Host Genetic Variation Research Articles

Aberrant microbiomes are associated with increased antibiotic resistance gene load in hybrid mice

Abstract Antibiotic resistance is a priority public health problem resulting from eco-evolutionary dynamics within microbial communities and their interaction at a mammalian host interface or geographical scale. The links between mammalian host genetics, bacterial gut community and antimicrobial resistance gene (ARG) content must be better understood in natural populations inhabiting heterogeneous environments. Hybridisation, the interbreeding of genetically divergent populations, influences different components of the gut microbial communities. However, its impact on bacterial traits such as antibiotic resistance is unknown. Here, we present that hybridisation might shape bacterial communities and ARG occurrence. We used amplicon sequencing to study the gut microbiome and to predict ARG composition in natural populations of house mice (Mus musculus). We compared gastrointestinal bacterial and ARG diversity, composition and abundance across a gradient of pure and hybrid genotypes in the European house mouse hybrid zone. We observed an increased overall predicted richness of ARG in hybrid mice. We found bacteria - ARG interactions by their co-abundance and detected phenotypes of extreme abundances in hybrid mice at the level of specific bacterial taxa and ARGs, mainly multidrug resistance genes. Our work suggests that mammalian host genetic variation impacts the gut microbiome and chromosomal ARGs. However, it raises further questions on how the mammalian host genetics impact ARGs via microbiome dynamics or environmental covariates.

Rapid Restructuring of Rhizosphere and Endospheric Fungal Communities with Drought in Multiple Lines of Domesticated Sunflower

Plant-associated mycobiomes can influence important host plant traits including those related to disease, nutrient acquisition, flowering phenology, stress tolerance, and productivity. Disentangling the complex multifaceted relationships between host plants and their associated mycobiomes is a critical first step toward generating improvements in environmental sustainability and/or plant productivity. Despite decades of work on these plant–fungal interactions, consequences of and mechanisms controlling these interactions are not well resolved, especially in the face of environmental stress such as drought. Moreover, plant differential genotypic responses under stress and associated mycobiome assembly dynamics are likely important in structuring communities but have been less well studied. We conducted a controlled drought stress experiment by manipulating water treatment in a diverse set of cultivated sunflower lines with different inherent drought resistance levels to evaluate how sunflower host genotypes and drought interacts to affect belowground fungal mycobiomes at the rhizospheric and endospheric levels. Our results demonstrated that fungal community structure was driven by watering treatment, plant genotype, treatment by genotype interactions, genotype by plant compartment interactions, and treatment by genotype by compartment interactions. Additionally, our analyses demonstrated the relative abundance of plant pathogens and arbuscular mycorrhizal fungi increased with host genetic variation, or heterozygosity, levels. Our study provides evidence for drought and genotypic drivers of belowground sunflower–fungi interactions and offers a framework for leveraging these interactions to further understand how mycobiome community structure can improve plant productivity under stress.

Genomic and Phenotypic Analysis of Salmonella enterica Bacteriophages Identifies Two Novel Phage Species

Bacteriophages (phages) are potential alternatives to chemical antimicrobials against pathogens of public health significance. Understanding the diversity and host specificity of phages is important for developing effective phage biocontrol approaches. Here, we assessed the host range, morphology, and genetic diversity of eight Salmonella enterica phages isolated from a wastewater treatment plant. The host range analysis revealed that six out of eight phages lysed more than 81% of the 43 Salmonella enterica isolates tested. The genomic sequences of all phages were determined. Whole-genome sequencing (WGS) data revealed that phage genome sizes ranged from 41 to 114 kb, with GC contents between 39.9 and 50.0%. Two of the phages SB13 and SB28 represent new species, Epseptimavirus SB13 and genera Macdonaldcampvirus, respectively, as designated by the International Committee for the Taxonomy of Viruses (ICTV) using genome-based taxonomic classification. One phage (SB18) belonged to the Myoviridae morphotype while the remaining phages belonged to the Siphoviridae morphotype. The gene content analyses showed that none of the phages possessed virulence, toxin, antibiotic resistance, type I–VI toxin–antitoxin modules, or lysogeny genes. Three (SB3, SB15, and SB18) out of the eight phages possessed tailspike proteins. Whole-genome-based phylogeny of the eight phages with their 113 homologs revealed three clusters A, B, and C and seven subclusters (A1, A2, A3, B1, B2, C1, and C2). While cluster C1 phages were predominantly isolated from animal sources, cluster B contained phages from both wastewater and animal sources. The broad host range of these phages highlights their potential use for controlling the presence of S. enterica in foods.

Genotype-environment associations reveal genes potentially linked to avian malaria infection in populations of an endemic island bird.

Patterns of pathogen prevalence are, at least partially, the result of coevolutionary host-pathogen interactions. Thus, exploring the distribution of host genetic variation in relation to infection by a pathogen within and across populations can provide important insights into mechanisms of host defence and adaptation. Here, we use a landscape genomics approach (Bayenv) in conjunction with genome-wide data (ddRADseq) to test for associations between avian malaria (Plasmodium) prevalence and host genetic variation across 13 populations of the island endemic Berthelot's pipit (Anthus berthelotii). Considerable and consistent spatial heterogeneity in malaria prevalence was observed among populations over a period of 15 years. The prevalence of malaria infection was also strongly positively correlated with pox (Avipoxvirus) prevalence. Multiple host loci showed significant associations with malaria prevalence after controlling for genome-wide neutral genetic structure. These sites were located near to or within genes linked to metabolism, stress response, transcriptional regulation, complement activity and the inflammatory response, many previously implicated in vertebrate responses to malarial infection. Our findings identify diverse genes - not just limited to the immune system - that may be involved in host protection against malaria and suggest that spatially variable pathogen pressure may be an important evolutionary driver of genetic divergence among wild animal populations, such as Berthelot's pipit. Furthermore, our data indicate that spatio-temporal variation in multiple different pathogens (e.g. malaria and pox in this case) may have to be studied together to develop a more holistic understanding of host pathogen-mediated evolution.

Heritable microbiome variation is correlated with source environment in locally adapted maize varieties.

Beneficial interactions with microorganisms are pivotal for crop performance and resilience. However, it remains unclear how heritable the microbiome is with respect to the host plant genotype and to what extent host genetic mechanisms can modulate plant-microbiota interactions in the face of environmental stresses. Here we surveyed 3,168 root and rhizosphere microbiome samples from 129 accessions of locally adapted Zea, sourced from diverse habitats and grown under control and different stress conditions. We quantified stress treatment and host genotype effects on the microbiome. Plant genotype and source environment were predictive of microbiome abundance. Genome-wide association analysis identified host genetic variants linked to both rhizosphere microbiome abundance and source environment. We identified transposon insertions in a candidate gene linked to both the abundance of a keystone bacterium Massilia in our controlled experiments and total soil nitrogen in the source environment. Isolation and controlled inoculation of Massilia alone can contribute to root development, whole-plant biomass production and adaptation to low nitrogen availability. We conclude that locally adapted maize varieties exert patterns of genetic control on their root and rhizosphere microbiomes that follow variation in their home environments, consistent with a role in tolerance to prevailing stress.

Host genetic variants associated with COVID-19 reconsidered in a Slovak cohort

We present the results of an association study involving hospitalized coronavirus disease 2019 (COVID-19) patients with a clinical background during the 3rd pandemic wave of COVID-19 in Slovakia. Seventeen single nucleotide variants (SNVs) in the eleven most relevant genes, according to the COVID-19 Host Genetics Initiative, were investigated. Our study confirms the validity of the influence of LZTFL1 and 2′-5′-oligoadenylate synthetase (OAS)1/OAS3 genetic variants on the severity of COVID-19. For two LZTFL1 SNVs in complete linkage disequilibrium, rs17713054 and rs73064425, the odds ratios of baseline allelic associations and logistic regressions (LR) adjusted for age and sex ranged in the four tested designs from 2.04 to 2.41 and from 2.05 to 3.98, respectively. The OAS1/OAS3 haplotype ‘gttg’ carrying a functional allele G of splice-acceptor variant rs10774671 manifested its protective function in the Delta pandemic wave. Significant baseline allelic associations of two DPP9 variants in all tested designs and two IFNAR2 variants in the Omicron pandemic wave were not confirmed by adjusted LR. Nevertheless, adjusted LR showed significant associations of NOTCH4 rs3131294 and TYK2 rs2304256 variants with severity of COVID-19. Hospitalized patients' reported comorbidities were not correlated with genetic variants, except for obesity, smoking (IFNAR2), and hypertension (NOTCH4). The results of our study suggest that host genetic variations have an impact on the severity and duration of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the differences in allelic associations between pandemic waves, they support the hypothesis that every new SARS-CoV-2 variant may modify the host immune response by reconfiguring involved pathways.

Polymorphisms of IFN signaling genes and FOXP4 influence the severity of COVID-19

BackgroundThe clinical manifestations of COVID-19 range from asymptomatic, mild to moderate, severe, and critical disease. Host genetic variants were recognized to affect the disease severity. However, the genetic landscape differs among various populations. Therefore, we explored the variants associated with COVID-19 severity in the Guangdong population.MethodsA total of 314 subjects were selected, of which the severe and critical COVID-19 patients were defined as “cases”, and the mild and moderate patients were defined as “control”. Twenty-two variants in interferon-related genes and FOXP4 were genotyped using the MassARRAY technology platform.ResultsIFN signaling gene MX1 rs17000900 CA + AA genotype was correlated with a reduced risk of severe COVID-19 in males (P = 0.001, OR = 0.050, 95%CI = 0.008–0.316). The AT haplotype comprised of MX1 rs17000900 and rs2071430 was more likely to protect against COVID-19 severity (P = 6.3E-03). FOXP4 rs1886814 CC genotype (P = 0.001, OR = 3.747, 95%CI = 1.746–8.043) and rs2894439 GA + AA genotype (P = 0.001, OR = 5.703, 95% CI = 2.045–15.903) were correlated with increased risk of severe COVID-19. Haplotype CA comprised of rs1886814 and rs2894439 was found to be correlated with adverse outcomes (P = 7.0E-04). FOXP4 rs1886814 CC (P = 0.0004) and rs2894439 GA + AA carriers had higher neutralizing antibody titers (P = 0.0018). The CA + AA genotype of MX1 rs17000900 tended to be correlated with lower neutralizing antibody titers than CC genotype (P = 0.0663), but the difference was not statistically significant.ConclusionOur study found a possible association between MX1 and FOXP4 polymorphisms and the severity of COVID-19. Distinguishing high-risk patients who develop severe COVID-19 will provide clues for early intervention and individual treatment strategies.

Immunocapture of cell surface proteins embedded in HIV envelopes uncovers considerable virion genetic diversity associated with different source cell types.

HIV particles in the blood largely originate from activated lymphocytes and can overshadow variants which may be expressed from other cell types. Investigations of virus persistence must be able to distinguish cells refractory to viral clearance that serve as reservoirs. To investigate additional cell types that may be associated with in vivo HIV expression we developed a virus particle immunomagnetic capture method targeting several markers of cellular origin that become embedded within virion envelopes during budding. We evaluated the ability of markers to better distinguish cell lineage source subpopulations by assessing combinations of different antibodies with cell-sorted in vitro culture and clinical specimens. Various deductive algorithms were designed to discriminate source cell lineages and subsets. From the particle capture algorithms, we identified distinct variants expressed within individuals that were associated with disparate cellular markers. Among the variants uncovered were minority-level viruses with drug resistance mutations undetected by sequencing and often were associated with markers indicative of myeloid lineage (CD3-/CD10-/CD16+ or /CD14+, and CD3-/CD16-/CD14-/CD11c+ or /HLA-DR+) cell sources. The diverse HIV genetic sequences expressed from different cell types within individuals, further supported by the appearance of distinct drug-resistant variants, highlights the complexity of HIV reservoirs in vivo which must be considered for HIV cure strategies. This approach could also be helpful in examining in vivo host cell origins and genetic diversity in infections involving other families of budding viruses.

Cryptic sexual reproduction in an emerging Eucalyptus shoot and foliar pathogen

AbstractEucalyptus scab and shoot malformation is an emerging disease and a serious threat to the global plantation forestry industry. The disease appeared in North Sumatra (Indonesia) in the early 2010s and the causal agent was recently described as a novel species, Elsinoe necatrix. Nothing is known regarding its possible origin or why it emerged rapidly to cause a serious local epidemic. To investigate its population biology, we developed 15 polymorphic microsatellite markers as well as mating‐type markers using genome sequences for two E. necatrix isolates. Isolates of the pathogen were collected from different host varieties at four locations in the Lake Toba region of North Sumatra and characterized using these markers. A high level of genotypic diversity was observed for all populations with little to no genetic differentiation between sampling areas. Discriminant analysis of principal components, genotype networks and analysis of molecular variance all showed a lack of population structure and a high level of gene flow among sampling regions. Mating‐type ratios and linkage disequilibrium analyses suggest that sexual recombination is likely to be occurring, although a sexual state has not been found for the pathogen. The results of this study highlight the fact that new genotypes of E. necatrix, probably arising from cryptic sexual recombination, will challenge efforts to manage the disease, and that breeding and selection for tolerance will require substantial host genetic diversity.

Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population.

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.

Effects of Leishmania major infection on the gut microbiome of resistant and susceptible mice

Cutaneous leishmaniasis, a parasitic disease caused by Leishmania major, is a widely frequent form in humans. To explore the importance of the host gut microbiota and to investigate its changes during L. major infection, two different groups of mouse models were assessed. The microbiome of two parts of the host gut—ileum and colon—from infected and non-infected mice were characterised by sequencing of 16S rDNA using an Ion Torrent PGM platform. Microbiome analysis was performed to reveal changes related to the susceptibility and the genetics of mice strains in two different gut compartments and to compare the results between infected and non-infected mice. The results showed that Leishmania infection affects mainly the ileum microbiota, whereas the colon bacterial community was more stable. Different biomarkers were determined in the gut microbiota of infected resistant mice and infected susceptible mice using LEfSe analysis. Lactobacillaceae was associated with resistance in the colon microbiota of all resistant mice strains infected with L. major. Genes related to xenobiotic biodegradation and metabolism and amino acid metabolism were primarily enriched in the small intestine microbiome of resistant strains, while genes associated with carbohydrate metabolism and glycan biosynthesis and metabolism were most abundant in the gut microbiome of the infected susceptible mice. These results should improve our understanding of host-parasite interaction and provide important insights into the effect of leishmaniasis on the gut microbiota. Also, this study highlights the role of host genetic variation in shaping the diversity and composition of the gut microbiome.Key points• Leishmaniasis may affect mainly the ileum microbiota while colon microbiota was more stable.• Biomarkers related with resistance or susceptibility were determined in the gut microbiota of mice.• Several pathways were predicted to be upregulated in the gut microbiota of resistant or susceptible mice.Graphical

Opening the Black Box of Host Range, Vectorial Diversity, and Genetic Variants of Genus Anaplasma: The Contributing Factors Toward Its Zoonosis.

Background: Genus Anaplasma of the family Anaplasmataceae possesses bacteria of hematopoietic origin, which are obligate intracellular Gram-negative bacteria transmitted mainly by tick vectors. The members of this group of infectious agents are not new as etiological agents of animal diseases worldwide. However, now, reports of their zoonotic potential have gained currency to study these pathogens. The emergence of new species of Anaplasma and the spread of existing species to new areas and hosts highlight the importance of monitoring and improving diagnostic and treatment options for zoonotic diseases caused by Anaplasma. Conclusion: This review focuses on the general and distinctive characteristics of Anaplasma spp., with particular emphasis on the novel species and their diverse spectrum of hosts as potential risk factors impacting its emerging zoonosis.

Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI]= 4.08, 95% confidence interval [CI]= 2.03-6.14; rs2894207, RERI= 3.37, 95% CI= 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.

High niche specificity and host genetic diversity of groundwater viruses.

Viruses are key members of microbial communities that exert control over host abundance and metabolism, thereby influencing ecosystem processes and biogeochemical cycles. Aquifers are known to host taxonomically diverse microbial life, yet little is known about viruses infecting groundwater microbial communities. Here, we analysed 16 metagenomes from a broad range of groundwater physicochemistries. We recovered 1571 viral genomes that clustered into 468 high-quality viral operational taxonomic units. At least 15% were observed to be transcriptionally active, although lysis was likely constrained by the resource-limited groundwater environment. Most were unclassified (95%), and the remaining 5% were Caudoviricetes. Comparisons with viruses inhabiting other aquifers revealed no shared species, indicating substantial unexplored viral diversity. In silico predictions linked 22.4% of the viruses to microbial host populations, including to ultra-small prokaryotes, such as Patescibacteria and Nanoarchaeota. Many predicted hosts were associated with the biogeochemical cycling of carbon, nitrogen, and sulfur. Metabolic predictions revealed the presence of 205 putative auxiliary metabolic genes, involved in diverse processes associated with the utilization of the host's intracellular resources for biosynthesis and transformation reactions, including those involved in nucleotide sugar, glycan, cofactor, and vitamin metabolism. Viruses, prokaryotes overall, and predicted prokaryotic hosts exhibited narrow spatial distributions, and relative abundance correlations with the same groundwater parameters (e.g. dissolved oxygen, nitrate, and iron), consistent with host control over viral distributions. Results provide insights into underexplored groundwater viruses, and indicate the large extent to which viruses may manipulate microbial communities and biogeochemistry in the terrestrial subsurface.

The role of HLA genetic variants in COVID-19 susceptibility, severity, and mortality: A global review.

The COVID-19 pandemic has had a profound global impact, with variations in susceptibility, severity, and mortality rates across different regions. While many factors can contribute to the spread and impact of the disease, specifically human leukocyte antigen (HLA) genetic variants have emerged as potential contributors to COVID-19 outcomes. In this comprehensive narrative review, we conducted a thorough literature search to identify relevant studies investigating the association between HLA genetic variants and COVID-19 outcomes. Additionally, we analyzed allelic frequency data from diverse populations to assess differences in COVID-19 incidence and severity. Our review provides insights into the immunological mechanisms involving HLA-mediated responses to COVID-19 and highlights potential research directions and therapeutic interventions. We found evidence suggesting that certain HLA alleles, such as HLA-A02, may confer a lower risk of COVID-19, while others, like HLA-C04, may increase the risk of severe symptoms and mortality. Furthermore, our analysis of allele frequency distributions revealed significant variations among different populations. Considering host genetic variations, particularly HLA genetic variants, is crucial for understanding COVID-19 susceptibility and severity. These findings have implications for personalized treatment and interventions based on an individual's genetic profile. However, further research is needed to unravel the precise mechanisms underlying the observed associations and explore the potential for targeted therapies or preventive measures based on HLA genetic variants.

GSTP, GSTT1, XRCC1 and CASP8 genetic variations are associated with human papillomavirus in women with cervical cancer from Zimbabwe

Aim: Investigate the role of host genetic variations in high-risk human papillomaviruses (HR-HPVs). Methods: This cross-sectional study recruited 238 cervical cancer patients. Variants in transport (ABCC2), xenobiotic metabolism ( GSTP, GSTT1, GSTM1, NQO1), DNA repair ( ERCC1, XRCC1), immune response ( TLR4) and apoptosis ( CASP8, FASL, p53) genes were characterized. Tumor DNA was genotyped for 14 HR-HPVs. Results: GSTP rs1695GG, XRCC1 rs1799782TT and GSTT1 del/del were associated with HPV51 (odds ratio [OR]: 3.9; 95% confidence interval [CI]: 1.3–11.7; p = 0.02) and HPV58 (OR: 2.4; 95% CI: 1.2–5.8; p = 0.048), respectively. CASP8 rs3834129del/del was associated with HPV16/18 (OR: 2.7; 95% CI: 1.2–6.0; p = 0.017) and HPV monoinfections (OR: 2.3; 95% CI: 1.2–4.4; p = 0.008). Conclusion: GSTP, GSTT1, XRCC1 and CASP8 variants were associated with HPV-positivity. With further research, a genetic-based screening tool can be developed, to use with HPV vaccines toward preventing cervical cancer.

The pleiotropic approach to coronavirus disease-19 pathogenesis: The impact of liver diseases associated host genetic variants.

Coronavirus disease-2019 (COVID-19) is a novel multisystemic viral disease caused pandemic. The disease impact involves liver and associated systems. Undoubtedly, host genetic background influences the predisposition and prediction of infection. Variants among human populations might increase susceptibility or protect against severe outcomes. In this manner, rs738409 variant of patatin-like phospholipase domain-containing protein 3 gene appears to be protective in some populations in spite of its aggravating effect on non-alcoholic fatty liver diseases (NAFLDs) and steatohepatitis. DRB1*15:01 allele of human leukocyte antigen is associated with protective effect in European and Japanese populations. DRB1*03:01 contrarily increases the susceptibility of severe COVID-19 infection in European populations. rs1260326 in glucokinase regulatory protein gene, rs112875651 in tribbles homolog 1 gene, rs429358 in apolipoprotein 1, and rs58542926 in transmembrane 6 superfamily 2 alleles are found related with NAFLD and obesity; thus, hypercoagulability and severe COVID-19 outcomes. In chronic or acute liver diseases, comorbid syndromes are the key factors to explain increased severity. There might not be a direct association between the variant and severe COVID-19 infection. As it is concluded, there are genes and variants known and unknown yet to be studied to reveal the association with disease severity.

Host genetic variants associated with susceptibility and severity of pneumococcal pneumonia in adult patients

BackgroundPneumococcal community-acquired pneumonia (P-CAP) is a major cause of morbidity and hospitalization. Several host genetics factors influencing risk of pneumococcal disease have been identified, with less information about its association with P-CAP. The aim of the study was to assess the influence of single nucleotide polymorphisms (SNP) within key genes involved in the innate immune response on the susceptibility to P-CAP and to study whether these polymorphic variants were associated with the severity and outcome of the episodes in a cohort of adult Caucasian patients.MethodsSeventeen SNPs from 7 genes (IL-R1, IL-4, IL-10, IL-12B, NFKBIA, NFKBIE, NFKBIZ) were analyzed. For susceptibility, a case-control study including a cohort of 57 adult with P-CAP, and 280 ethnically matched controls was performed. Genetic influence on clinical severity and outcome was evaluated in a prospective observational study including all consecutive adult P-CAP patients from November 2015 to May 2017.ResultsThe NFKBIA polymorphism rs696 and a haplotype combination were associated with susceptibility to P-CAP (OR = 0.62, p = 0.005 and OR = 0.63, p = 0.008, respectively). The SNP IL4 rs2227284 was associated with severe P-CAP (OR = 2.17, p = 0.04). IL-R1 (rs3917267) and IL-10 (rs3024509) variants were related with respiratory failure (OR = 3.31, p = 0.001 and OR = 0.18, p = 0.003, respectively) as well as several haplotype combinations in NFKBIA, NFKBIZ, IL-R1 and IL-10 (p = 0,02, p = 0,01, p = 0,001, p = 0,03, respectively). CURB-65 values were associated with the IL-10 rs3024509 variant (beta = − 0.4, p = 0.04), and with haplotype combinations of NFKBIZ and IL-10 (p = 0.05, p = 0.04, respectively). Genetic variants in IL-10 (rs3024509) and in IL-12B (rs730691) were associated with PSI values (beta = − 0.54, p = 0.01, and beta = − 0.28, p = 0.04, respectively), as were allelic combinations in IL-R1 (p = 0.02) and IL-10 (p = 0.01). Finally, several polymorphisms in the IL-R1 gene (rs13020778, rs2160227, & rs3917267) were associated with the time elapsed until clinical stability (beta = − 0.83, p = 0.03; beta = − 1, p = 0.02 and beta = 1.07, p = 0.008, respectively).ConclusionsA genetic variant in NFKBIA was associated with susceptibility to P-CAP in adult Caucasian patients and genetic variants from key cytokines of the innate immune response (Il-4, IL-10, IL-R1 and IL-12B) and NF-κB inhibitors were associated with different phenotypes of severe P-CAP. If validated, these SNPs may help to identify people at risk of P-CAP or severe P-CAP on which preventive measures could be applied.

Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes.

HIV infection continues to be a major global public health issue. The population heterogeneity in susceptibility or resistance to HIV-1 and progression upon infection is attributable to, among other factors, host genetic variation. Therefore, identifying population-specific variation and genetic modifiers of HIV infectivity can catapult the invention of effective strategies against HIV-1 in African populations. Here, we investigated whole genome sequences of 390 unrelated HIV-positive and -negative individuals from Botswana. We report 27.7 million single nucleotide variations (SNVs) in the complete genomes of Botswana nationals, of which 2.8 million were missing in public databases. Our population structure analysis revealed a largely homogenous structure in the Botswana population. Admixture analysis showed elevated components shared between the Botswana population and the Niger-Congo (65.9%), Khoe-San (32.9%), and Europeans (1.1%) ancestries in the population of Botswana. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated. The most deleterious variants were enriched in five genes: ACTRT2 (the Actin Related Protein T2), HOXD12 (homeobox D12), ABCB5 (ATP binding cassette subfamily B member 5), ATP8B4 (ATPase phospholipid transporting 8B4) and ABCC12 (ATP Binding Cassette Subfamily C Member 12). These genes are enriched in the glycolysis and gluconeogenesis (p < 2.84e-6) pathways and therefore, may contribute to the emerging field of immunometabolism in which therapy against HIV-1 infection is being evaluated. Published transcriptomic evidence supports the role of the glycolysis/gluconeogenesis pathways in the regulation of susceptibility to HIV, and that cumulative effects of genetic modifiers in glycolysis/gluconeogenesis pathways may potentially have effects on the expression and clinical variability of HIV-1. Identified genes and pathways provide novel avenues for other interventions, with the potential for informing the design of new therapeutics.

Associations between Host Genetic Variants and Subgingival Microbiota in Patients with the Metabolic Syndrome

Associations between Host Genetic Variants and Subgingival Microbiota in Patients with the Metabolic Syndrome