Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10 − 20). This effect was consistent in both pediatric (p = 9.92 × 10 − 6) and adult (p = 9.73 × 10 − 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10 − 8 , beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10 − 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10 − 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10 − 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses.
ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe COVID-19 in humans.
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IRF1 governs the differential interferon-stimulated gene responses in human monocytes and macrophages by regulating chromatin accessibility Graphical abstract Highlights d Human myeloid cells show lineage-specific transcriptional responses to TLR activation d Monocytes display an exaggerated pro-inflammatory profile in response to TLR8 ligand d TLR4 engagement elicits robust ISG response in macrophages but not in monocytes d IRF1 governs chromatin accessibility at ISG loci in TLR4stimulated macrophages
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