An atlas of genetic variation for linking pathogen-induced cellular traits to human disease

Wang, Liuyang; Pittman, Kelly J.; Barker, Jeffrey R.; Salinas, Raul; Stanaway, Ian B.; Carroll, Robert J.; Balmat, Tom; Ingham, Andy; Gopalakrishnan, Anusha M.; Gibbs, Kyle D.; Antonia, Alejandro L.; Heitman, Joseph; Lee, Soo Chan; Jarvick, Gail P.; Denny, Joshua C.; DeLong, Mark; Valdivia, Raphael H.; Crosslin, David R.; Ko, Dennis C.

doi:10.1101/202325

Cited by 15 publications

(29 citation statements)

References 95 publications

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“…These studies have identified regulatory variants related to immune activation that act in cis or in trans (e.g., master regulators detected at IFNB1, IRF2, TLR1, or CR1), which are generally cell context dependent, and have revealed major overlaps between such variants and GWAS hits (see, for example, Kim-Hellmuth et al, 2017;Lee et al, 2014;Pala et al, 2017;Piasecka et al, 2018). These findings suggest that regulatory variation may underlie genetic associations with complex organismal phenotypes, such as infectious or autoimmune diseases (Wang et al, 2018).…”

Section: Individual-and Population-level Variation Of Immune Phenotypesmentioning

confidence: 99%

Human Immunology through the Lens of Evolutionary Genetics

Quintana-Murci

2019

Cell

120

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Pathogen-imposed selection pressures have been paramount during human evolution. Detecting such selection signatures in ancient and modern human genomes can thus help us to identify genes of temporal and spatial immunological relevance. Admixture with ancient hominins and between human populations has been a source of genetic diversity open to selection by infections. Furthermore, cultural transitions, such as the advent of agriculture, have exposed humans to new microbial threats, with impacts on host defense mechanisms. The integration of population genetics and systems immunology holds great promise for the increased understanding of the factors driving immune response variation between individuals and populations.

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Section: Individual-and Population-level Variation Of Immune Phenotypesmentioning

confidence: 99%

Human Immunology through the Lens of Evolutionary Genetics

Quintana-Murci

2019

Cell

120

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“…Recently, immunophenotyping based on the performance of the cells of immune system in in vitro models has been successfully carried out in humans. These cellular immunogenetics studies have identified phenotypic variation in cellular responses which then were linked to genetic variations and cellular mechanisms that control the resistance to bacterial infection in human populations (Ko et al, 2013;Alvarez et al, 2017;Wang et al, 2018). In cattle,…”

Section: Introductionmentioning

confidence: 99%

The effect of host genetics on in vitro performance of bovine monocyte-derived macrophages

Emam

Tabatabaei

Sargolzaei

et al. 2019

Journal of Dairy Science

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The dynamic interaction between the host and pathogens, along with environmental factors, influences the regulation of mammalian immune responses. Therefore, comprehensive in vivo immune-phenotyping during an active response to a pathogen can be complex and prone to confounding effects. Evaluating critical fundamental aspects of the immune system at a cellular level is an alternative approach to reduce this complexity. Therefore, the objective of the current study was to examine an in vitro model for functional phenotyping of bovine monocyte-derived macrophages (MDM), cells which play a crucial role at all phases of inflammation, as well influence downstream immune responses. As indicators of MDM function, phagocytosis and nitric oxide (NO −) production were tested in MDM of 16 cows in response to 2 common bacterial pathogens of dairy cows, Escherichia coli and Staphylococcus aureus. Notable functional variations were observed among the individuals (coefficient of variation: 33% for phagocytosis and 70% in the production of NO −). The rank correlation analysis revealed a significant, positive, and strong correlation (rho = 0.92) between NO − production in response to E. coli and S. aureus, and a positive but moderate correlation (rho = 0.58) between phagocytosis of E. coli and S. aureus. To gain further insight into this trait, another 58 cows were evaluated solely for NO − response against E. coli. The pedigree of the tested animals was added to the statistical model and the heritability was estimated to be 0.776. Overall, the finding of this study showed a strong effect of host genetics on the in vitro activities of MDM and the possibility of ranking Holstein cows based on the in vitro functional variation of MDM.

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“…In the reductionist approaches, the interactions of the sub-system with pathogens are examined in a controlled environment. In this approach, the performance of the sub-system is the criterion of classification, instead of the holistic approach that is based on the outcome of infection 8,9 . Due to the fact that the sub-system, i.e.…”

mentioning

confidence: 99%

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

Emam

Cánovas

Islas‐Trejo

et al. 2020

Sci Rep

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Reactive Nitrogen Species (RNS) are a group of bactericidal molecules produced by macrophages in response to pathogens in a process called oxidative burst. Nitric oxide (NO −) is a member of RNS produced from arginine by inducible Nitric Oxide Synthase (iNOS) enzyme. The activity of iNOS and production of NO − by macrophages following stimulation is one of the indicators of macrophage polarization towards M1/proinflammatory. Production of NO − by bovine monocyte-derived macrophage (MDM) and mouse peritoneal macrophages has been shown to be strongly associated with host genetic with the heritability of 0.776 in bovine MDM and 0.8 in mouse peritoneal macrophages. However, the mechanism of genetic regulation of macrophage response has remained less explored. In the current study, the transcriptome of bovine MDMs was compared between two extreme phenotypes that had been classified as high and low responder based on NO − production. The results showed that 179 and 392 genes were differentially expressed (DE) between high and low responder groups at 3 and 18 hours after exposure to Escherichia coli, respectively. A set of 11 Transcription Factors (TFs) (STAT1,

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An atlas of genetic variation for linking pathogen-induced cellular traits to human disease

Abstract: Summary 35Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with disease. To facilitate moving from associations to disease mechanisms, we leveraged the role of pathogens in shaping human evolution with the Hi-HOST Phenome Project

Cited by 15 publications

References 95 publications

Human Immunology through the Lens of Evolutionary Genetics

Human Immunology through the Lens of Evolutionary Genetics

The effect of host genetics on in vitro performance of bovine monocyte-derived macrophages

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

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