The evolutionary landscape of host immunity genes involved in respiratory and other immune-related diseases, and their association with severe COVID-19 outcomes
Christopher N Cross, Alessandro Lisi, Faith C Simmonds, Kareem Washington, Thomas Heinbockel, Michael C Campbell
doi:10.1101/2025.08.28.25334640
Background Given its high mortality and broad societal impacts, the COVID-19 pandemic is a particularly notable global outbreak of a respiratory illness in the 21 st century. Although previous studies have identified several genes associated with COVID-19 susceptibility, relatively little is known about the genes contributing to severe COVID-19, including their evolutionary histories. In the current study, we analyzed IL-4, TLR2, CCL2, and SLC11A1-four immunity genes that have been implicated in severe COVID-19 and other immune-related diseases-in globally diverse populations from the 1000 Genomes Project. We also tested for associations between genetic variation in these genes and clinical COVID-19 phenotypes in more than 4,000 laboratory-confirmed COVID-19-positive individuals from Italy.
Competing interests The authors have no relevant financial or non-financial interests to disclose.
Author contributions All authors contributed to the study conception and design. Material preparation and analyses were
References
Abecasis, Auton, Brooks, Depristo, Durbin, An integrated map of genetic variation from 1,092 human genomes, Nature
Abhimanyu, Bose, Jha, Genome Variation, Consortium, Footprints of genetic susceptibility to pulmonary tuberculosis: cytokine gene variants in north Indians, Indian J Med Res
Aliperti, Sgueglia, Aniello, Vitale, Fucci et al., Identification, Characterization, and Regulatory Mechanisms of a Novel EGR1 Splicing Isoform, Genome Biol Evol
Amat, Louha, Benet, Guiddir, Bourgoin-Heck et al., The IL-4 rs2070874 polymorphism may be associated with the severity of recurrent viral-induced wheeze, Pediatr Pulmonol
Amiel, Lyonnet, Hirschsprung disease, associated syndromes, and genetics: a review, J Med Genet
Antonio, Nguyen, Arthur, Matsui, Host et al., SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues, Cell Rep
Araújo, Sgorlon, Aguiar, Cidrão, Teixeira et al., Influence of polymorphic variations of IFNL, HLA, and IL-6 genes in severe cases of COVID-19, Exp Biol Med
Asano, Boisson, Onodi, Matuozzo, Moncada-Velez et al., Xlinked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19, Sci Immunol
Badla, Hanifa, Jain, Naofal, Halabi et al., Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients: a case series, Sci Rep
Balamayooran, Batra, Balamayooran, Cai, Jeyaseelan, Monocyte chemoattractant protein 1 regulates pulmonary host defense via neutrophil recruitment during Escherichia coli infection, Infect Immun
Balanovsky, Petrushenko, Mirzaev, Abdullaev, Gorin et al., Variation of genomic sites associated with severe covid-19 across populations: Global and national patterns, Pharmgenomics Pers Med
Bandelt, Forster, Röhl, Median-joining networks for inferring intraspecific phylogenies, Mol Biol Evol
Bank, Andersen, Burisch, Pedersen, Roug et al., Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a Danish cohort, PLoS One
Basu-Ray, Almaddah, Adeboye, Soos, Cardiac Manifestations Of Coronavirus (COVID-19)
Ben-Ali, Barbouche, Bousnina, Chabbou, Dellagi, Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients, Clin Diagn Lab Immunol
Bergström, Mccarthy, Hui, Almarri, Ayub et al., Insights into human genetic variation and population history from 929 diverse genomes, Genetics
Bhattacharyya, Fang, Tourtellotte, Varga, Egr-1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis), J Pathol
Bone, Siewert, Jha, Klarin, Damrauer et al., Multitrait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits, Alzheimers Res Ther
Brosnahan, Jonkman, Kugler, Munger, Kaufman, COVID-19 and respiratory system disorders: Current knowledge, future clinical and translational research questions, Arterioscler Thromb Vasc Biol
Butler-Laporte, Povysil, Kosmicki, Cirulli, Drivas et al., Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative, PLoS Genet
Byun, Han, Walsh, Park, Bondy et al., Shared genomic architecture between COVID-19 severity and numerous clinical and physiologic parameters revealed by LD score regression analysis, Sci Rep
Campbell, Hirbo, Townsend, Tishkoff, The peopling of the African continent and the diaspora into the new world, Curr Opin Genet Dev
Campbell, Ranciaro, Human adaptation, demography and cattle domestication: an overview of the complexity of lactase persistence in Africa, Hum Mol Genet
Campbell, Smith, Harvey, Population genetic evidence for positive and purifying selection acting at the human IFN-γ locus in Africa, Genes Immun
Campbell, Tishkoff, African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping, Annu Rev Genomics Hum Genet
Carter, Nguyen, Byars, Voskarides, Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles, BMC Med Genet
Celik, Genc, Dursun, A bioinformatic approach to investigating cytokine genes and their receptor variants in relation to COVID-19 progression, International Journal of Immunogenetics
Chen, Zhang, Wei, Cai, Yao et al., Association between cytokine profiles and lung injury in COVID-19 pneumonia, Respir Res
Consortium, Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome, Nature
Cortez, Muxfeldt, Monocyte chemoattractant protein-1 and hypertension: An overview, Hipertens Riesgo Vasc
Cox, Morales, Woerner, Sozanski, Wall et al., The allele frequency spectrum in genome-wide human variation data reveals signals of differential demographic history in three large world populations, PLoS One
Cruickshank, Deschoolmeester, Svensson, Howell, Bazakou et al., Rapid Dendritic Cell Mobilisation to the Large Intestinal Epithelium is Associated with Resistance to Trichuris muris Infection, The Journal of Immunology
Danecek, Auton, Abecasis, Albers, Banks et al., The variant call format and VCFtools, Bioinformatics
Degenhardt, Ellinghaus, Juzenas, Lerga-Jaso, Wendorff et al., Detailed stratified GWAS analysis for severe COVID-19 in four European populations, Hum Mol Genet
Deplancke, Alpern, Gardeux, The Genetics of Transcription Factor DNA Binding Variation, Cell
Dheda, Perumal, Moultrie, Perumal, Esmail et al., The intersecting pandemics of tuberculosis and COVID-19: population-level and patient-level impact, clinical presentation, and corrective interventions, Lancet Respir Med
Eldar-Yedidia, Hillel, Cohen, Bar-Meir, Freier-Dror et al., Association of tolllike receptors polymorphism and intrauterine transmission of cytomegalovirus, PLoS One
Fallerini, Daga, Mantovani, Benetti, Picchiotti et al., Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested casecontrol study, Elife
Fay, Wu, Hitchhiking under positive Darwinian selection, Genetics
Fricke-Galindo, Valencia, Genetics Insight for COVID-19 Susceptibility and Severity: A Review, Front Immunol
Ghafouri-Fard, Noroozi, Vafaee, Branicki, Poṡpiech et al., Effects of host genetic variations on response to, susceptibility and severity of respiratory infections, Biomed Pharmacother
Gomes, Teixeira-Cunha, Figueiredo, Almeida, Alves et al., Bacterial clearance in septic mice is modulated by MCP-1/CCL2 and nitric oxide, Shock
Gravel, Henn, Gutenkunst, Indap, Marth et al., Demographic history and rare allele sharing among human populations, Proc Natl Acad Sci U S A
Grolmusz, Bozsik, Papp, Patócs, Germline Genetic Variants of Viral Entry and Innate Immunity May Influence Susceptibility to SARS-CoV-2 Infection: Toward a Polygenic Risk Score for Risk Stratification, Front Immunol
Han, Ma, Li, Liu, Zhao et al., Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors, Emerg Microbes Infect
Herman, Gharini, Dinarti, Clinical cardiac manifestations in patients with coronavirus disease 2019 (COVID-19), Journal of thee Medical Sciences (Berkala Ilmu Kedokteran)
Hermisson, Pennings, Soft sweeps and beyond: Understanding the patterns and probabilities of selection footprints under rapid adaptation
Hermisson, Pfaffelhuber, The pattern of genetic hitchhiking under recurrent mutation, Electronic Journal of Probability
Higham, Douka, Wood, Ramsey, Brock et al., The timing and spatiotemporal patterning of Neanderthal disappearance, Nature
Hohenlohe, Phillips, Cresko, USING POPULATION GENOMICS TO DETECT SELECTION IN NATURAL POPULATIONS: KEY CONCEPTS AND METHODOLOGICAL CONSIDERATIONS, Int J Plant Sci
Hou, Zhao, Martin, Kallianpur, Chung et al., New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis, BMC Med
Hrdlickova, De Almeida, Borek, Withoff, Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease, Biochim Biophys Acta
Kelleher, Etheridge, Mcvean, Efficient coalescent simulation and genealogical analysis for large sample sizes, PLoS Comput Biol
Khan, Shafiei, Longoria, Schoggins, Savani et al., SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway, Elife
Khatib, Benslimane, Elbashir, Coyle, Maslamani, Within-Host Diversity of SARS-CoV-2 in COVID-19 Patients With Variable Disease Severities, Front Cell Infect Microbiol
Kim, Elnaggar, Varnado, Feehan, Tauzier et al., A bioinformatic analysis of T-cell epitope diversity in SARS-CoV-2 variants: association with COVID-19 clinical severity in the United States population, Front Immunol
Kosmicki, Horowitz, Banerjee, Lanche, Marcketta et al., Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals, Am J Hum Genet
Krieger, Vissichelli, Leichtle, Kashioris, Sabo et al., Immunological determinants of clinical outcomes in COVID-19: A quantitative perspective
Kucher, Babushkina, Sleptcov, Nazarenko, Genetic Control of Human Infection with SARS-CoV-2, Russian Journal of Genetics
Kumar, Ambrosini, Bucher, SNP2TFBS -a database of regulatory SNPs affecting predicted transcription factor binding site affinity, Nucleic Acids Res
Landrum, Lee, Riley, Jang, Rubinstein et al., ClinVar: public archive of relationships among sequence variation and human phenotype, Nucleic Acids Res
Langton, Bourke, Lie, Reiff, Natu et al., The influence of HLA genotype on the severity of COVID-19 infection, Hladnikia
Li, He, Tan, Li, Zhao et al., Transcription factor EGR2 alleviates autoimmune uveitis via activation of GDF15 to modulate the retinal microglial phenotype, Proc Natl Acad Sci
Li, Liu, Kim, Min, Zhang, Gene Expression Variability within and between Human Populations and Implications toward Disease Susceptibility, PLoS Computational Biology
Lin, Wang, Shen, Yi, Li et al., Genetic Variants, Circulating Level of MCP1 with Risk of Chronic Obstructive Pulmonary Disease: A Case-Control Study, Pharmacogenomics and personalized medicine
Lin, Wang, Shen, Yi, Li et al., Genetic Variants, Circulating Level of MCP1 with Risk of Chronic Obstructive Pulmonary Disease: A Case-Control Study, Pharmgenomics Pers Med
Lisi, Campbell, CLUES2 Companion: Computational pipelines to estimate, visualize, and date selection on multi-locus sites, bioRxiv,
doi:10.1101/2025.06.10.658975Lisi, Campbell, Ferrer-Admetlla, Liang, Korneliussen et al., Polaris: Polarization of ancestral and derived polymorphic alleles for inferences of extended haplotype homozygosity in human populations. bioRxiv, Mol Biol Evol
Lisi, Campbell, Polaris: Polarization of ancestral and derived polymorphic alleles for inferences of extended haplotype homozygosity in human populations, Bioinformatics
Liu, Zhang, Huang, Yang, Wang et al., Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury, Natl Sci Rev
Liu, Zhao, Zhu, Zhang, Wang, 3'UTR polymorphisms in NRAMP1 are associated with the susceptibility to pulmonary tuberculosis: A MOOSE-compliant meta-analysis, Medicine
Lohmueller, Bustamante, Clark, Detecting directional selection in the presence of recent admixture in African-Americans, Genetics
Loktionov, Kobzeva, Karpenko, Sergeeva, Orlov et al., GWASsignificant loci and severe COVID-19: analysis of associations, link with thromboinflammation syndrome, gene-gene, and gene-environmental interactions, Front Genet
Ma, Zhang, Jiang, Sun, Ming et al., A novel dominant mutation in the SOX10 gene in a Chinese family with Waardenburg syndrome type II, Mol Med Rep
Mallah, Ghorab, Al-Salmi, Abdellatif, Tharmaratnam et al., COVID-19: breaking down a global health crisis, Annals of Clinical Microbiology and Antimicrobials
Mantovani, Daga, Fallerini, Baldassarri, Benetti et al., Rare variants in Tolllike receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients, Genes Immun
Marinelli, Ferreira, Ierullo, Ku, Lilly et al., Prospective clinical, virologic, and immunologic assessment of COVID-19 in transplant recipients, Transplantation
Meilang, Zhang, Zhang, Zhao, Tian et al., Polymorphisms in the SLC11A1 gene and tuberculosis risk: a meta-analysis update, Int J Tuberc Lung Dis
Messer, Petrov, Population genomics of rapid adaptation by soft selective sweeps, Trends Ecol Evol
Moorjani, Sankararaman, Fu, Przeworski, Patterson et al., A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years, Proc Natl Acad Sci U S A
Mukherjee, Huda, Babu, Toll-like receptor polymorphism in host immune response to infectious diseases: A review, Scand J Immunol
Musa, Musa, Musa, Musa, Ranciaro et al., Addressing Africa's pandemic puzzle: Perspectives on COVID-19 transmission and mortality in sub-Saharan Africa, Int J Infect Dis
Namkoong, Edahiro, Takano, Nishihara, Shirai et al., DOCK2 is involved in the host genetics and biology of severe COVID-19, Nature
Namkoong, Kurashima, Morimoto, Hoshino, Hasegawa et al., Epidemiology of pulmonary nontuberculous Mycobacterial disease, japan, Emerg Infect Dis
Nielsen, Vaughn, Deng, Inference and applications of ancestral recombination graphs, Nat Rev Genet
Ogus, Yoldas, Ozdemir, Uguz, Olcen et al., The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease, Eur Respir J
Pabst, Yenice, Lennarz, Tuleta, Nickenig et al., Toll-Like Receptor 2 Gene Polymorphisms Arg677Trp and Arg753Gln in Chronic Obstructive Pulmonary Disease, Lung
Paim, Lopes-Ribeiro, Silva, Andrade, Moraes et al., Will a little change do you good? A putative role of polymorphisms in COVID-19, Immunology Letters
Pairo-Castineira, Clohisey, Klaric, Bretherick, Rawlik et al., Genetic mechanisms of critical illness in COVID-19, Nature
Patarčić, Gelemanović, Kirin, Kolčić, Theodoratou et al., The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis, Sci Rep
Peter, Huerta-Sanchez, Nielsen, Pagani, Schiffels et al., Tracing the route of modern humans out of Africa by using 225 human genome sequences from Ethiopians and Egyptians, Am J Hum Genet
Pham, Bonello, Castiblanco, Le, Sigala et al., The rs1024611 regulatory region polymorphism is associated with CCL2 allelic expression imbalance, PLoS One
Porcu, Sadler, Lepik, Auwerx, Wood et al., Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome, Nat Commun
Posada, Crandall, Intraspecific gene genealogies: trees grafting into networks, Trends Ecol Evol
Pritchard, Pickrell, Coop, The genetics of human adaptation: hard sweeps, soft sweeps, and polygenic adaptation, Curr Biol
Przeworski, Coop, Wall, The signature of positive selection on standing genetic variation, Evolution
Racimo, Sankararaman, Nielsen, Huerta-Sánchez, Evidence for archaic adaptive introgression in humans, Nat Rev Genet
Ramasamy, Subbian, Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis, Clin Microbiol Rev
Ranciaro, Campbell, Hirbo, Ko, Froment et al., Genetic origins of lactase persistence and the spread of pastoralism in Africa, Am J Hum Genet
Raza, Abbasi, An Evolutionary Insight Into the Heterogeneous Severity Pattern of the SARS-CoV-2 Infection, Frontiers in Genetics
Rizvi, Rizvi, Raza, Abbas, Fatima et al., Implication of single nucleotide polymorphisms in Interleukin-10 gene (rs1800896 and rs1800872) with severity of COVID-19, J Med Hum Genet
Roca-Umbert, Caro-Consuegra, Londono-Correa, Rodriguez-Lozano, Vicente et al., Understanding signatures of positive natural selection in human zinc transporter genes, Sci Rep
Ronen, Udpa, Halperin, Bafna, Learning natural selection from the site frequency spectrum, Genetics
Rozas, Ferrer-Mata, Sánchez-Delbarrio, Guirao-Rico, Librado et al., DnaSP 6: DNA sequence polymorphism analysis of large data sets, Mol Biol Evol
Saba, Nur, Alam, Howlader, Islam et al., Missense variant rs75603675 within TMPRSS2 gene is associated with the increased risk of severe form of COVID-19, Gene Rep
Sabah-Özcan, Gürel, The polymorphism rs4696480 in the TLR2 gene is associated with psoriasis patients in the Turkish population, Immunol Lett
Sabeti, Reich, Higgins, Levine, Richter et al., Detecting recent positive selection in the human genome from haplotype structure, Nature
Sakagami, Witherspoon, Nakajima, Jinnai, Wooding et al., Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci, Genes Immun
Saleh, Ramadan, Arram, Toll-like receptor-2 Arg753Gln and Arg677Trp polymorphisms and susceptibility to pulmonary and peritoneal tuberculosis, APMIS
Sanctis, García, Moreno, Hajduch, Coronavirus infection: An immunologists' perspective, Scand J Immunol
Sapkota, Hijikata, Matsushita, Tanaka, Ieki et al., Association of SLC11A1 (NRAMP1) polymorphisms with pulmonary Mycobacterium avium complex infection, Hum Immunol
Schildkraut, Gallagher, Morimoto, Lange, Haworth et al., Epidemiology of nontuberculous mycobacterial pulmonary disease in Europe and Japan by Delphi estimation, Respir Med
Schimke, Marques, Baiocchi, De Souza Prado, Fonseca et al., Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States, Cells
Shihabi, Lukic, Cubric-Curik, Brajkovic, Oršanić et al., Identification of selection signals on the X-chromosome in East Adriatic sheep: A new complementary approach, Front Genet
Simula, Jasemi, Cossu, Manca, Sanna et al., The genetic landscape of systemic rheumatic diseases: A comprehensive multigene-panel study identifying key gene polymorphisms, Pharmaceuticals
Smatti, Al-Sarraj, Albagha, Yassine, Host Genetic Variants Potentially Associated With SARS-CoV-2: A Multi-Population Analysis, Front Genet
Sookaromdee, Wiwanitkit, Joob, Genetic polymorphisms namely TLR2 Gene Arg753gln and Arg677trp polymorphisms and tuberculosis: Comparison on the effects of molecular weight alterations, Biomedical and Biotechnology Research Journal (BBRJ)
Stagas, Papaetis, Orphanidou, Kostopoulos, Syriou et al., Polymorphisms of the NRAMP1 gene: Distribution and susceptibility to the development of pulmonary tuberculosis in the Greek population, Medical Science Monitor
Sun, Pan, Tian, Chen, Critically-ill COVID-19 susceptibility gene CCR3 shows natural selection in sub-Saharan Africans, Infect Genet Evol
Szpiech, Hernandez, selscan: an efficient multithreaded program to perform EHH-based scans for positive selection, Mol Biol Evol
Szpiech, Selscan 2.0: Scanning for sweeps in unphased data, Bioinformatics
Tajima, Nei, Estimation of evolutionary distance between nucleotide sequences, Mol Biol Evol
Tang, Yin, Hu, Mei, Controlling Cytokine Storm Is Vital in COVID-19, Front Immunol
Totura, Whitmore, Agnihothram, Schäfer, Katze et al., Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome Coronavirus infection, MBio
Valle, Kim-Schulze, Huang, Beckmann, Nirenberg et al., An inflammatory cytokine signature predicts COVID-19 severity and survival, Nat Med
Van Blokland, Lanting, Ori, Vonk, Warmerdam et al., Using symptombased case predictions to identify host genetic factors that contribute to COVID-19 susceptibility, PLoS One
Van Der Made, Simons, Schuurs-Hoeijmakers, Van Den Heuvel, Mantere et al., Presence of genetic variants among young men with severe COVID-19, JAMA
Vaughn, Nielsen, Fast and accurate estimation of selection coefficients and allele histories from ancient and modern DNA, Mol Biol Evol
Velavan, Pallerla, Rüter, Kremsner, Krishna, Host genetic factors determining COVID-19 susceptibility and severity, EBioMedicine
Vinson, Agarwal, Dai, Anzalone, Lee et al., COVID-19 in solid organ transplantation: Results of the National COVID Cohort Collaborative, Transplant Direct
Voight, Adams, Frisse, Qian, Hudson et al., Interrogating multiple aspects of variation in a full resequencing data set to infer human population size changes, Proceedings of the National Academy of Sciences
Voight, Kudaravalli, Wen, Pritchard, A map of recent positive selection in the human genome, PLoS Biol
Wang, Balmat, Antonia, Constantine, Henao et al., An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility, Genome Med
Wei, Dimicoli, Bueso-Ramos, Yang, Neuberg, Toll-like receptor alterations in myelodysplastic syndrome, Leukemia
Weir, Cockerham, Estimating F-Statistics for the Analysis of Population Structure, Evolution
Wu, Ding, Li, Liu, Cheng et al., Trans-ethnic genome-wide association study of severe COVID-19, Commun Biol
Wu, Liu, Chen, Wang, Zhang et al., Polymorphisms of TLR2, TLR4 and TOLLIP and tuberculosis in two independent studies, Biosci Rep
Wu, Mcgoogan, Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention, JAMA
Xu, Li, Yang, Jiang, Zhou et al., Association of CCL2 gene variants with osteoarthritis, Arch Med Res
Xu, Yang, Pei, Editorial: Genetic pleiotropy in complex traits and diseases, Front Genet
Zaid, Doré, Dubuc, Archambault, Flamand et al., Chemokines and eicosanoids fuel the hyperinflammation within the lungs of patients with severe COVID-19, J Allergy Clin Immunol
Zecevic, Kotur, Ristivojevic, Gasic, Skodric-Trifunovic et al., Genomewide association study of COVID-19 outcomes reveals novel host genetic risk loci in the Serbian population, Front Genet
Zhang, Lucas, Veturi, Drivas, Bone et al., Large-scale genomic analyses reveal insights into pleiotropy across circulatory system diseases and nervous system disorders, Nat Commun
Zhang, Verma, Feng, Melo, Mcquillan et al., Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection, Proc Natl Acad Sci
Zhang, Verma, Feng, Melo, Mcquillan et al., Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection, Res Sq,
doi:10.21203/rs.3.rs-673011/v1Zhang, Zhang, Casanova, Su, Team, Severe COVID-19 in the young and healthy: monogenic inborn errors of immunity?, Nat Rev Immunol
Zheng, Karki, Williams, Yang, Fitzpatrick et al., TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines, Nat Immunol
DOI record:
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"abstract": "<jats:p>Background\nGiven its high mortality and broad societal impacts, the COVID-19 pandemic is a particularly notable global outbreak of a respiratory illness in the 21<jats:sup>st</jats:sup> century. Although previous studies have identified several genes associated with COVID-19 susceptibility, relatively little is known about the genes contributing to severe COVID-19, including their evolutionary histories. In the current study, we analyzed <jats:italic>IL-4</jats:italic>, <jats:italic>TLR2</jats:italic>, <jats:italic>CCL2</jats:italic>, and <jats:italic>SLC11A1</jats:italic>—four immunity genes that have been implicated in severe COVID-19 and other immune-related diseases—in globally diverse populations from the 1000 Genomes Project. We also tested for associations between genetic variation in these genes and clinical COVID-19 phenotypes in more than 4,000 laboratory-confirmed COVID-19–positive individuals from Italy. \n\nResults\nBased on our analyses, we identified 72 single nucleotide polymorphisms (SNPs) across these genes as targets of positive selection, including several derived alleles shared with archaic Neanderthal and/or Denisovan genomes—a finding not previously reported in the literature. Furthermore, we found that common SNPs—implicated in respiratory diseases such as tuberculosis and chronic obstructive pulmonary disorder—were also under selection. Functional predictions based on <jats:italic>in silico</jats:italic> analyses revealed that a subset of selected alleles map to transcription factor binding sites and are predicted to affect binding affinity. In addition, our genetic association analyses uncovered significant correlations between derived alleles in the coding region of <jats:italic>TLR2</jats:italic> and COVID-19 severity. Interestingly, these candidate alleles occurred at relatively low frequency in western European and East Asian populations but were absent in populations of African and South Asian descent. \n\nConclusions\nOverall, our study provides new insights into the evolution of biologically relevant immunity genes in the modern human lineage and highlights genetic variants that may underlie differential risk for severe COVID-19.</jats:p>",
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