Smoking and SARS-CoV-2 Impair Dendritic Cells and Regulate DC-SIGN Expression in Tissues (preprint)

The current spreading novel coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three SARS-CoV-2 host receptors (ACE2, DC-SIGN and L-SIGN) and DC status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of smokers, non-smokers and COVID-19 patients. We found smoking increased DC-SIGN gene expression and inhibited DC maturation and its ability of T cell stimulation. In COVID-19, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Strikingly, DCs shifted from cDCs to pDCs in COVID-19, but the shift was trapped in an immature stage (CD22+ or ANXA1+ DC) with MHCII downregulation in severe cases. This observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically recognize SARS-CoV-2. Our study provides insights into smoking effect on COVID-19 risk and the profound modulation of DC function in severe COVID-19.

Electronic Health Record-Based Genome-Wide Meta-Analysis and Mendelian Randomization Identify Metabolic and Phenotypic Consequences of Non-Alcoholic Fatty Liver Disease (preprint)

Non-alcoholic fatty liver disease (NAFLD) has been associated with several blood biomarkers and chronic diseases. Whether these associations underlie causal effects remains to be determined. We aimed at identifying blood metabolites, blood proteins and human diseases that are causally impacted by the presence of NAFLD using Mendelian randomization. We created a NAFLD genetic instrument from NAFLD loci (MTARC1, GCKR, LPL, TRIB1, LMO3, FTO, TM6SF2, APOE and PNPLA3) identified in a new electronic health record based-GWAS meta-analysis (6715 cases and 682,748 controls). We found a potentially causal effect of NAFLD on tyrosine metabolism as well as on blood levels of eight proteins that could potentially represent new early biomarkers of NAFLD. Using results from the UK Biobank, FinnGen and the COVID-19 Host Genetics Initiative, we found that NAFLD was not causally associated with diseases outside the spectrum of liver diseases, suggesting that the resolution of NAFLD might not prevent other diseases.

Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19 (preprint)

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We therefore used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n=1,038) and eQTLGen (n=31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n=3,301) with COVID-19-associated loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). We found that the expression of 20 genes in lung and 31 genes in blood was associated with COVID-19. Of these genes, only three (LZTFL1, SLC6A20 and ABO) had been previously linked with COVID-19 in GWAS. The novel loci included genes involved in interferon pathways (IL10RB, IFNAR2 and OAS1). Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in MR analysis; increased plasma levels were associated with an increased risk of having COVID-19 and risk of severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigation. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.

The landscape of host genetic factors involved in infection to common viruses and SARS-CoV-2 (preprint)

IntroductionHumans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities. MethodsWe conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. ResultsSignals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DR{beta}i at positions 11, 13, 71, and 74 for Epstein-Barr Virus (EBV), Varicella Zoster Virus (VZV), Human Herpes virus 7, (HHV7) and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P<5.0x10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, as well as CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0*10-15 (MCV), NTN5: P=1.1x10-9 (BKV), and P2RY13: P=1.1x10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases; from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions. ConclusionsOur study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study (preprint)

ObjectivesTo use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. DesignTwo-sample Mendelian randomization (MR) analysis. SettingSummary-level genetic association data. ParticipantsParticipants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants). Main outcomes and measuresLung ACE2 and TMPRSS2 expression and plasma ACE2 levels. ResultsThere were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4x10-4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes. ConclusionsThis study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification. Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. C_LIO_LISerine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor. C_LIO_LIExpression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19. C_LI What this study addsO_LIWe used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels. C_LIO_LIOur findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression. C_LIO_LIWe found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies. C_LI