Next Generation Rare Variant Discovery in Multiplex AD Families

多重 AD 家族中下一代罕见变异的发现

• 批准号: 10214751
• 负责人: David B. Goldstein
• 金额: $ 15.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214751
• 关键词: 2019-nCoV; Acute; Affect; Age; Alcohol consumption; Alcohols; Antigenic Variation; Antigens; Award; Beer; Beverages; COVID-19; COVID-19 pandemic; Cessation of life; Characteristics; Chromosome 6; Cigarette; Clinical; Common Cold; Complex; Consensus; Consumption; Contracts; Data; Demographic Factors; Diabetes Mellitus; Diagnosis; Disease; Distal; Dose; Drug usage; Epidemic; Ethnic Origin; Exposure to; Family; Frequencies; Future; Genes; Genetic; Genetic Variation; Goals; HLA Antigens; Health; Health Campaign; Health Status; Heavy Drinking; Heritability; Human; Hypertension; Immune response; Immunity; Incidence; Individual; Infection; Infectious Mononucleosis; Interview; Major Histocompatibility Complex; Mediating; Medical; Morbidity - disease rate; New York; Obesity; Outcome; Participant; Pharmaceutical Preparations; Play; Population; Predisposition; Production; Psychiatric Diagnosis; Public Health; Quarantine; Recording of previous events; Recovery; Reporting; Research; Resources; Risk; Role; SARS coronavirus; Serologic tests; Shelter facility; Symptoms; T-Lymphocyte; Taiwan; Testing; Time; Vaccines; Variant; Viral; Virus; Virus Diseases; Wine; World Health Organization; adverse outcome; alcohol effect; alcohol measurement; alcohol misuse; alcohol risk; alcohol screening; alcohol use disorder; comorbidity; cytokine; disorder prevention; drinking; exome sequencing; experience; health goals; high risk; immune function; improved; lifestyle factors; medical attention; member; mortality; mortality statistics; next generation; pandemic disease; programs; psychiatric symptom; rare variant; respiratory; respiratory virus; response; screening; sex; vaccine development

The World Health Organization (WHO) is currently reporting 4,793,076 confirmed cases of COVID-19 infection world-wide with 316,341 deaths. With each new pandemic the population is at risk until vaccines and medications can be developed. Quarantine of the entire population appears to be only alternative until sufficient time elapses for vaccine development. Therefore, an important public health goal is to determine who must be sheltered in place and who can resume normal activities. Older individuals appear to be disproportionately adversely affected by the virus. Although immune functioning tends to wane with age, genetic and lifestyle factors appear to greatly alter susceptibility. The goal of this project is to identify individuals who may be more or less resilient due to their lifetime use of alcohol. Those with an alcohol use disorder (AUD) may have a greater risk for adverse consequences of SARS-CoV-2 exposure, yet low dose consumption may improve immune functioning. A better understanding of whether alcohol use has a different effect at low doses than at high doses is critical to public health campaigns that advise the public on safe use of alcohol. Genetic variation in the Major Histocompatiblity Locus (MHC) located on chromosome 6 plays an important role in immune functioning. Variation in the human leucocyte antigens (HLA) have been significantly associated with many diseases and hold promise for personalized antigen-specific disease prevention. Having this information available, as part of routine medical screening in the future, would enable us to stratify the population into those needing sheltering in place and those who do not. This project would determine the feasibility of using HLA gene variation along with screening for alcohol use as an important part of stratifying the population at the onset of viral epidemics. The present proposal builds on existing resources from participants for whom exome sequencing and/or HLA serology was completed and utilizes the extensive alcohol use histories, psychiatric diagnoses, and health histories obtained at baseline. New interviews concerning alcohol use, both distal and proximal, current health status, and exposure histories for the SARS- CoV-2 virus will enable us to determine their contribution to infection and progression. We will contrast those with AUD with those without and unaffected members of high risk versus low risk families in (Aim 1). In Aim 2, we will assess levels of recent and past alcohol consumption to viral response. Genetic variation in the major histocompatibility complex (HLA) region will be tested for association with outcome among those that are demonstrated to have been exposed (Aim 3).

世界卫生组织 (WHO) 目前报告了 4,793,076 例确诊病例 全球范围内出现新冠肺炎 (COVID-19) 感染，导致 316,341 人死亡。每一次新的大流行，人口数量都在 在开发出疫苗和药物之前，存在风险。出现全民隔离 在疫苗开发有足够时间之前，这是唯一的替代方案。因此，一个 重要的公共卫生目标是确定谁必须就地避难以及谁可以恢复 正常活动。老年人似乎受到不成比例的不利影响 病毒。尽管免疫功能往往会随着年龄的增长而减弱，但遗传和生活方式因素似乎会影响免疫功能。 大大改变易感性。该项目的目标是确定可能更多或更多的个人 由于终生饮酒，他们的恢复能力较差。患有酒精使用障碍 (AUD) 的人可能 接触 SARS-CoV-2 造成不良后果的风险更大，但剂量较低 食用可以改善免疫功能。更好地了解饮酒是否会影响 低剂量与高剂量的不同效果对于建议的公共卫生运动至关重要 公众安全饮酒。主要组织相容性基因座 (MHC) 的遗传变异 位于 6 号染色体上，在免疫功能中发挥着重要作用。人性的变异 白细胞抗原 (HLA) 与许多疾病显着相关并具有前景 用于个性化抗原特异性疾病预防。提供这些信息，作为 未来的例行医疗筛查将使我们能够将人群分为以下几类： 需要就地避难的人和不需要避难的人。该项目将确定以下项目的可行性 使用 HLA 基因变异以及酒精使用筛查作为分层的重要组成部分 病毒流行开始时的人口。 本提案建立在参与者的现有资源之上，这些参与者的外显子组 测序和/或 HLA 血清学已完成并利用广泛的饮酒史， 基线时获得的精神病诊断和健康史。新采访涉及 饮酒情况（远端和近端）、当前健康状况以及 SARS 暴露史 CoV-2 病毒将使我们能够确定它们对感染和进展的贡献。我们将 将患有 AUD 的人与没有或未受影响的高风险成员和低风险成员进行对比 （目标 1）中的家庭。在目标 2 中，我们将评估最近和过去的饮酒水平对病毒的影响 回复。将测试主要组织相容性复合体 (HLA) 区域的遗传变异 与被证明已暴露的人群的结果相关（目标 3）。

项目成果

Factors influencing COVID-19 Infection in older individuals: History of Alcohol Use Disorder, Major Depressive illness, genetic variation and current use of alcohol.

影响老年人感染 COVID-19 的因素：酒精使用障碍史、重度抑郁症、遗传变异和当前饮酒情况。

• DOI: 10.1101/2021.12.06.21267386
• 发表时间: 2021
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Hill,ShirleyY;Holmes,BrianJ;Locke-Wellman,Jeannette
• 通讯作者: Locke-Wellman,Jeannette