Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Publisher Copyright: Copyright © 2021Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean, 36.7 years) from a cohort of 1202 male patients aged 0.5 to 99 years (mean, 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean, 38.7 years) tested carry such TLR7 variants (P = 3.5 × 10−5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n = 2) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients from a cohort of 262 male patients with severe COVID-19 pneumonia (mean, 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is <6.5 × 10−4. We show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.Peer reviewe

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean, 36.7 years) from a cohort of 1202 male patients aged 0.5 to 99 years (mean, 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean, 38.7 years) tested carry such TLR7 variants (P = 3.5 × 10 −5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n = 2) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients from a cohort of 262 male patients with severe COVID-19 pneumonia (mean, 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is <6.5 × 10 −4. We show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract

Promoción de la salud y entornos saludables

Acn&eacute; juvenil, presentaci&oacute;n de 2 casos cl&iacute;nicosAlta ingesta de prote&iacute;nas y su relaci&oacute;n con el aumento de tejido adiposo en preescolaresAn&aacute;lisis para la integraci&oacute;n entre salud y educaci&oacute;n para el desarrollo de programas de promoci&oacute;nCalidad de los estilos de vida de funcionarios acad&eacute;micos de la Universidad del Biob&iacute;oCambios en el patr&oacute;n de consumo de alimentos en ni&ntilde;os con un kiosco saludableCaracter&iacute;sticas del sue&ntilde;o habitual y su relaci&oacute;n con el nivel de somnolencia diurna en adolescentesCaracterizaci&oacute;n de informaci&oacute;n acerca de promoci&oacute;n de salud poblaci&oacute;n urbana de Temuco, Regi&oacute;n de la Araucan&iacute;a, ChileComportamiento sexual durante el embarazo en usuarias de centros de salud, La Florida, Santiago, 2006Estado nutricional y actividad f&iacute;sica en escolares de 1&ordm;, 5&ordm; y 8&ordm; b&aacute;sico de Arica&iquest;Est&aacute;n los padres informados si sus hijos tienen miedo a la atenci&oacute;n dental?Evaluaci&oacute;n cualitativa del componente promocional de un programa psicosocial en poblaci&oacute;n escolar vulnerableEvaluaci&oacute;n de la efectividad de la aplicaci&oacute;n del Programa Educativo "Quiero mi boca siempre sana"Evaluaci&oacute;n estad&iacute;stica del uso de edulcorantes alimentarios en una poblaci&oacute;n de SantiagoEvoluci&oacute;n de la prematurez y caracter&iacute;sticas sociodemogr&aacute;ficas de la poblaci&oacute;n materna en ChileFactores de riesgo asociados a prevalencia de caries en alumnos del Ej&eacute;rcito de ChileH&aacute;bitos alimentarios en escolares de distinto tipo de establecimientos educacionalesNivel de conocimientos de los habitantes de Loncoche sobre enfermedades parasitarias, IX, Regi&oacute;n, Chile 2009Nutrici&oacute;n y condiciones socioecon&oacute;micas de escolares de la escuela Jes&uacute;s Mar&iacute;a Sifontes, Los Teques, VenezuelaRelaci&oacute;n entre dificultad para comprar cigarrillos, lugares de venta y curso en adolescente

Promoción de la salud y entornos saludables

Acn&eacute; juvenil, presentaci&oacute;n de 2 casos cl&iacute;nicosAlta ingesta de prote&iacute;nas y su relaci&oacute;n con el aumento de tejido adiposo en preescolaresAn&aacute;lisis para la integraci&oacute;n entre salud y educaci&oacute;n para el desarrollo de programas de promoci&oacute;nCalidad de los estilos de vida de funcionarios acad&eacute;micos de la Universidad del Biob&iacute;oCambios en el patr&oacute;n de consumo de alimentos en ni&ntilde;os con un kiosco saludableCaracter&iacute;sticas del sue&ntilde;o habitual y su relaci&oacute;n con el nivel de somnolencia diurna en adolescentesCaracterizaci&oacute;n de informaci&oacute;n acerca de promoci&oacute;n de salud poblaci&oacute;n urbana de Temuco, Regi&oacute;n de la Araucan&iacute;a, ChileComportamiento sexual durante el embarazo en usuarias de centros de salud, La Florida, Santiago, 2006Estado nutricional y actividad f&iacute;sica en escolares de 1&ordm;, 5&ordm; y 8&ordm; b&aacute;sico de Arica&iquest;Est&aacute;n los padres informados si sus hijos tienen miedo a la atenci&oacute;n dental?Evaluaci&oacute;n cualitativa del componente promocional de un programa psicosocial en poblaci&oacute;n escolar vulnerableEvaluaci&oacute;n de la efectividad de la aplicaci&oacute;n del Programa Educativo "Quiero mi boca siempre sana"Evaluaci&oacute;n estad&iacute;stica del uso de edulcorantes alimentarios en una poblaci&oacute;n de SantiagoEvoluci&oacute;n de la prematurez y caracter&iacute;sticas sociodemogr&aacute;ficas de la poblaci&oacute;n materna en ChileFactores de riesgo asociados a prevalencia de caries en alumnos del Ej&eacute;rcito de ChileH&aacute;bitos alimentarios en escolares de distinto tipo de establecimientos educacionalesNivel de conocimientos de los habitantes de Loncoche sobre enfermedades parasitarias, IX, Regi&oacute;n, Chile 2009Nutrici&oacute;n y condiciones socioecon&oacute;micas de escolares de la escuela Jes&uacute;s Mar&iacute;a Sifontes, Los Teques, VenezuelaRelaci&oacute;n entre dificultad para comprar cigarrillos, lugares de venta y curso en adolescente

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10-5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

BACKGROUND: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. METHODS: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. RESULTS: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10 CONCLUSIONS: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old