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

病毒感染，包括人类免疫缺陷病毒(HIV)、丙型肝炎病毒(HCV) 和严重急性呼吸综合征冠状病毒2(SARS-CoV-2) 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传染性疾病的反应 并在感染后产生不良的健康后果。尽管之前的全基因组 关联研究(GWAS)已经确定了与糖尿病易感性和疾病进展相关的基因座。 几种感染，了解宿主遗传和表观遗传因素在慢性病中的作用 在病毒感染的背景下，疾病并存、衰老和长期结果一直是 受制于样本量、不同的总体和不一致的测量/定义 关键的表型。最近的表观基因组关联研究发现了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、慢性肾脏疾病)，以及艾滋病毒感染。然而， 在患有非传染性疾病的人中，非传染性疾病事件和死亡率的表观遗传学预测因子基本上未知 病毒感染。病毒感染(如艾滋病毒)可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 已经成为一种新的生物衰老的生物标志物，可以预测疾病的结局和 死亡率。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素。 以及以下目标中的死亡率。1)确定与年龄相关的遗传和表观遗传预测因子 多民族退伍军人中HIV感染的发病率、死亡率及其修饰效果； 2)确定与多种疾病的发病率和死亡率有关的遗传和表观遗传因素 民族退伍军人感染丙型肝炎病毒；3)确定长期遗传和表观遗传因素 新冠肺炎在人群中的并存、加速衰老和死亡的调节作用 多民族退伍军人。 影响：包括艾滋病毒、丙型肝炎病毒和SARS-CoV-2在内的病毒感染广泛影响退伍军人 健康，并通过一定范围降低生活质量(健康寿命)和预期寿命(寿命 合并症的症状。病毒感染后发病和死亡的分子机制 艾滋病毒、丙型肝炎病毒和SARS-CoV-2的感染在很大程度上是未知的。拟议的遗传和 表观遗传学研究可以揭示连接病毒感染的遗传和表观遗传因素(急性、 多民族退伍军人中慢性和已解决的)和主要的非传染性疾病结局和死亡率 阐明新的预防和干预的潜在目标，提供对 全民共病和老龄化进程，发展系统化、精准化医学 改善退伍军人健康的策略。

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.