key: cord-0790659-75betyc2
authors: Patrick, Matthew T.; Zhang, Haihan; Wasikowski, Rachael; Prens, Errol P.; Weidinger, Stephan; Gudjonsson, Johann E.; Elder, James T.; He, Kevin; Tsoi, Lam C.
title: Associations between COVID-19 and skin conditions identified through epidemiology and genomic studies
date: 2021-01-21
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2021.01.006
sha: 757c1616142ff23affb877f7a8026878e23bb9b7
doc_id: 790659
cord_uid: 75betyc2

Background COVID-19 is commonly associated with skin manifestations, and may also exacerbate existing skin diseases, yet the relationship between COVID-19 and skin diseases remains unclear. Objective By investigating this relationship through a multi-omics approach, we sought to ascertain whether patients with skin conditions are more susceptible to COVID-19. Methods We conducted an epidemiological study and then compared gene expression across nine different inflammatory skin conditions and SARS-CoV-2 infected bronchial epithelial cell lines, then performed a GWAS trans-disease meta-analysis between COVID-19 susceptibility and two skin diseases (psoriasis and atopic dermatitis). Results Skin conditions, including psoriasis and atopic dermatitis, increase the risk of COVID-19 (OR=1.55, p=1.4x10 -9 ), but decrease the risk of mechanical ventilation (OR=0.22, p=8.5x10 -5 ). We observed significant overlap in gene expression between the infected normal bronchial epithelial cells (NHBE) and inflammatory skin diseases, such as psoriasis, and atopic dermatitis. For genes that are commonly induced in both the SARS-CoV-2 infection and skin diseases, there are four S100 family members located in the epidermal differentiation complex (EDC), and we also identified the ‘IL-17 signaling pathway’ (p=4.9x10 -77 ) as one of the most significantly enriched pathways. Furthermore, a shared genome-wide significant locus in the epidermal differentiation complex (EDC) was identified between psoriasis and SARS-CoV-2 infection, with the lead marker being a significant eQTL for S100A12 (p=3.3x10 -7 ). Conclusion Together our findings suggest association between inflammatory skin conditions and higher risk of COVID-19, but with less severe course, and highlight shared components involved in anti-COVID19 immune response.

Genes were considered to be significantly up-regulated in the cases if they have FDR≤0.05 and log 2 Fold 230 Change (FC) ≥ 1 in the differential expression analysis when compared with the controls. KEGG Pathway 231 enrichment was performed on the up-regulated genes from each dataset using a web-based pathway 232 analysis tool, Enrichr 76 . Pathways were compared between datasets, using Association analysis based on 233 SubSETs (ASSET) 77 to detect the most significant subset, and also the datasets belonging to each 234 significant pathway. To avoid biasing the results towards any one dataset, we adopted an equally 235 weighted analysis, supplying the same sample size to ASSET for each dataset. 

Confirming previous research 49 , we found African Americans to be at substantially higher risk of COVID-251 19 than Caucasians (OR=4.86, p=4.1x10 -93 ), with other ethnic groups also having significantly elevated 252 risk compared to Caucasians (Table 1a) . We observed an increased risk with age and obesity: OR=21.04, 253 p=1.6x10 -38 for age ≥80 compared to the youngest group; OR=2.06, p=6.2x10 -15 for BMI ≥40 kg/m 2 (i.e.

"Obese 3") compared to non-obese. Social disadvantage was only significant for the highest compared 255 to the lowest quartile (OR=1.67, p=2.3x10 -8 

In parallel with the investigation of individual genes, we conducted pathway-level analysis using data 

TLR2 is only present in the rheumatoid arthritis pathway, whereas S100A7, S100A7 and S100A9 only 

418 rs12564811 is a significant eQTL in whole blood 109 for S100A12 (p=3.3x10 -7 ), one of the genes which was 419 up-regulated in each of the 5 skin conditions and NHBE. It is also an eQTL for LCE1E in GTEx exposed skin 420 (p=1.0x10 -11 ) and not exposed skin (p=7.1x10 -10 

Furthermore, rs12564811 is a eQTL for LCE3A (p=1.9x10 -7 ) and LCE3C (p=1.1x10 -4 ) in exposed skin, as 424 well as LCE3D (p=3.5x10 -5 ) in esophagus mucosa (epithelium) 99, 100 . We applied colocalization analysis in 425 GTEx using a colocalization approach (fastENLOC 111 ) which takes advantage of multiple imputation and 426 pre-computed signal clusters. In total, the eQTL signals of nine genes expressing in 14 tissue types were 427 colocalized with the GWAS signals in the same regions, with exposed skin having the highest number of 428 J o u r n a l P r e -p r o o f colocalized eQTL signals (7 out of 9, including LCE1E). However, none of the colocalizations had a high 429 regional colocalization probability (RCP), with LCE4A being the most probable candidate (RCP=0.015),

indicating it may be difficult to reach a firm conclusion with regard to the target genes. LCE3 genes have 

COVID-19 patients with skin conditions. Notably, COVID-19 is known to affect multiple organs 120 and has 449 been found to replicate effectively in gut epithelia 121 , but more work is needed to determine whether 450 this is also true of the skin.

Interestingly, we found having a previous diagnosis of sore throat (tonsillitis or pharyngitis) elevated the 

This lack of association may be due to the low sample size, and it is also possible some of the deaths , TDMA p=2.4x10 -9 ), in proximity to a known psoriasis locus indicated for NFKBIA 132 

We analyzed transcriptome data (RNA-seq and microarray) from multiple different skin diseases 539 because our epidemiological evidence suggests they may all have effect on COVID-19 susceptibility.

Steps were taken to ensure comparability of these results. All the RNA-seq studies were analyzed using 541 DESeq2 137 , and the microarray studies using limma 138 

It is also important to point out we do not combine the data through meta-or mega-analysis. Instead,

we apply multiple testing adjustment (FDR) and separately report the significantly up-regulated genes in 550 each study. Although some studies may have more power to detect up-regulated genes than others due 

TNF inhibitors did not significantly increase COVID-19 hospitalization 154 .

Overall, our study has highlighted the significant link between skin conditions and COVID-19. By further 569 revealing the shared genomic components, this work will serve as an important study to reveal T  EPS TI1  GBP5  CXCL5  TNFS  F14  C1Q  TNF  1  MM  P1  3  TN  IP  1  TE  P Recombination rate (cM/Mb) q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q qq q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q qq q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q 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q q qq Recombination rate (cM/Mb) q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q qq q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q 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q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q qq q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q q 

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The reproductive number of COVID-19 is higher compared to SARS coronavirus

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CDC. Symptoms of Coronavirus

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COVID-19 and dermatology: a comprehensive guide for dermatologists

Cutaneous manifestations in COVID-19: a first perspective

Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): A prospective study from China and Italy

Diversity of clinical appearance of cutaneous manifestations in the course of COVID-19

Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases

SARS-CoV-2 infection presenting as a febrile rash

Cutaneous lesions in a patient with COVID-19: are they related?

Petechial Skin Rash Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Digitate Papulosquamous Eruption Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

COVID-19) infection-induced chilblains: A case report with histopathologic findings

Acral cutaneous lesions in the time of COVID-19

CHILBLAIN-LIKE ACRAL LESIONS DURING THE COVID-19 PANDEMIC

Cutaneous Barriers and Skin Immunity: Differentiating A Connected Network

Psoriasis and the risk of pneumonia: a population-based study

Risk of hospitalization and death due to infection in people with psoriasis: a population-based cohort study using the Clinical Practice Research Datalink

Risk of Serious Infection, Opportunistic Infection, and Herpes Zoster among Patients with Psoriasis in the United Kingdom

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Increased Risk of Cutaneous and Systemic Infections in Atopic Dermatitis-A Cohort Study

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Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study

Periodontitis and risk of psoriasis: a systematic review and meta-analysis

Dermatological diseases presented before COVID-19: Are patients with psoriasis and superficial fungal infections more vulnerable to the COVID-19?

Covid-19 and exacerbation of psoriasis

New-onset pustular psoriasis in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing Coronavirus Disease

OpenSAFELY: factors associated with COVID-19 death in 17 million patients

Immunology of psoriasis

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The GTEx Consortium atlas of genetic regulatory effects across human tissues

ICAM-1 regulates the survival of influenza virus in lung epithelial cells during the early stages of infection

A novel immune biomarker IFI27 discriminates between influenza and bacteria in patients with suspected respiratory infection

Interactions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression

Interleukin-32: An endogenous danger signal or master regulator of intracellular pathogen infections-Focus on leishmaniases

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KEGG: new perspectives on genomes, pathways, diseases and drugs

Targeting the interleukin-17 pathway to prevent acute respiratory distress syndrome associated with SARS-CoV-2 infection

The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis

Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis

Systematic identification of genetic influences on methylation across the human life course

PhenomeXcan: Mapping the genome to the phenome through the transcriptome

Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms

Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses

If the link missed:Could inflammatory skin disorders with barrier dysfunction increase the risk of

Abnormal epidermal barrier recovery in uninvolved skin supports the notion of an epidermal pathogenesis of psoriasis

Predicting Skin Barrier Dysfunction and Atopic Dermatitis in Early Infancy

Transepidermal water loss measured with the Tewameter TM300 in burn scars

Local burn injury impairs epithelial permeability and antimicrobial peptide barrier function in distal unburned skin

Type I and Type III Interferons -Induction, Signaling, Evasion, and Application to Combat COVID-19

Comorbidities and multi-organ injuries in the treatment of COVID-19

SARS-CoV-2 productively infects human gut enterocytes

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Significant expression of FURIN and ACE2 on oral epithelial cells may facilitate the efficiency of SARS-CoV-2 entry

Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

Pre-existing immunity to SARS-CoV-2: the knowns and unknowns

How does rhinovirus cause the common cold cough?

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Deaths: Leading Causes for 2017

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Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Multiancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

The preclinical phase of PsA: a challenge for the epidemiologist

Early symptoms of systemic lupus erythematosus (SLE) recalled by 339 SLE patients

Tissue-specific tolerance in fatal Covid-19

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limma powers differential expression analyses for RNA-sequencing and microarray studies

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Optimizing RNA-Seq Mapping with STAR

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Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease

Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis

The protective and pathogenic roles of IL-17 in viral infections: friend or foe?

Distinct effects of asthma and COPD comorbidity on disease expression and outcome in patients with COVID-19

A Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice

The impact of the COVID-19 pandemic on patients with chronic plaque psoriasis being treated with biological therapy: the Northern Italy experience

Incidence of severe COVID-19 outcomes in psoriatic patients treated with systemic therapies during the pandemic: a Biobadaderm cohort analysis

The Risk of Respiratory Tract Infections in Psoriasis Patients Treated With IL-23-pathway Inhibiting Biologics: A Meta-Estimate of Pivotal Trials Relevant to Decision-Making During the COVID-19 Pandemic

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry

Animal models for COVID-19

A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis