Host Genetic and Epigenetic Factors of the Progression, Comorbidities and Outcomes of Viral Infection

病毒感染进展、合并症和结果的宿主遗传和表观遗传因素

• 批准号: 10485494
• 负责人: Vincent Charles Marconi
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485494
• 关键词: 2019-nCoV; Acceleration; Acute; Affect; Age; Aging; Algorithms; Antiviral Therapy; Biological Aging; COVID-19 impact; Chronic; Chronic Disease; Chronic Kidney Failure; Communicable Diseases; Congestive Heart Failure; Coronary heart disease; DNA Methylation; Data; Diabetes Mellitus; Diagnostic; Disease; Disease Outcome; Disease Progression; Electronic Health Record; Epigenetic Process; Ethnic Population; General Population; Genetic; Genetic Markers; Genetic Predisposition to Disease; HIV; HIV Infections; Health; Healthcare Systems; Heart failure; Hepatitis C; Hepatitis C virus; Human; Human Genetics; Human Genome; Immune; Immune response; Immune system; Immunologics; Individual; Infection; Infectious Agent; Inflammatory; Integration Host Factors; Intervention; Life Expectancy; Link; Liver Cirrhosis; Liver Fibrosis; Longevity; Measurement; Mediation; Mendelian randomization; Modeling; Modification; Molecular; Morbidity - disease rate; Multiomic Data; Organ; Outcome; Pathway interactions; Persons; Phenotype; Population Heterogeneity; Predisposition; Prevention; Process; Prognosis; Quality of life; Risk Factors; Role; SARS-CoV-2 infection; Sample Size; Site; Stroke; System; Therapeutic; Veterans; Virus Diseases; advanced analytics; age related; chronic liver disease; comorbidity; disorder risk; epigenetic marker; epigenome-wide association studies; genetic variant; genome wide association study; genomic locus; healthspan; improved; insight; longitudinal analysis; methylation biomarker; mortality; multi-ethnic; multiple chronic conditions; novel marker; pathogen; precision medicine; programs; response

Viral infections including Human immunodeficiency virus (HIV), hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have placed a substantial strain on human health and the health care system. These infections have specifically had broad impacts on veteran health in the US. Host factors influence how humans respond to infectious agents and develop adverse health outcomes after infection. Although previous genome-wide association studies (GWAS) have identified loci associated with susceptibility and progression for several infections, understanding the role of host genetic and epigenetic factors on chronic disease comorbidities, aging, and long-term outcomes in the setting of viral infections has been hampered by sample size, heterogeneous populations, and discordant measurements/definitions of key phenotypes. Recent epigenome-wide association studies (EWAS) have uncovered DNA methylation markers associated with noncommunicable diseases (NCDs, such as coronary heart disease, diabetes, heart failure, chronic kidney disease), as well as HIV infection. However, the epigenetic predictors for incident NCDs and mortality are largely unknown among people with viral infections. Viral infections (e.g., HIV) can have a substantial impact on epigenetics, which may affect long-term health outcomes. Additionally, acceleration of the epigenetic clock or age has emerged as a novel biomarker of biological aging and can predict disease outcomes and mortality. Therefore, we will systematically investigate genetic and epigenetic predictors of NCDs and mortality in the following Aims. 1) To identify genetic and epigenetic predictors of age-related morbidity and mortality as well as modification effect of HIV infection among multi-ethnic veterans; 2) To identify genetic and epigenetic factors associated with morbidity and mortality among multi- ethnic veterans with HCV infection; 3) To identify genetic and epigenetic factors of long-term comorbidities, accelerated aging and mortality, as well as mediation effect of COVID-19 among multi-ethnic veterans. Impact: Viral infections including HIV, HCV and SARS-CoV-2 broadly affects veteran’s health and reduces the quality of life (healthspan) and life expectancy (lifespan) through a range of comorbidities. The molecular mechanisms underlying the morbidity and mortality after viral infections of HIV, HCV and SARS-CoV-2 are largely unknown. The proposed genetic and epigenetic study can reveal the genetic and epigenetic factors linking viral infection (acute, chronic, and resolved) and major NCD outcomes and mortality among multi-ethnic veterans, shed lights on potential targets for new prevention and intervention, provide insights into the comorbidity and aging process for all people, and develop systematic and precision medicine strategies to improve veteran’s health.

病毒感染，包括人类免疫缺陷病毒（HIV）、丙型肝炎病毒（HCV） 和严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）已经对 对人类健康和医疗保健系统造成压力。这些感染特别具有广泛的 对美国退伍军人健康的影响宿主因素影响人类对感染性疾病的反应 病原体并在感染后产生不良健康结果。虽然以前的全基因组 关联研究（GWAS）已经确定了与易感性和进展相关的基因座， 几种感染，了解宿主遗传和表观遗传因素对慢性 疾病合并症，衰老，以及病毒感染的长期结果， 受样本量、异质人群和不一致测量/定义的阻碍 关键的表型。最近的表观基因组关联研究（EWAS）揭示了DNA 与非传染性疾病（非传染性疾病，如冠心病）相关的甲基化标志物 疾病、糖尿病、心力衰竭、慢性肾病）以及HIV感染。但 非传染性疾病发病率和死亡率的表观遗传预测因素在患有非传染性疾病的人群中基本上是未知的。 病毒感染病毒感染（例如，艾滋病毒）可以对表观遗传学产生重大影响， 可能会影响长期的健康结果。此外，表观遗传时钟或年龄的加速 已经成为生物衰老的一种新的生物标志物，可以预测疾病的结果， mortality.因此，我们将系统地研究非传染性疾病的遗传和表观遗传预测因子， 和死亡率在以下目标。1)确定与年龄相关的遗传和表观遗传预测因子， 发病率和死亡率以及艾滋病毒感染对多族裔退伍军人的影响; 2)确定与多发性硬化症患者发病率和死亡率相关的遗传和表观遗传因素， HCV感染的少数民族退伍军人; 3）确定长期HCV感染的遗传和表观遗传因素， 合并症，加速衰老和死亡率，以及COVID-19的中介作用， 多民族退伍军人。 影响：包括HIV，HCV和SARS-CoV-2在内的病毒感染广泛影响退伍军人 健康和减少生活质量（健康寿命）和预期寿命（寿命）通过一系列 合并症病毒感染后发病率和死亡率的分子机制 HIV、HCV和SARS-CoV-2的感染在很大程度上是未知的。建议的基因和 表观遗传学研究可以揭示与病毒感染相关的遗传和表观遗传因素（急性， 慢性和解决）和主要非传染性疾病的结果和死亡率在多民族退伍军人，脱落 阐明新的预防和干预的潜在目标， 发展系统化、精准化医学 改善退伍军人健康的策略。