MHC) region from all genomic analyses to avoid the confounding of methods by the unusual genetic architecture and extensively high levels of LD at this locus, which could lead to the inflation of identified COVID-19-associated genes and pathways.…”

Section: Discussionmentioning

confidence: 99%

Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19

Qiu

Deng

et al. 2022

Genome Med

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Background Understanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown. Methods We constructed a computational framework to characterize the host genetics that influence immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets containing healthy controls and patients with mild, moderate, and severe symptom (N = 606,534 cells). We collected 10 predefined gene sets including inflammatory and cytokine genes to calculate cell state score for evaluating the immunological features of individual immune cells. Results We found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly expressed genes increased with the severity of COVID-19. Three cell subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were highly expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significantly up-regulated genes, including S100A12, S100A8, S100A9, and IFITM1, confer higher risk to the dysregulated immune response among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality including elevation of proliferation, migration, and chemotaxis. Moreover, we observed an increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues. The enhanced interactions of CXCR6+ memory CD8+T cells with epithelial cells facilitate the recruitment of this specific population of T cells to airways, promoting CD8+T cell-mediated immunity against COVID-19 infection. Conclusions We uncover a major genetics-modulated immunological shift between mild and severe infection, including an elevated expression of genetics-risk genes, increase in inflammatory cytokines, and of functional immune cell subsets aggravating disease severity, which provides novel insights into parsing the host genetic determinants that influence peripheral immune cells in severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19

Qiu

Deng

et al. 2022

Genome Med

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“…Using single-cell RNA sequencing (scRNA-seq) techniques, Poch and colleagues generated the first atlas of intrahepatic T cells in PSC and identified a previously uncharacterized population of liver-resident CD4 + T cells that likely contribute to the pathogenesis of PSC [ 84 ]. Xiang and colleagues [ 85 ] developed a computational framework to integrate GWAS summary statistics with scRNA-seq data and revealed genetically modulated liver cell subpopulations for PBC. They found that cholangiocytes show significant enrichment with PBC-related genetic association signals, with the ORMDL3 gene showing the highest expression level in cholangiocytes compared with other liver cells.…”

Section: Genetically Regulated Expression and Single Cell Analysesmentioning

confidence: 99%

How genetic risk contributes to autoimmune liver disease

Ellinghaus

2022

Semin Immunopathol

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Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.

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“…As immune-mediated diseases, the immune cells recruited by cholangiocyte secretion significantly altered the composition of intrahepatic immune cells and are involved in disease pathogenesis and regulation of biliary repair ( 144 ). ScRNA-seq of liver of PBC patients indicated that ORMDL3 + cholangiocytes displayed higher interaction with immune cells such as macrophages and monocytes, which might play a role in the pathogenesis of PBC ( 145 ).…”

Section: Role Of Immune Cells In Biliary Repair In Cholangiopathiesmentioning

confidence: 99%

Role of Immune Cells in Biliary Repair

et al. 2022

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The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.

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Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis

Cited by 21 publications

References 94 publications

Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19

Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19

How genetic risk contributes to autoimmune liver disease

Role of Immune Cells in Biliary Repair

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