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In the version of this article initially published, the name of one author was incorrect (James P. Santo). The correct name is James P. Di Santo. The error has been corrected in the HTML and PDF versions of the article.
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The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.
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Variación Genética/inmunología , Inmunidad Innata/genética , Inmunidad Adaptativa/genética , Adulto , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.
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Predisposición Genética a la Enfermedad , Hipersensibilidad , Inflamación , Humanos , Estudio de Asociación del Genoma Completo , Hipersensibilidad/genética , Inflamación/genética , Subunidad p50 de NF-kappa B/genética , Biobanco del Reino UnidoRESUMEN
Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting "genome-to-genome" association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1. Through in silico modeling and in vitro preS1-NTCP binding assays, we observed that the associated HBV mutations are in proximity to the NTCP variant when bound and together partially increase binding affinity to NTCP S267F. Furthermore, we identified significant associations between HLA-A variation and viral mutations in HLA-A-restricted T cell epitopes. We used in silico binding prediction tools to evaluate the impact of the associated HBV mutations on HLA presentation and observed that mutations that result in weaker binding affinities to their cognate HLA alleles were enriched. Overall, our results suggest the emergence of HBV escape mutations that might alter the interaction between HBV PreS1 and its cellular receptor NTCP during viral entry into hepatocytes and confirm the role of HLA class I restriction in inducing HBV epitope variations.
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Virus de la Hepatitis B , Mutación , Transportadores de Anión Orgánico Sodio-Dependiente , Simportadores , Humanos , Virus de la Hepatitis B/genética , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Simportadores/genética , Simportadores/metabolismo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Hepatitis B Crónica/virología , Hepatitis B Crónica/genética , Genoma Viral , Antígenos de Superficie de la Hepatitis B/genética , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Genómica/métodos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismoRESUMEN
Over the past four decades, research on the natural history of HIV infection has described how HIV wreaks havoc on human immunity and causes AIDS. HIV host genomic research, which aims to understand how human genetic variation affects our response to HIV infection, has progressed from early candidate gene studies to recent multi-omic efforts, benefiting from spectacular advances in sequencing technology and data science. In addition to invading cells and co-opting the host machinery for replication, HIV also stably integrates into our own genome. The study of the complex interactions between the human and retroviral genomes has improved our understanding of pathogenic mechanisms and suggested novel preventive and therapeutic approaches against HIV infection.
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Variación Genética , Genoma Humano , Infecciones por VIH/patología , VIH-1/patogenicidad , Interacciones Huésped-Patógeno , Infecciones por VIH/genética , Infecciones por VIH/virología , HumanosRESUMEN
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.
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Factores de Transcripción , Dedos de Zinc , Humanos , Dedos de Zinc/genética , Factores de Transcripción/genética , Evolución Biológica , Elementos Transponibles de ADN/genética , GenómicaRESUMEN
A strong genetic predictor of outcome following untreated HIV-1 infection is the carriage of specific alleles of human leukocyte antigens (HLAs) that present viral epitopes to T cells. Residual variation in outcome measures may be attributed, in part, to viral adaptation to HLA-restricted T cell responses. Variants of the endoplasmic reticulum aminopeptidases (ERAPs) influence the repertoire of T cell epitopes presented by HLA alleles as they trim pathogen-derived peptide precursors to optimal lengths for antigen presentation, along with other functions unrelated to antigen presentation. We investigated whether ERAP variants influence HLA-associated HIV-1 adaptation with demonstrable effects on overall HIV-1 disease outcome. Utilizing host and viral data of 249 West Australian individuals with HIV-1 subtype B infection, we identified a novel association between two linked ERAP2 single nucleotide polymorphisms (SNPs; rs2248374 and rs2549782) with plasma HIV RNA concentration (viral load) (P adjusted = 0.0024 for both SNPs). Greater HLA-associated HIV-1 adaptation in the HIV-1 Gag gene correlated significantly with higher viral load, lower CD4+ T cell count and proportion; P = 0.0103, P = 0.0061, P = 0.0061, respectively). When considered together, there was a significant interaction between the two ERAP2 SNPs and HLA-associated HIV-1 adaptation on viral load (P = 0.0111). In a comprehensive multivariate model, addition of ERAP2 haplotypes and HLA associated adaptation as an interaction term to known HLA and CCR5 determinants and demographic factors, increased the explanatory variance of population viral load from 17.67% to 45.1% in this dataset. These effects were not replicated in publicly available datasets with comparably sized cohorts, suggesting that any true global epistasis may be dependent on specific HLA-ERAP allelic combinations. Our data raises the possibility that ERAP2 variants may shape peptide repertoires presented to HLA class I-restricted T cells to modulate the degree of viral adaptation within individuals, in turn contributing to disease variability at the population level. Analyses of other populations and experimental studies, ideally with locally derived ERAP genotyping and HLA-specific viral adaptations are needed to elucidate this further.
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Aminopeptidasas , Epistasis Genética , Infecciones por VIH , VIH-1 , Polimorfismo de Nucleótido Simple , Humanos , Aminopeptidasas/genética , Infecciones por VIH/inmunología , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/genética , Australia , Masculino , Femenino , Antígenos HLA/genética , Carga Viral , Adulto , Persona de Mediana EdadRESUMEN
The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.
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Genoma Viral , Infecciones por VIH , VIH-1 , Antígenos HLA , Humanos , VIH-1/genética , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/genética , Antígenos HLA/genética , Antígenos HLA/inmunología , Variación Genética , Carga Viral , Estudios de Cohortes , Selección Genética , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunologíaRESUMEN
In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Mycobacterium tuberculosis/genética , Tanzanía/epidemiología , Tuberculosis/epidemiología , Genotipo , VirulenciaRESUMEN
BACKGROUND: Antiretroviral therapy (ART)-related weight gain is of particular concern in people with HIV (PWH). While weight gain was observed among PWH receiving tenofovir alafenamide (TAF), little is known about the potential reversibility after TAF discontinuation. We evaluated weight and metabolic changes 12 months after TAF discontinuation in the Swiss HIV Cohort Study. METHODS: We included participants who received at least six months of TAF-containing ART between January 2016 and March 2023. Using multivariable mixed-effect models, changes in weight and lipid levels were compared between individuals who continued TAF and those who switched to one of the following TAF-free regimens: TDF-based ART, dolutegravir/lamivudine (DTG/3TC), or long-acting cabotegravir/rilpivirine (CAB/RPV). RESULTS: Of 6555 participants (median age 54 years, 24.3% female, 13% Black), 5485 (83.7%) continued and 1070 (16.3%) stopped TAF. Overall, discontinuing TAF was associated with an adjusted mean weight change of -0.54 kg (95% CI -0.98 to -0.11) after 12 months. In stratified analyses, switching from TAF to TDF led to an adjusted mean weight decrease of -1.84 kg (CI -2.72 to -0.97), and to a decrease in mean total cholesterol (-0.44 mmol/L) and triglycerides (-0.38 mmol/L) after 12 months. Switching from TAF-based ART to DTG/3TC (-0.17 kg, CI -0.82 to 0.48) or long-acting CAB/RPV (-0.64 kg, CI -2.16 to 0.89) did not lead to reductions in weight. CONCLUSIONS: Replacing TAF with TDF in PWH led to a decrease in body weight and an improved lipid profile within one year. Weight changes were not observed among individuals who switched to DTG/3TC or long-acting CAB/RPV.
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BACKGROUND AND AIMS: The clinical spectrum of human infection by HEV ranges from asymptomatic to severe acute hepatitis. Furthermore, HEV can cause diverse neurological manifestations, especially Parsonage-Turner syndrome. Here, we used a large-scale human genomic approach to search for genetic determinants of severe clinical presentations of HEV infection. APPROACH AND RESULTS: We performed whole genome sequencing in 3 groups of study participants with PCR-proven acute HEV infection: (1) 24 patients with symptomatic acute hepatitis E; (2) 12 patients with HEV-associated Parsonage-Turner syndrome; and (3) 16 asymptomatic blood donors (controls). For variant calling and annotation, we used GATK4 best practices followed by Variant Effect Predictor (VEP) and Annovar. For variant classification, we implemented the American College of Medical Genetics and Genomics/Association for Molecular Pathology Bayesian classification framework in R. Variants with a probability of pathogenicity >0.9 were considered damaging. We used all genes with at least 1 damaging variant as input for pathway enrichment analyses.We observed a significant enrichment of type I interferon response pathways in the symptomatic hepatitis group: 10 out of 24 patients carried a damaging variant in one of 9 genes encoding either intracellular viral sensors ( IFIH1 , DDX58 , TLR3 , POLR3B , POLR3C ) or other molecules involved in type I interferon response [interferon regulatory factor 7 ( IRF7 ), MYD88 , OAS3 , GAPDH ]. We did not find any enriched pathway in the Parsonage-Turner syndrome group or in the controls. CONCLUSIONS: Our results highlight the essential role of type I interferon in preventing symptomatic acute hepatitis E.
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Upon recognition of aberrantly located DNA, the innate immune sensor cyclic GMP-AMP synthase (cGAS) activates stimulator of IFN genes (STING)/IFN regulatory factor (IRF)3-driven antiviral responses. In this study, we characterized the ability of a specific variant of the human cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted toward the possibility for an additional binding site for a potential cellular cofactor in cGAS dimers. However, cGAS(wild-type [WT]) or cGAS(P261H)-reconstituted THP-1 cGAS knockout cells shared steady-state expression of IFN-stimulated genes, as opposed to cells expressing the enzymatically inactive cGAS(G212A/S213A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared with cGAS knockout or cGAS(G212A/S213A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared with cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend toward a slightly reduced type I IFN response as compared with PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a baseline antiviral state rendering cells more refractory to IFN-stimulated gene-sensitive viral infections. rs610913 failed to grossly differ phenotypically from the WT gene, suggesting that cGAS(P261H) and WT cGAS share a similar ability to sense viral infections in vivo.
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Inmunidad Innata , Virosis , Humanos , ADN Viral/inmunología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/inmunología , Nucleotidiltransferasas/metabolismo , Transducción de Señal , Virosis/genética , Virosis/inmunología , Virosis/prevención & controlRESUMEN
The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.
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Envejecimiento , ADN Mitocondrial , Mamíferos , Envejecimiento/genética , Animales , ADN Mitocondrial/genética , Mamíferos/genética , Mitocondrias/genética , Mutación , NucleótidosRESUMEN
BACKGROUND: Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. RESULTS: By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9 kb and another within 13-16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp (base pair) and a second arm at 13,447-13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. CONCLUSIONS: Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.
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Genoma Mitocondrial , Animales , Humanos , Mitocondrias , ADN Mitocondrial/genética , Genoma Humano , Estructura Secundaria de Proteína , ADN de Cadena Simple , MamíferosRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is associated with acute respiratory infection. We sought to identify RSV variants associated with prolonged infection. METHODS: Among healthy term infants we identified those with prolonged RSV infection and conducted (1) a human genome-wide association study (GWAS) to test the dependence of infection risk on host genotype, (2) a viral GWAS for association with prolonged RSV infection using RSV whole-genome sequencing, (3) an analysis of all viral public sequences, (4) an assessment of immunological responses, and (5) a summary of all major functional data. Analyses were adjusted for viral/human population structure and host factors associated with infection risk. RESULTS: We identified p.E123K/D and p.P218T/S/L in G protein that were associated with prolonged infection (Padj = .01). We found no evidence of host genetic risk for infection. The RSV variant positions approximate sequences that could bind a putative viral receptor, heparan sulfate. CONCLUSIONS: Using analysis of both viral and host genetics we identified a novel RSV variant associated with prolonged infection in otherwise healthy infants and no evidence supporting host genetic susceptibility to infection. As the capacity of RSV for chronicity and its viral reservoir are not defined, these findings are important for understanding the impact of RSV on chronic disease and endemicity.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Lactante , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/genética , Cohorte de Nacimiento , Estudio de Asociación del Genoma Completo , Virus Sincitial Respiratorio Humano/genética , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.
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Enfermedades Óseas Metabólicas , Infecciones por VIH , Osteoporosis , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios de Cohortes , VIH , Suiza/epidemiología , Osteoporosis/epidemiología , Osteoporosis/genética , Osteoporosis/inducido químicamente , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Factores de Riesgo , Densidad Ósea/genética , Enfermedades Óseas Metabólicas/inducido químicamente , Enfermedades Óseas Metabólicas/complicaciones , Enfermedades Óseas Metabólicas/epidemiología , Tenofovir/efectos adversosRESUMEN
BACKGROUND: In people with human immunodeficiency virus (HIV) (PWH), individual polygenic risk scores (PRSs) are associated with coronary artery disease (CAD) events. Whether PRSs are associated with subclinical CAD is unknown. METHODS: In Swiss HIV Cohort Study participants of European descent, we defined subclinical CAD as presence of soft, mixed, or high-risk plaque (SMHRP) on coronary computed tomography (CT) angiography, or as participants in the top tertile of the study population's coronary artery calcium (CAC) score, using noncontrast CT. We obtained univariable and multivariable odds ratios (ORs) for subclinical CAD endpoints based on nongenetic risk factors, and validated genome-wide PRSs built from single nucleotide polymorphisms associated with CAD, carotid intima-media thickness (IMT), or longevity in the general population. RESULTS: We included 345 genotyped participants (median age, 53 years; 89% male; 96% suppressed HIV RNA); 172 and 127 participants had SMHRP and CAC, respectively. CAD-associated PRS and IMT-associated PRS were associated with SMHRP and CAC (all P < .01), but longevity PRS was not. Participants with unfavorable CAD-PRS (top quintile) had an adjusted SMHRP OR = 2.58 (95% confidence interval [CI], 1.18-5.67), and a CAC OR = 3.95 (95% CI, 1.45-10.77) vs. bottom quintile. Unfavorable nongenetic risk (top vs. bottom quintile) was associated with adjusted SMHRP OR = 24.01 (95% CI, 9.75-59.11), and a CAC-OR = 65.07 (95% CI, 18.48-229.15). Area under the receiver operating characteristic curve increased when we added CAD-PRS to nongenetic risk factors (SMHRP: 0.75 and 0.78, respectively; CAC: 0.80 and 0.83, respectively). CONCLUSIONS: In Swiss PWH, subclinical CAD is independently associated with an individual CAD-associated PRS. Combining nongenetic and genetic cardiovascular risk factors provided the most powerful subclinical CAD prediction.
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Enfermedad de la Arteria Coronaria , Infecciones por VIH , Humanos , Masculino , Persona de Mediana Edad , Femenino , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/complicaciones , Grosor Intima-Media Carotídeo , Estudios de Cohortes , VIH , Suiza/epidemiología , Factores de Riesgo , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiologíaRESUMEN
BACKGROUND: People with human immunodeficiency virus (HIV; PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count. RESULTS: We included 536 cases with a first CAD event (2000-2021; median age, 56 years; 87% male; 84% with suppressed HIV RNA) and 1464 event-free controls. Cases had higher latest leukocyte count before CAD event than controls (median [interquartile range], 6495 [5300-7995] vs 5900 [4910-7200]; P < .01), but leukocytosis (>11 000/µL) was uncommon (4.3% vs 2.1%; P = .01). In the highest versus lowest leukocyte quintile at latest time point before CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years before the event were significantly associated with CAD events. CONCLUSIONS: PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors.
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Enfermedad de la Arteria Coronaria , Infecciones por VIH , Humanos , Masculino , Persona de Mediana Edad , Femenino , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/complicaciones , Estudios Longitudinales , VIH , Estudios de Casos y Controles , Estudios de Cohortes , Factores de Riesgo , Recuento de Leucocitos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiologíaRESUMEN
Infectious diseases are particularly challenging for genome-wide association studies (GWAS) because genetic effects from two organisms (pathogen and host) can influence a trait. Traditional GWAS assume individual samples are independent observations. However, pathogen effects on a trait can be heritable from donor to recipient in transmission chains. Thus, residuals in GWAS association tests for host genetic effects may not be independent due to shared pathogen ancestry. We propose a new method to estimate and remove heritable pathogen effects on a trait based on the pathogen phylogeny prior to host GWAS, thus restoring independence of samples. In simulations, we show this additional step can increase GWAS power to detect truly associated host variants when pathogen effects are highly heritable, with strong phylogenetic correlations. We applied our framework to data from two different host-pathogen systems, HIV in humans and X. arboricola in A. thaliana. In both systems, the heritability and thus phylogenetic correlations turn out to be low enough such that qualitative results of GWAS do not change when accounting for the pathogen shared ancestry through a correction step. This means that previous GWAS results applied to these two systems should not be biased due to shared pathogen ancestry. In summary, our framework provides additional information on the evolutionary dynamics of traits in pathogen populations and may improve GWAS if pathogen effects are highly phylogenetically correlated amongst individuals in a cohort.
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Enfermedades Transmisibles , Estudio de Asociación del Genoma Completo , Enfermedades Transmisibles/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Fenotipo , Filogenia , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo HeredableRESUMEN
Genome-wide association studies rely on the statistical inference of untyped variants, called imputation, to increase the coverage of genotyping arrays. However, the results are often suboptimal in populations underrepresented in existing reference panels and array designs, since the selected single nucleotide polymorphisms (SNPs) may fail to capture population-specific haplotype structures, hence the full extent of common genetic variation. Here, we propose to sequence the full genomes of a small subset of an underrepresented study cohort to inform the selection of population-specific add-on tag SNPs and to generate an internal population-specific imputation reference panel, such that the remaining array-genotyped cohort could be more accurately imputed. Using a Tanzania-based cohort as a proof-of-concept, we demonstrate the validity of our approach by showing improvements in imputation accuracy after the addition of our designed add-on tags to the base H3Africa array.