Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
Authors: Fallerini Chiara , Daga Sergio , Mantovani Stefania , Benetti Elisa , Picchiotti Nicola , Francisci Daniela , Paciosi Francesco , Schiaroli Elisabetta , Baldassarri Margherita , Fava Francesca , Palmieri Maria , Ludovisi Serena , Castelli Francesco , Quiros-Roldan Eugenia , Vaghi Massimo , Rusconi Stefano , Siano Matteo , Bandini Maria , Spiga Ottavia , Capitani Katia , Furini Simone , Mari Francesca ,   GEN-COVID Multicenter Study, Valentino Floriana , Doddato Gabriella , Giliberti Annarita , Tita Rossella , Amitrano Sara , Bruttini Mirella , Croci Susanna , Meloni Ilaria , Mencarelli Maria Antonietta , Lo Rizzo Caterina , Pinto Anna Maria , Di Sarno Laura , Beligni Giada , Tommasi Andrea , Iuso Nicola , Montagnani Francesca , Fabbiani Massimiliano , Rossetti Barbara , Zanelli Giacomo , Bargagli Elena , Bergantini Laura , D’Alessandro Miriana , Cameli Paolo , Bennett David , Anedda Federico , Marcantonio Simona , Scolletta Sabino , Franchi Federico , Mazzei Maria Antonietta , Guerrini Susanna , Conticini Edoardo , Cantarini Luca , Frediani Bruno , Tacconi Danilo , Spertilli Chiara , Feri Marco , Donati Alice , Scala Raffaele , Guidelli Luca , Spargi Genni , Corridi Marta , Nencioni Cesira , Croci Leonardo , Caldarelli Gian Piero , Spagnesi Maurizio , Romani Davide , Piacentini Paolo , Desanctis Elena , Cappelli Silvia , Canaccini Anna , Verzuri Agnese , Anemoli Valentina , Ognibene Agostino , Monforte Antonella D’Arminio , Miraglia Federica Gaia , Girardis Massimo , Venturelli Sophie , Busani Stefano , Cossarizza Andrea , Antinori Andrea , Vergori Alessandra , Emiliozzi Arianna , Gabrieli Arianna , Riva Agostino , Scotton Pier Giorgio , Andretta Francesca , Panese Sandro , Scaggiante Renzo , Gatti Francesca , Parisi Saverio Giuseppe , Baratti Stefano , Antoni Melania Degli , Monica Matteo Della , Piscopo Carmelo , Capasso Mario , Russo Roberta , Andolfo Immacolata , Iolascon Achille , Fiorentino Giuseppe , Carella Massimo , Castori Marco , Merla Giuseppe , Squeo Gabriella Maria , Aucella Filippo , Raggi Pamela , Marciano Carmen , Perna Rita , Bassetti Matteo , Di Biagio Antonio , Sanguinetti Maurizio , Masucci Luca , Valente Serafina , Mandalà Marco , Giorli Alessia , Salerni Lorenzo , Zucchi Patrizia , Parravicini Pierpaolo , Menatti Elisabetta , Trotta Tullio , Giannattasio Ferdinando , Coiro Gabriella , Lena Fabio , Coviello Domenico A , Mussini Cristina , Bosio Giancarlo , Martinelli Enrico , Mancarella Sandro , Tavecchia Luisa , Gori Marco , Crotti Lia , Parati Gianfranco , Gabbi Chiara , Zanella Isabella , Rizzi Marco , Maggiolo Franco , Ripamonti Diego , Bachetti Tiziana , La Rovere Maria Teresa , Sarzi-Braga Simona , Bussotti Maurizio , Chiariello Mario , Belli Mary Ann , Dei Simona , Renieri Alessandra , Mondelli Mario U , Frullanti Elisa 
Published: March 2021

Background:Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods:This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.Results:Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusions:Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19.Funding:Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative.Clinical trial number:NCT04549831.