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PURPOSE: TTN truncating variants (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCMs), however their penetrance for DCM in general populations is low. More broadly, patients with cardiomyopathies (CMs) often exhibit other cardiac conditions, such as atrial fibrillation (Afib), which has also been linked to TTNtvs. This retrospective analysis aims to characterize the relationship between different cardiac conditions in those with TTNtvs and identify individuals with the highest risk of DCM. METHODS: In this work we leverage longitudinal electronic health record and exome sequencing data from approximately 450,000 individuals in 2 health systems to statistically confirm and pinpoint the genetic footprint of TTNtv-related diagnoses aside from CM, such as Afib, and determine whether vetting additional significantly associated phenotypes better stratifies CM risk across those with TTNtvs. We focused on TTNtvs in exons with a percentage spliced in >90% (hiPSI TTNtvs), a representation of constitutive cardiac expression. RESULTS: When controlling for CM and Afib, other cardiac conditions retained only nominal association with TTNtvs. A sliding window analysis of TTNtvs across the locus confirms that the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in percent spliced in ≤90% exons (loPSI TTNtvs). The combination of hiPSI TTNtv status and early Afib diagnosis (before age 60) found a subset of TTNtv individuals at high risk for CM. The prevalence of CM in this subset was 33%, a rate that was 3.5 fold higher than that in individuals with hiPSI TTNtvs (9% prevalence), 5-fold higher than that in individuals without TTNtvs with early Afib (6% prevalence), and 80-fold higher than that in the general population. CONCLUSION: Our retrospective analyses revealed that those with hiPSI TTNtvs and early Afib (â¼1/2900) have a high prevalence of CM (33%), far exceeding that in other individuals with TTNtvs and in those without TTNtvs with an early Afib diagnosis. These results show that combining phenotypic information along with genomic population screening can identify patients at higher risk for progressing to symptomatic heart failure.
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Fibrilação Atrial , Cardiomiopatias , Cardiomiopatia Dilatada , Cardiopatias , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/genética , Estudos Retrospectivos , Prevalência , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Conectina/genética , Conectina/metabolismo , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/genéticaRESUMO
Chronic exposure to high levels of arsenic in drinking water can have wide-ranging health effects and is a global health concern. The domestic well population of the western Great Basin (WGB) is at increased risk of exposure to arsenic due to the hydrologic, geologic, and climatic setting of the region. A logistic regression (LR) model was developed to predict the probability of elevated arsenic (≥5 µg/L) in alluvial aquifers and assess the potential geologic hazard level posed to domestic well populations. Alluvial aquifers are susceptible to arsenic contamination, which is a concern because they are the primary source of water for domestic well users of the WGB. The probability of elevated arsenic at a domestic well is strongly influenced by tectonic and geothermal variables, including the total Quaternary fault length in the hydrographic basin and the distance between the sampled well and a geothermal system. The model had an overall accuracy of 81%, sensitivity of 92%, and specificity of 55%. Results show a >50% probability of elevated arsenic in untreated well water for approximately 49 thousand (64%) alluvial-aquifer domestic well users in northern Nevada, northeastern California, and western Utah.
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Arsênio , Água Potável , Água Subterrânea , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Monitoramento AmbientalRESUMO
Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1ß, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.
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Asbestose/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Mesotelioma/genética , RecQ Helicases/genética , Adulto , Idoso , Animais , Asbesto Crocidolita , Família , Feminino , Instabilidade Genômica , Heterozigoto , Humanos , Incidência , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
PURPOSE: To identify conditions that are candidates for population genetic screening based on population prevalence, penetrance of rare variants, and actionability. METHODS: We analyzed exome and medical record data from >220,000 participants across two large population health cohorts with different demographics. We performed a gene-based collapsing analysis of rare variants to identify genes significantly associated with disease status. RESULTS: We identify 74 statistically significant gene-disease associations across 27 genes. Seven of these conditions have a positive predictive value (PPV) of at least 30% in both cohorts. Three are already used in population screening programs (BRCA1, BRCA2, LDLR), and we also identify four new candidates for population screening: GCK with diabetes mellitus, HBB with ß-thalassemia minor and intermedia, PKD1 with cystic kidney disease, and MIP with cataracts. Importantly, the associations are actionable in that early genetic screening of each of these conditions is expected to improve outcomes. CONCLUSION: We identify seven genetic conditions where rare variation appears appropriate to assess in population screening, four of which are not yet used in screening programs. The addition of GCK, HBB, PKD1, and MIP rare variants into genetic screening programs would reach an additional 0.21% of participants with actionable disease risk, depending on the population.
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Genes BRCA2 , Testes Genéticos , Exoma , Predisposição Genética para Doença , Humanos , Valor Preditivo dos Testes , Sequenciamento do ExomaRESUMO
The effect of ultraviolet radiation (UVR) on photosynthetic efficiency and the resulting mechanisms against UV exposure employed by phytoplankton are not completely understood. To address this knowledge gap, we developed a novel close-coupled, wavelength-configurable platform designed to produce precise and repeatable in vitro irradiation of Corethron hystrix, a member of a genera found abundantly in the Southern Ocean where UV exposure is high. We aimed to determine its metabolic, protective, and repair mechanisms as a function of varying levels of specific electromagnetic energy. Our results show that the physiological responses to each energy level of UV have a negative linear decrease in the photosynthetic efficiency of photosystem II proportional to UV intensity, corresponding to a large increase in the turnover time of quinone reoxidation. Gene expression changes of photosystem II-related reaction center proteins D1, CP43, and CP47 showed coordinated downregulation whereas the central metabolic pathway demonstrated mixed expression of up and downregulated transcripts after UVR exposure. These results suggest that while UVR may damage photosynthetic machinery, oxidative damage may limit production of new photosynthetic and electron transport complexes as a result of UVR exposure.
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Diatomáceas/genética , Diatomáceas/efeitos da radiação , Regulação para Baixo , Regulação da Expressão Gênica/efeitos da radiação , Fotossíntese/efeitos da radiação , Raios UltravioletaRESUMO
Importance: Genetic information is not being used to identify women at lower risk of breast cancer or other diseases in clinical practice. With the new US Preventive Services Task Force guidelines lowering the age for mammogram screening for all, there is a potential benefit in identifying women at lower risk of disease who may defer the start of mammographic screening. This genetic risk-based approach would help mitigate overscreening, associated costs, and anxiety. Objective: To assess breast cancer incidence and age of onset among women at low genetic risk compared with women at average risk and evaluate the potential to delay mammography on the basis of genetic risk stratification. Design, Setting, and Participants: This retrospective case-control study included 25â¯591 women from the Healthy Nevada Project sequenced by Helix between 2018 and 2022. Data extracted from electronic health records at the end of 2022 (mean length of electronic health record available was 12 years) were used for the analysis in 2023. Main Outcomes and Measures: Breast cancer diagnosis was identified from electronic health records. Classification to the low-risk genetic group required (1) the absence of pathogenic variants or a variant of uncertain significance in BRCA1, BRCA2, PALB2, ATM, or CHEK2, and (2) a low polygenic risk score (bottom 10%) using a 313-single-nucleotide variant model. Results: Of 25â¯591 women in the study (mean [SD] age was 53.8 [16.9] years), 2338 women (9.1%) were classified as having low risk for breast cancer; 410 women (1.6%) were classified as high risk; and 22â¯843 women (89.3%) as average risk. There was a significant reduction in breast cancer diagnosis among the low-risk group (hazard ratio, 0.39; 95% CI, 0.29-0.52; P < .001). By 45 years of age, 0.69% of women in the average-risk group were diagnosed with breast cancer, whereas women in the low-risk group reached this rate at 51 years. By 50 years of age, 1.41% of those in the average-risk group were diagnosed with breast cancer, whereas those in the low-risk group reached this rate at age 58 years. These findings suggest that deferring mammogram screening by 5 to 10 years for women at low risk of breast cancer aligns with new draft recommendations. Conclusions and Relevance: The findings of this retrospective case-control study underscore the value of genetics in individualizing the onset of breast cancer screening. Improving breast cancer risk stratification by implementing both high-risk and low-risk strategies in screening can refine preventive measures and optimize health care resource allocation.
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Neoplasias da Mama , Feminino , Humanos , Pessoa de Meia-Idade , Lactente , Adolescente , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Estudos Retrospectivos , Mamografia , Fatores de RiscoRESUMO
Systematic determination of novel variant pathogenicity remains a major challenge, even when there is an established association between a gene and phenotype. Here we present Power Window (PW), a sliding window technique that identifies the impactful regions of a gene using population-scale clinico-genomic datasets. By sizing analysis windows on the number of variant carriers, rather than the number of variants or nucleotides, statistical power is held constant, enabling the localization of clinical phenotypes and removal of unassociated gene regions. The windows can be built by sliding across either the nucleotide sequence of the gene (through 1D space) or the positions of the amino acids in the folded protein (through 3D space). Using a training set of 350k exomes from the UK Biobank (UKB), we developed PW models for well-established gene-disease associations and tested their accuracy in two independent cohorts (117k UKB exomes and 65k exomes sequenced at Helix in the Healthy Nevada Project, myGenetics, or In Our DNA SC studies). The significant models retained a median of 49% of the qualifying variant carriers in each gene (range 2%-98%), with quantitative traits showing a median effect size improvement of 66% compared with aggregating variants across the entire gene, and binary traits' odds ratios improving by a median of 2.2-fold. PW showcases that electronic health record-based statistical analyses can accurately distinguish between novel coding variants in established genes that will have high phenotypic penetrance and those that will not, unlocking new potential for human genomics research, drug development, variant interpretation, and precision medicine.
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Variação Genética , Humanos , Variação Genética/genética , Dobramento de Proteína , Fenótipo , Sequência de Bases/genética , Predisposição Genética para Doença/genética , Exoma/genéticaRESUMO
BACKGROUND: Interventions are needed to help people reduce exposure to harmful chemicals from everyday products and lifestyle habits. Report-back of individual exposures is a potential pathway to increasing environmental health literacy (EHL) and readiness to reduce exposures. OBJECTIVES: Our objective was to determine if report-back of endocrine-disrupting chemicals (EDCs) can reduce EDC exposure, increase EHL, and increase readiness to change (i.e., to implement EDC exposure-reduction behaviors). METHODS: Participants in the Healthy Nevada Project completed EHL and readiness-to-change surveys before (n = 424) and after (n = 174) a report-back intervention. Participants used mail-in kits to measure urinary biomarkers of EDCs. The report-back of results included urinary levels, information about health effects, sources of exposure, and personalized recommendations to reduce exposure. RESULTS: EHL was generally very high at baseline, especially for questions related to the general pollution. For questions related to chemical exposures, responses varied across several demographics. Statistically reliable improvements in EHL responses were seen after report-back. For readiness to change, 72% were already or planning to change their behaviors. Post-intervention, women increased their readiness (p = 0.053), while men decreased (p = 0.007). When asked what challenges they faced in reducing exposure, 79% cited not knowing what to do. This dropped to 35% after report-back. Participants with higher propylparaben were younger (p = 0.03) and women and participants who rated themselves in better health had higher levels of some phthalates (p = 0.02-0.003 and p = 0.001-0.003, respectively). After report-back, monobutyl phthalate decreased among the 48 participants who had valid urine tests before and after the intervention (p < 0.001). CONCLUSIONS: The report-back intervention was successful as evidenced by increased EHL behaviors, increased readiness to change among women, and a decrease in monobutyl phthalate. An EHL questionnaire more sensitive to chemical exposures would help differentiate high and low literacy. Future research will focus on understanding why men decreased their readiness to change and how the intervention can be improved for all participants.
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Exposição Ambiental , Letramento em Saúde , Humanos , Nevada , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Exposição Ambiental/análise , Disruptores Endócrinos/urina , Saúde Ambiental , Adulto Jovem , Idoso , Poluentes Ambientais/urina , Poluentes Ambientais/análise , Inquéritos e Questionários , AdolescenteRESUMO
Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.
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Infecções Assintomáticas , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Alelos , Antígenos HLA/genética , Pessoa de Meia-Idade , Adulto , Estudos Prospectivos , Idoso , Predisposição Genética para DoençaRESUMO
We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.
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Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Medicina Estatal , Proteína BRCA1/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Frequência do Gene , Haplótipos , Escócia/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteína BRCA2/genética , Testes GenéticosRESUMO
Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified. These findings suggest that memory T-cell immunity to seasonal coronaviruses does not strongly influence the outcome of SARS-CoV-2 infection in unvaccinated individuals.
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Adverse Childhood Experiences are stressful and traumatic events occurring before the age of eighteen shown to cause mental and physical health problems, including increased risk of obesity. Obesity remains an ongoing national challenge with no predicted solution. We examine a subset of the Healthy Nevada Project, focusing on a multi-ethnic cohort of 15,886 sequenced participants with recalled adverse childhood events, to study how ACEs and their genotype-environment interactions affect BMI. Specifically, the Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records and social health determinants questionnaire to identify: 1) the effect of ACEs on BMI in the absence of genetics; 2) the effect of genotype-environment interactions on BMI; 3) how these gene-environment interactions differ from standard genetic associations of BMI. The study found very strong significant associations between the number of adverse childhood experiences and adult obesity. Additionally, we identified fifty-five common and rare variants that exhibited gene-interaction effects including three variants in the CAMK1D gene and four variants in LHPP; both genes are linked to schizophrenia. Surprisingly, none of the variants identified with interactive effects were in canonical obesity-related genes. Here we show the delicate balance between genes and environment, and how the two strongly influence each other.
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In this research, we examine and identify the implications of Adverse Childhood Experiences (ACEs) on a range of health outcomes, with particular focus on a number of mental health disorders. Many previous studies observed that traumatic childhood events are linked to long-term adult diseases using the standard Adverse Childhood Experience Questionnaire. The study cohort was derived from the Healthy Nevada Project, a volunteer-based population health study in which each adult participant is invited to take a retrospective questionnaire that includes the Adverse Childhood Experience Questionnaire, the 12-item Short Form Survey measuring quality of life, and self-reported incidence of nine mental disorders. Using participant's cross-referenced electronic health records, a phenome-wide association analysis of 1,703 phenotypes and the incidence of ACEs examined links between traumatic events in childhood and adult disease. These analyses showed that many mental disorders were significantly associated with ACEs in a dose-response manner. Similarly, a dose response between ACEs and obesity, chronic pain, migraine, and other physical phenotypes was identified. An examination of the prevalence of self-reported mental disorders and incidence of ACEs showed a positive relationship. Furthermore, participants with less adverse childhood events experienced a higher quality of life, both physically and mentally. The whole-phenotype approach confirms that ACEs are linked with many negative adult physical and mental health outcomes. With the nationwide prevalence of ACEs as high as 67%, these findings suggest a need for new public health resources: ACE-specific interventions and early childhood screenings.
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The clinical value of population-based genetic screening projects depends on the actions taken on the findings. The Healthy Nevada Project (HNP) is an all-comer genetic screening and research project based in northern Nevada. HNP participants with CDC Tier 1 findings of hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), or familial hypercholesterolemia (FH) are notified and provided with genetic counseling. However, the HNP subsequently takes a "hands-off" approach: it is the responsibility of notified participants to share their findings with their healthcare providers, and providers are expected to implement the recommended action plans. Thus, the HNP presents an opportunity to evaluate the efficiency of participant and provider responses to notification of important genetic findings, using electronic health records (EHRs) at Renown Health (a large regional hospital in northern Nevada). Out of 520 HNP participants with findings, we identified 250 participants who were notified of their findings and who had an EHR. 107 of these participants responded to a survey, with 76 (71%) indicating that they had shared their findings with their healthcare providers. However, a sufficiently specific genetic diagnosis appeared in the EHRs and problem lists of only 22 and 10%, respectively, of participants without prior knowledge. Furthermore, review of participant EHRs provided evidence of possible relevant changes in clinical care for only a handful of participants. Up to 19% of participants would have benefited from earlier screening due to prior presentation of their condition. These results suggest that continuous support for both participants and their providers is necessary to maximize the benefit of population-based genetic screening. We recommend that genetic screening projects require participants' consent to directly document their genetic findings in their EHRs. Additionally, we recommend that they provide healthcare providers with ongoing training regarding documentation of findings and with clinical decision support regarding subsequent care.
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COVID-19 vaccines are safe and highly effective, but some individuals experience unpleasant reactions to vaccination. As the majority of adults in the United States have received a COVID-19 vaccine this year, there is an unprecedented opportunity to study the genetics of reactions to vaccination via surveys of individuals who are already part of genetic research studies. Here, we have queried 17,440 participants in the Helix DNA Discovery Project and Healthy Nevada Project about their reactions to COVID-19 vaccination. Our genome-wide association study identifies an association between severe difficulties with daily routine after vaccination and HLA-A∗03:01. This association was statistically significant only for those who received the Pfizer-BioNTech vaccine (BNT162b2; n = 3,694; p = 4.70E-11; OR = 2.07 [95% CI 1.67-2.56]), and showed a smaller effect size in those who received the Moderna vaccine (mRNA-1273; n = 3,610; p = 0.005; OR = 1.32 [95% CI 1.09-1.59]). In Pfizer-BioNTech recipients, HLA-A∗03:01 was associated with a 2-fold increase in risk of self-reported severe difficulties with daily routine following vaccination. The effect was consistent across ages, sexes, and whether the person had previously had a COVID-19 infection. The reactions experienced by HLA-A∗03:01 carriers were driven by associations with chills, fever, fatigue, and generally feeling unwell.
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Hydrothermal vent ecosystems support diverse life forms, many of which rely on symbiotic associations to perform functions integral to survival in these extreme physicochemical environments. Epsilonproteobacteria, found free-living and in intimate associations with vent invertebrates, are the predominant vent-associated microorganisms. The vent-associated polychaete worm, Alvinella pompejana, is host to a visibly dense fleece of episymbionts on its dorsal surface. The episymbionts are a multispecies consortium of Epsilonproteobacteria present as a biofilm. We unraveled details of these enigmatic, uncultivated episymbionts using environmental genome sequencing. They harbor wide-ranging adaptive traits that include high levels of strain variability analogous to Epsilonproteobacteria pathogens such as Helicobacter pylori, metabolic diversity of free-living bacteria, and numerous orthologs of proteins that we hypothesize are each optimally adapted to specific temperature ranges within the 10-65 degrees C fluctuations characteristic of the A. pompejana habitat. This strategic combination enables the consortium to thrive under diverse thermal and chemical regimes. The episymbionts are metabolically tuned for growth in hydrothermal vent ecosystems with genes encoding the complete rTCA cycle, sulfur oxidation, and denitrification; in addition, the episymbiont metagenome also encodes capacity for heterotrophic and aerobic metabolisms. Analysis of the environmental genome suggests that A. pompejana may benefit from the episymbionts serving as a stable source of food and vitamins. The success of Epsilonproteobacteria as episymbionts in hydrothermal vent ecosystems is a product of adaptive capabilities, broad metabolic capacity, strain variance, and virulent traits in common with pathogens.
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Adaptação Biológica/fisiologia , Metabolismo Energético/fisiologia , Epsilonproteobacteria/genética , Genômica/métodos , Modelos Moleculares , Poliquetos/microbiologia , Simbiose , Temperatura , Animais , Sequência de Bases , Análise por Conglomerados , Modelos Biológicos , Dados de Sequência Molecular , Oceano Pacífico , RNA Ribossômico/genética , Análise de Sequência de DNA , Especificidade da EspécieRESUMO
Genomic-guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of single-nucleotide polymorphisms and structural variation. Here, we introduce the Helix PGx database, an open-source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short-read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project. The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low-frequency star alleles, as well as a disproportionate fraction (36%) of all novel predicted loss-of-function variants identified. Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10 times higher frequency in one or more subgroups with non-European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high-risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard-of-care screening of these 4 pharmacogenes could impact nearly half of the general population.
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Sistema Enzimático do Citocromo P-450/genética , DNA/genética , Frequência do Gene/genética , Alelos , Bases de Dados de Ácidos Nucleicos , Genômica/métodos , Genótipo , Humanos , Farmacogenética/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Air pollution has been linked to increased susceptibility to SARS-CoV-2. Thus, it has been suggested that wildfire smoke events may exacerbate the COVID-19 pandemic. OBJECTIVES: Our goal was to examine whether wildfire smoke from the 2020 wildfires in the western United States was associated with an increased rate of SARS-CoV-2 infections in Reno, Nevada. METHODS: We conducted a time-series analysis using generalized additive models to examine the relationship between the SARS-CoV-2 test positivity rate at a large regional hospital in Reno and ambient PM2.5 from 15 May to 20 Oct 2020. RESULTS: We found that a 10 µg/m3 increase in the 7-day average PM2.5 concentration was associated with a 6.3% relative increase in the SARS-CoV-2 test positivity rate, with a 95% confidence interval (CI) of 2.5 to 10.3%. This corresponded to an estimated 17.7% (CI: 14.4-20.1%) increase in the number of cases during the time period most affected by wildfire smoke, from 16 Aug to 10 Oct. SIGNIFICANCE: Wildfire smoke may have greatly increased the number of COVID-19 cases in Reno. Thus, our results substantiate the role of air pollution in exacerbating the pandemic and can help guide the development of public preparedness policies in areas affected by wildfire smoke, as wildfires are likely to coincide with the COVID-19 pandemic in 2021.
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Poluentes Atmosféricos , COVID-19 , Incêndios Florestais , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Humanos , Nevada , Pandemias , Material Particulado/efeitos adversos , Material Particulado/análise , SARS-CoV-2 , Fumaça/efeitos adversos , Estados Unidos/epidemiologiaRESUMO
Clinical conditions correlated with elevated triglyceride levels are well-known: coronary heart disease, hypertension, and diabetes. Underlying genetic and phenotypic mechanisms are not fully understood, partially due to lack of coordinated genotypic-phenotypic data. Here we use a subset of the Healthy Nevada Project, a population of 9,183 sequenced participants with longitudinal electronic health records to examine consequences of altered triglyceride levels. Specifically, Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records to identify: (1) rare and common single-variant genome-wide associations; (2) gene-based associations using a Sequence Kernel Association Test; (3) phenome-wide associations with triglyceride levels; and (4) pleiotropic variants linked to triglyceride levels. The study identified 549 significant single-variant associations (p < 8.75 × 10-9), many in chromosome 11's triglyceride hotspot: ZPR1, BUD13, APOC3, APOA5. A well-known protective loss-of-function variant in APOC3 (R19X) was associated with a 51% decrease in triglyceride levels in the cohort. Sixteen gene-based triglyceride associations were identified; six of these genes surprisingly did not include a single variant with significant associations. Results at the variant and gene level were validated with the UK Biobank. The combination of a single-variant genome-wide association, a gene-based association method, and phenome wide-association studies identified rare and common variants, genes, and phenotypes associated with elevated triglyceride levels, some of which may have been overlooked with standard approaches.