Stratified analyses refine association between TLR7 rare variants and severe COVID-19

GenOMICC Investigators; Jannik Boos; Caspar I. van der Made; Gayatri Ramakrishnan; Eamon Coughlan; Rosanna Asselta; Britt Sabina Löscher; Luca V.C. Valenti; Rafael de Cid; Luis Bujanda; Antonio Julià; Erola Pairo-Castineira; J. Kenneth Baillie; Sandra May; Berina Zametica; Julia Heggemann; Agustín Albillos; Jesus M. Banales; Jordi Barretina; Natalia Blay; Paolo Bonfanti; Maria Buti; Javier Fernandez; Sara Marsal; Daniele Prati; Luisa Ronzoni; Nicoletta Sacchi

doi:10.1016/j.xhgg.2024.100323

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

GenOMICC Investigators
, Jannik Boos
, Caspar I. van der Made
, Gayatri Ramakrishnan
, Eamon Coughlan
, Rosanna Asselta
, Britt Sabina Löscher
, Luca V.C. Valenti
, Rafael de Cid
, Luis Bujanda
, Antonio Julià
, Erola Pairo-Castineira
, J. Kenneth Baillie
, Sandra May
, Berina Zametica
, Julia Heggemann
, Agustín Albillos
, Jesus M. Banales
, Jordi Barretina
, Natalia Blay

Paolo Bonfanti, Maria Buti, Javier Fernandez, Sara Marsal, Daniele Prati, Luisa Ronzoni, Nicoletta Sacchi

University of Bonn
Radboud University Nijmegen
University of Edinburgh
Humanitas University
IRCCS Istituto Clinico Humanitas - Rozzano (Milano)
Kiel University
University of Milan
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
CORE Program. Germans Trias i Pujol Research Institute (IGTP)
Grup de Recerca en Impacte de Les Malalties Cròniques I Les Seves Trajectòries (GRIMTra) (IGTP)
Hospital Universitario Donostia
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
Vall d'Hebron Research Institute
Hospital Ramon y Cajal
Ikerbasque Basque Foundation for Science
University of Navarra
University of Milan - Bicocca
University of Barcelona
European Foundation for the Study of Chronic Liver Failure (EF CLif)
Galliera Hospital

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.

Original language	English
Article number	100323
Journal	Human Genetics and Genomics Advances
Volume	5
Issue number	4
DOIs	https://doi.org/10.1016/j.xhgg.2024.100323
Publication status	Published - 10 Oct 2024

Keywords

burden analysis
host genetics
immune deficiency
infection
innate immunity
rare variants
SARS-CoV-2
targeted sequencing
toll-like receptor 7
variant collapsing analysis

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10.1016/j.xhgg.2024.100323Licence: CC BY-NC-ND

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GenOMICC Investigators, Boos, J., van der Made, C. I., Ramakrishnan, G., Coughlan, E., Asselta, R., Löscher, B. S., Valenti, L. V. C., de Cid, R., Bujanda, L., Julià, A., Pairo-Castineira, E., Baillie, J. K., May, S., Zametica, B., Heggemann, J., Albillos, A., Banales, J. M., Barretina, J., ... Sacchi, N. (2024). Stratified analyses refine association between TLR7 rare variants and severe COVID-19. Human Genetics and Genomics Advances, 5(4), Article 100323. https://doi.org/10.1016/j.xhgg.2024.100323

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title = "Stratified analyses refine association between TLR7 rare variants and severe COVID-19",

abstract = "Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4\% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24\% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.",

keywords = "burden analysis, host genetics, immune deficiency, infection, innate immunity, rare variants, SARS-CoV-2, targeted sequencing, toll-like receptor 7, variant collapsing analysis",

author = "\{GenOMICC Investigators\} and Jannik Boos and \{van der Made\}, \{Caspar I.\} and Gayatri Ramakrishnan and Eamon Coughlan and Rosanna Asselta and L{\"o}scher, \{Britt Sabina\} and Valenti, \{Luca V.C.\} and \{de Cid\}, Rafael and Luis Bujanda and Antonio Juli{\`a} and Erola Pairo-Castineira and Baillie, \{J. Kenneth\} and Sandra May and Berina Zametica and Julia Heggemann and Agust{\'i}n Albillos and Banales, \{Jesus M.\} and Jordi Barretina and Natalia Blay and Paolo Bonfanti and Maria Buti and Javier Fernandez and Sara Marsal and Daniele Prati and Luisa Ronzoni and Nicoletta Sacchi and Valeria Rimoldi and Paraboschi, \{Elvezia M.\} and Alessandra Bandera and Flora Peyvandi and Giacomo Grasselli and Francesco Blasi and Francesco Malvestiti and Serena Pelusi and Cristiana Bianco and Lorenzo Miano and Angela Lombardi and Pietro Invernizzi and Alessio Gerussi and Giuseppe Citerio and Andrea Biondi and Valsecchi, \{Maria Grazia\} and Cazzaniga, \{Marina Elena\} and Giuseppe Foti and Ilaria Beretta and Mariella D'Angi{\`o} and Bettini, \{Laura Rachele\} and Olly Hamilton and Emma Carter and Paula Saunderson",

year = "2024",

month = oct,

day = "10",

doi = "10.1016/j.xhgg.2024.100323",

language = "English",

volume = "5",

journal = "Human Genetics and Genomics Advances",

issn = "2666-2477",

publisher = "Elsevier Inc.",

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GenOMICC Investigators, Boos, J, van der Made, CI, Ramakrishnan, G, Coughlan, E, Asselta, R, Löscher, BS, Valenti, LVC, de Cid, R, Bujanda, L, Julià, A, Pairo-Castineira, E, Baillie, JK, May, S, Zametica, B, Heggemann, J, Albillos, A, Banales, JM, Barretina, J, Blay, N, Bonfanti, P, Buti, M, Fernandez, J, Marsal, S, Prati, D, Ronzoni, L & Sacchi, N 2024, 'Stratified analyses refine association between TLR7 rare variants and severe COVID-19', Human Genetics and Genomics Advances, vol. 5, no. 4, 100323. https://doi.org/10.1016/j.xhgg.2024.100323

TY - JOUR

T1 - Stratified analyses refine association between TLR7 rare variants and severe COVID-19

AU - GenOMICC Investigators

AU - Boos, Jannik

AU - van der Made, Caspar I.

AU - Ramakrishnan, Gayatri

AU - Coughlan, Eamon

AU - Asselta, Rosanna

AU - Löscher, Britt Sabina

AU - Valenti, Luca V.C.

AU - de Cid, Rafael

AU - Bujanda, Luis

AU - Julià, Antonio

AU - Pairo-Castineira, Erola

AU - Baillie, J. Kenneth

AU - May, Sandra

AU - Zametica, Berina

AU - Heggemann, Julia

AU - Albillos, Agustín

AU - Banales, Jesus M.

AU - Barretina, Jordi

AU - Blay, Natalia

AU - Bonfanti, Paolo

AU - Buti, Maria

AU - Fernandez, Javier

AU - Marsal, Sara

AU - Prati, Daniele

AU - Ronzoni, Luisa

AU - Sacchi, Nicoletta

AU - Rimoldi, Valeria

AU - Paraboschi, Elvezia M.

AU - Bandera, Alessandra

AU - Peyvandi, Flora

AU - Grasselli, Giacomo

AU - Blasi, Francesco

AU - Malvestiti, Francesco

AU - Pelusi, Serena

AU - Bianco, Cristiana

AU - Miano, Lorenzo

AU - Lombardi, Angela

AU - Invernizzi, Pietro

AU - Gerussi, Alessio

AU - Citerio, Giuseppe

AU - Biondi, Andrea

AU - Valsecchi, Maria Grazia

AU - Cazzaniga, Marina Elena

AU - Foti, Giuseppe

AU - Beretta, Ilaria

AU - D'Angiò, Mariella

AU - Bettini, Laura Rachele

AU - Hamilton, Olly

AU - Carter, Emma

AU - Saunderson, Paula

PY - 2024/10/10

Y1 - 2024/10/10

N2 - Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.

AB - Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.

KW - burden analysis

KW - host genetics

KW - immune deficiency

KW - infection

KW - innate immunity

KW - rare variants

KW - SARS-CoV-2

KW - targeted sequencing

KW - toll-like receptor 7

KW - variant collapsing analysis

U2 - 10.1016/j.xhgg.2024.100323

DO - 10.1016/j.xhgg.2024.100323

M3 - Article

SN - 2666-2477

VL - 5

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 4

M1 - 100323

ER -

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Abstract

Keywords

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