Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation, causing parental origin-specific monoallelic gene expression. Zinc finger protein 57 (ZFP57) is critical for ...maintenance of this epigenetic memory during post-fertilization reprogramming, yet incomplete penetrance of
mutations in humans and mice suggests additional effectors. We reveal that ZNF445/ZFP445, which we trace to the origins of imprinting, binds imprinting control regions (ICRs) in mice and humans. In mice, ZFP445 and ZFP57 act together, maintaining all but one ICR in vivo, whereas earlier embryonic expression of ZNF445 and its intolerance to loss-of-function mutations indicate greater importance in the maintenance of human imprints.
Host genomics of SARS-CoV-2 infection Redin, Claire; Thorball, Christian W; Fellay, Jacques
European journal of human genetics : EJHG,
08/2022, Volume:
30, Issue:
8
Journal Article
Peer reviewed
Open access
Abstract
SARS-CoV-2 infected a large fraction of humans in the past 2 years. The clinical presentation of acute infection varies greatly between individuals, ranging from asymptomatic or mild to ...life-threatening COVID-19 pneumonia with multi-organ complications. Demographic and comorbid factors explain part of this variability, yet it became clear early in the pandemic that human genetic variation also plays a role in the stark differences observed amongst SARS-CoV-2 infected individuals. Using tools and approaches successfully developed for human genomic studies in the previous decade, large international collaborations embarked in the exploration of the genetic determinants of multiple outcomes of SARS-CoV-2 infection, with a special emphasis on disease severity. Genome-wide association studies identified multiple common genetic variants associated with COVID-19 pneumonia, most of which in regions encoding genes with known or suspected immune function. However, the downstream, functional work required to understand the precise causal variants at each locus has only begun. The interrogation of rare genetic variants using targeted, exome, or genome sequencing approaches has shown that defects in genes involved in type I interferon response explain some of the most severe cases. By highlighting genes and pathways involved in SARS-CoV-2 pathogenesis and host-virus interactions, human genomic studies not only revealed novel preventive and therapeutic targets, but also paved the way for more individualized disease management.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•The interindividual variability in response to infection is largely unexplained.•Genome-wide technologies are powerful tools to investigate infections.•GWAS have provided insight into resistance and ...susceptibility to infection.•GWAS have demonstrated the role of major genes in infectious disease outcomes.•GWAS have increased our insight into immune response and host-pathogen interplay.
Over the past few years, genome-wide association studies (GWAS) have been increasingly applied to identify host genetic factors influencing clinical and laboratory traits related to immunity and infection, and to understand the interplay between the host and the microbial genomes. By screening large cohorts of individuals suffering from various infectious diseases, GWAS explored resistance against infection, natural history of the disease, development of life-threatening clinical signs, and innate and adaptive immune responses. These efforts provided fundamental insight on the role of major genes in the interindividual variability in the response to infection and on the mechanisms of the immune response against human pathogens both at the individual and population levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 ...activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Krüppel‐associated box (KRAB)‐containing zinc finger proteins (KZFPs) are encoded in the hundreds by the genomes of higher vertebrates, and many act with the heterochromatin‐inducing KAP1 as ...repressors of transposable elements (TEs) during early embryogenesis. Yet, their widespread expression in adult tissues and enrichment at other genetic loci indicate additional roles. Here, we characterized the protein interactome of 101 of the ~350 human KZFPs. Consistent with their targeting of TEs, most KZFPs conserved up to placental mammals essentially recruit KAP1 and associated effectors. In contrast, a subset of more ancient KZFPs rather interacts with factors related to functions such as genome architecture or RNA processing. Nevertheless, KZFPs from coelacanth, our most distant KZFP‐encoding relative, bind the cognate KAP1. These results support a hypothetical model whereby KZFPs first emerged as TE‐controlling repressors, were continuously renewed by turnover of their hosts’ TE loads, and occasionally produced derivatives that escaped this evolutionary flushing by development and exaptation of novel functions.
Synopsis
In this resource, elucidation of the interactome of 101 Krüppel‐associated box (KRAB)‐containing zinc finger proteins (KZFPs) offers insights into the evolution of this largest subfamily of human transcription factors and uncovers unexpected functions of its most ancient members.
Evolutionarily young KZFPs interact with the co‐repressor KAP1 in order to repress transposable elements.
Evolutionarily old KZFPs are weak KAP1 binders.
More ancient KZFPs bind specific interactors, which include factors involved in chromatin organization and RNA metabolism.
An examination of coelacanth KZFPs indicates that these proteins likely first emerged as bona fide repressors of transposable elements.
Comprehensive interaction mapping of the KRAB domain zinc finger transcription factor family shows conservation of their function in KAP1 binding and identifies novel binding partners of the most ancient members.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Association between cannabis use and development of atherosclerotic cardiovascular disease (ASCVD) is inconsistent and challenging to interpret, given existing study limitations.
Sixty five ...independent single-nucleotide polymorphisms (SNPs), obtained from a genome-wide association study on lifetime cannabis use, were employed as genetic instruments to estimate the effects of genetically indexed cannabis use on risk of coronary artery disease (CAD) and acute ischemic stroke (IS) using a two-sample Mendelian randomization (MR) approach. Summary statistics on CAD (CARDIoGRAMplusC4D; 60,801 cases and 123,504 controls) and IS (MEGASTROKE; 34,217 cases and 406,111 controls) were obtained separately. A comprehensive review of the observational literature on cannabis use and CAD or IS was also performed and contrasted with MR results.
There was no causal effect of cannabis use on the risk of CAD (odds ratio (OR) per ever-users vs. never-users 0.93; 95% confidence interval (CI), 0.83 to 1.03) or IS (OR 1.05; 95%CI, 0.93 to 1.19). Sensitivity analyses yielded similar results, and no heterogeneity and directional pleiotropy was observed. Our meta-analysis of observational studies showed no significant association between ever use of cannabis with risk of CAD (k = 6 studies; OR
= 1.23, 95%CI 0.78 to 1.69), nor with IS (k = 6 studies; OR
= 1.22, 95%CI 0.95 to 1.50).
Using a genetic approach approximating a clinical trial does not provide evidence consistent with a causal effect of genetic predisposition to cannabis use on CAD or IS development. Further studies are needed to replicate our findinds, an to investigate more precisely the risk of ASCVD in relation to the quantity, type, route of administration, or the age at exposure to cannabis.
Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence ...suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines.
We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~ 5 million genetic variants and antibody responses using single marker and gene burden tests.
We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.
Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.
ClinicalTrials.gov , NCT01699893.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups of transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes ...are often grouped in clusters reflecting amplification by gene and segment duplication since the gene family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, and that KZFPs facilitate the co-option of the regulatory potential of TEs for the benefit of the host. Here, we present a comprehensive survey of the genetic features and genomic targets of human KZFPs, notably completing past analyses by adding data on close to a hundred family members. General principles emerge from our study of the TE-KZFP regulatory system, which point to multipronged evolutionary mechanisms underlaid by highly complex and combinatorial modes of action with strong influences on human speciation.
Fc receptor (FcR) genes collectively have copy number and allelic polymorphisms that have been implicated in multiple inflammatory and autoimmune diseases. This variation might also be involved in ...etiology of infectious diseases. The protective role of Fc-mediated antibody-function in HIV-1 immunity has led to the investigation of specific polymorphisms in FcR genes on acquisition, disease progression, and vaccine efficacy in natural history cohorts. The purpose of this review is not only to explore these known HIV-1 host genetic associations, but also to re-evaluate them in the context of genome-wide data. In the current era of effective anti-retroviral therapy, the potential impact of such variation on post-treatment cohorts cannot go unheeded and is discussed here in the light of current findings. Specific polymorphisms associating with HIV-1 pathogenesis have previously been genotyped by assays that captured only the single-nucleotide polymorphism (SNP) of interest without relative information of neighboring variants. With recent technological advances, variation within these genes can now be characterized using next-generation sequencing, allowing precise annotation of the whole chromosomal region. We herein also discuss updates in the annotation of common FcR variants that have been previously associated with HIV-1 pathogenesis.
Introduction
Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Whether suPAR level predicts the presence and the severity of coronary artery ...disease (CAD), and of incident death and myocardial infarction (MI) in subjects with suspected CAD, is unknown.
Methods and Results
We measured plasma suPAR levels in 3367 subjects (67% with CAD) recruited in the Emory Cardiovascular Biobank and followed them for adverse cardiovascular (CV) outcomes of death and MI over a mean 2.1±1.1 years. Presence of angiographic CAD (≥50% stenosis in ≥1 coronary artery) and its severity were quantitated using the Gensini score. Cox's proportional hazard survival and discrimination analyses were performed with models adjusted for established CV risk factors and C‐reactive protein levels. Elevated suPAR levels were independently associated with the presence of CAD (P<0.0001) and its severity (P<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youden's index) predicted future risk of MI (hazard ratio HR=3.2; P<0.0001), cardiac death (HR=2.62; P<0.0001), and the combined endpoint of death and MI (HR=1.9; P<0.0001), even after adjustment of covariates. The C‐statistic for a model based on traditional risk factors was improved from 0.72 to 0.74 (P=0.008) with the addition of suPAR.
Conclusion
Elevated levels of plasma suPAR are associated with the presence and severity of CAD and are independent predictors of death and MI in patients with suspected or known CAD.
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