%0 Journal Article %J Genome Med %D 2021 %T Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. %A Kasela, Silva %A Ortega, Victor E %A Martorella, Molly %A Garudadri, Suresh %A Nguyen, Jenna %A Ampleford, Elizabeth %A Pasanen, Anu %A Nerella, Srilaxmi %A Buschur, Kristina L %A Barjaktarevic, Igor Z %A Barr, R Graham %A Bleecker, Eugene R %A Bowler, Russell P %A Comellas, Alejandro P %A Cooper, Christopher B %A Couper, David J %A Criner, Gerard J %A Curtis, Jeffrey L %A Han, MeiLan K %A Hansel, Nadia N %A Hoffman, Eric A %A Kaner, Robert J %A Krishnan, Jerry A %A Martinez, Fernando J %A McDonald, Merry-Lynn N %A Meyers, Deborah A %A Paine, Robert %A Peters, Stephen P %A Castro, Mario %A Denlinger, Loren C %A Erzurum, Serpil C %A Fahy, John V %A Israel, Elliot %A Jarjour, Nizar N %A Levy, Bruce D %A Li, Xingnan %A Moore, Wendy C %A Wenzel, Sally E %A Zein, Joe %A Langelier, Charles %A Woodruff, Prescott G %A Lappalainen, Tuuli %A Christenson, Stephanie A %K Adult %K Aged %K Aged, 80 and over %K Angiotensin-Converting Enzyme 2 %K Asthma %K Bronchi %K Cardiovascular Diseases %K COVID-19 %K Gene Expression %K Genetic Variation %K Humans %K Middle Aged %K Obesity %K Pulmonary Disease, Chronic Obstructive %K Quantitative Trait Loci %K Respiratory Mucosa %K Risk Factors %K SARS-CoV-2 %K Smoking %X

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

%B Genome Med %V 13 %P 66 %8 2021 04 21 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33883027?dopt=Abstract %R 10.1186/s13073-021-00866-2 %0 Journal Article %J Nat Commun %D 2018 %T Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. %A Emdin, Connor A %A Khera, Amit V %A Chaffin, Mark %A Klarin, Derek %A Natarajan, Pradeep %A Aragam, Krishna %A Haas, Mary %A Bick, Alexander %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Ardissino, Diego %A Wilson, James G %A Schunkert, Heribert %A McPherson, Ruth %A Watkins, Hugh %A Elosua, Roberto %A Bown, Matthew J %A Samani, Nilesh J %A Baber, Usman %A Erdmann, Jeanette %A Gupta, Namrata %A Danesh, John %A Chasman, Daniel %A Ridker, Paul %A Denny, Joshua %A Bastarache, Lisa %A Lichtman, Judith H %A D'Onofrio, Gail %A Mattera, Jennifer %A Spertus, John A %A Sheu, Wayne H-H %A Taylor, Kent D %A Psaty, Bruce M %A Rich, Stephen S %A Post, Wendy %A Rotter, Jerome I %A Chen, Yii-Der Ida %A Krumholz, Harlan %A Saleheen, Danish %A Gabriel, Stacey %A Kathiresan, Sekar %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Disease %K Gene Frequency %K Genetic Testing %K Genetic Variation %K Humans %K Obesity %K Phenotype %K Proteins %K Respiratory Hypersensitivity %K United Kingdom %X

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

%B Nat Commun %V 9 %P 1613 %8 2018 04 24 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29691411?dopt=Abstract %R 10.1038/s41467-018-03911-8