Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

Nakanishi, Teruyuki; Pigazzini, Sara; Degenhardt, Frauke; Cordioli, Mattia; Butler‐Laporte, Guillaume; Maya-Miles, Douglas; Bujanda, Luís; Bouysran, Youssef; Niemi, Mari; Palom, Adriana; Ellinghaus, David; Khan, Atlas; Martínez-Bueno, Manuel; Rolker, Selina; Amitrano, Sara; Roade, Luisa; Fava, Francesca; Spinner, Christoph D.; Prati, Daniele; Bernardo, David; García, Féderico; Darcis, Gilles; Fernández‐Cadenas, Israel; Holter, Jan Cato; Bañales, Jesús M.; Frithiof, Robert; Kiryluk, Krzysztof; Duga, Stefano; Asselta, Rosanna; Pereira, Alexandre C.; Romero–Gómez, Manuel; Nafría-Jiménez, Beatriz; Hov, Johannes R.; Migeotte, Isabelle; Renieri, Alessandra; Planas, Anna M.; Ludwig, Kerstin U.; Buti, María; Rahmouni, Souad; Alarcón‐Riquelme, Marta E.; Schulte, Eva C.; Franke, André; Karlsen, Tom H.; Valenti, Luca; Zeberg, Hugo; Richards, J. Brent; Ganna, Andrea

doi:10.1172/jci152386

Cited by 95 publications

(74 citation statements)

References 48 publications

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“…It is important to remark that these association signals found in males were not associated with the presence of comorbidities (see Supplementary Figure 4). In fact, genetic effects were only found for younger males (<60 years old), consistent with other studies [25] and strongly supporting those comorbidities outweigh genetic effects in disease outcomes in the older patients.…”

Section: Discussionsupporting

confidence: 90%

A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes

Carracedo

2021

Preprint

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We describe the results of the Spanish Coalition to Unlock Research on Host Genetics on COVID-19 (SCOURGE). In sex-disaggregated genome-wide studies of COVID-19 hospitalization, we found two known loci associated among males (SLC6A20-LZTFL1 and IFNAR2), and a novel one among females (TLE1). Meta-analyses with independent studies revealed two novel associations (AQP3 and ARHGAP33) and replicated ELF5. A genetic risk score predicted COVID-19 severity, especially among younger males. We found less SNP-heritability and larger heritability differences by age (<60/≥60 years) among males than females. Inbreeding depression was associated with COVID-19 hospitalization and severity, and the effect was stronger among older males.

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Section: Discussionsupporting

confidence: 90%

A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes

Carracedo

2021

Preprint

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“…Acquired HLH/MAS complicates diverse, mostly viral, infections, malignancies, autoimmune and autoinflammatory disorders ( Brisse et al., 2016a ), and treatment with chimeric antigen receptor (CAR) T cells ( Neelapu et al., 2018 ). Five of six candidate genes at the major 3p21.31 risk locus for severe COVID-19 ( Ellinghaus et al., 2020 ; Nakanishi et al, 2021 ; Pairo-Castineira et al., 2021 ) point toward DC-T cell interactions ( Kaser, 2020 ), remarkable as that hyperinflammation shares features with HLH/MAS, including hemophagocytosis ( Lucas et al., 2020 ; Prieto-Pérez et al., 2020 ). It remains unclear why excessive T cell activation by FAMIN-impaired DCs results in enhanced immunosurveillance of tumors but fails to control IAV infection.…”

Section: Discussionmentioning

confidence: 99%

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation

et al. 2022

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Summary Still’s disease, the paradigm of autoinflammation- cum -autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still’s disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4 + and CD8 + T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD + -dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.

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“…9,10 ) and an over twofold increased risk of mortality for individuals under 60 (ref. 13 ). Additionally, the risk variants at this locus are carried by >60% of individuals with South Asian ancestry (SAS), compared to 15% of European ancestry (EUR) groups, partially explaining the ongoing higher death rate in this population in the UK 14,15 .…”

mentioning

confidence: 99%

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

et al. 2021

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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies (GWAS) identified the 3p21.31 region as conferring a two-fold increased risk of respiratory failure. Here, using a combined multiomics and machine-learning approach, we identify the gain-of-function risk A allele of a single-nucleotide polymorphism (SNP), rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, Leucine Zipper Transcription Factor Like 1 ( LZTFL1 ). Selective spatial transcriptomic analysis of COVID-19 patient lung biopsies shows the presence of signals associated with epithelial-mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1 . We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely to be responsible for the 3p21.31 associated risk. As the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may provide a therapeutic target.

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Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

Cited by 95 publications

References 48 publications

A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes

A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

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