Diabetic Complications and Genetic Variants in the Million Veterans Program
百万退伍军人计划中的糖尿病并发症和遗传变异
基本信息
- 批准号:10655281
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdolescentAdultAgeBlood PressureBody mass indexCaringCharacteristicsClinicalComplications of Diabetes MellitusConsensusDNADataDevelopmentDiabetes MellitusDiabetic KetoacidosisDiagnosisDiseaseEFRACEmergency SituationEpigenetic ProcessEthnic OriginExclusionEye diseasesGene ExpressionGenesGeneticGenetic LoadGenetic RiskGenetic studyGenomeGlycosylated hemoglobin AGoalsHealthHeart failureHypoglycemiaIndividualInsulinInsulin-Dependent Diabetes MellitusKidney DiseasesLibrariesLife StyleLiteratureMediatingMediationMendelian randomizationMethodsMethylationModelingModificationMolecularMorbidity - disease rateMutationNatural HistoryNon-Insulin-Dependent Diabetes MellitusOutcomeOutpatientsParticipantPathway interactionsPatternPersonsPhenotypePhysiologicalProcessPrognosisProteinuriaRaceReportingRetinal DiseasesRiskRisk FactorsSiteSystemTestingTimeTranslationsVeteransVisitclinical riskclinical translationcomorbiditycostdemographicsdiabeticepigenome-wide association studiesepigenomicsgene environment interactiongenetic disorder diagnosisgenetic variantgenome wide association studygenome-widegenomic locusimprovedinsulin dependent diabetes mellitus onsetmacrovascular diseasemilitary servicemortalitymulti-ethnicmultiple omicsnon-geneticnovel therapeuticspersonalized carepersonalized medicinephenomicspolygenic risk scoreprecision medicinepredictive modelingpreservationprogramsstatisticstrait
项目摘要
Diabetes (DM) complications are the major cause of its morbidity, mortality, and costs. MVP009 has
advanced understanding of the underlying genetics. Since DM care does not take advantage of progress in
genetics, we propose to use genetics to support both clinical translation and mechanistic discovery.
In MVP009, we utilized highly specific phenotypes in genome-wide association studies (GWAS) of
(i) heart failure (HF) with preserved vs. reduced ejection fraction; (ii) hypoglycemia – severe (emergency visits)
and incidental (outpatient visits); (iii) kidney disease; and (iv) eye disease. We also found that although typical,
“juvenile-onset type 1 diabetes (T1D)” excludes military service, at least 10% of Veterans with presumed T2D
in MVP may have “adult onset T1D” – largely unrecognized. We now propose to extend these findings.
Consistent with the Precision Medicine in Diabetes Consensus Report, our Aims target precision in
(i) diagnosis (genetic T1D vs. T2D), (ii) treatment [combining genetic with traditional risk factors (RF)], and (iii)
prognosis (epigenomic contributions to complications) – to incorporate genetics so that care can be more
accurate and individualized, and identify mechanisms that can lead to discovery of new treatments.
Aim 1: Assess the contributions of T1D and T2D genetic loads to the clinical characteristics
and disease trajectories of people presumed to have T2D. We will model multiethnic genetic risk with T1D
and T2D polygenic risk scores (PRS, with multiethnic data from large recent studies); each MVP Veteran will
have both a T1D and a T2D PRS. Outcomes will include incident DM, and the disease trajectory: age and BMI
at onset, time to insulin Rx, and ketoacidosis and hypoglycemia. We will evaluate the utility of the PRS to
identify Veterans with DM who would benefit from definitive T1D testing and/or early use of insulin.
Aim 2: Assess the combined contributions of genetic/nongenetic RF to development of
complications. (SubAim a) Identify effect modifications between RF and complications. Genetic
interaction analyses will include lifestyle, demographics, and comorbidities (e.g., blood pressure, HbA1c), as
modifiers of the risk of complications conferred by disease loci and PRS. We will use both hypothesis-testing
approaches for known loci and PRS, and hypothesis-generating approaches (using genome-wide G×E
modeling) to examine interactions associated with diabetic eye disease (DED), kidney disease (DKD), HF, and
hypoglycemia, and causal associations using state-of-the-art Mendelian Randomization (MR), including
multivariable and mediation MR. (SubAim b) Develop and test predictive models. We will use summary
statistics from the MVP GWAS and the literature, to develop separate PRS using the “best practice” recent
method, for DED, DKD, HF, and hypoglycemia, and PheWAS with the PRSs to elucidate previously unknown
RFs. Utilizing the PRS, PheWAS, information from SubAim (a), clinical RF, and treatments, we will develop
genome-informed predictive models that will be evaluated in eMERGE and more recent MVP participants.
Aim 3: Identify epigenomic markers and molecular systems underlying DM complications.
Epigenomic changes regulate gene expression, can mediate environmental and physiologic effects, and have
been associated with T2D and related glycemic traits. We hypothesize that differential methylation will also be
associated with DM complications. Methylation information using the EPIC chip (>850,000 sites) will be
available on >30,000 Veterans, and can be imputed in other Veterans, allowing epigenomic and multi-omic
methods such as aggregation analysis and epigenome-wide association studies to (i) identify associations with
the complications of DM as well as hypoglycemia, and (ii) identify the genes and pathways involved.
Impact: The genetics of diagnosis, G×E, epigenomics, and predictive models should both aid
translation – to identify risk in individuals, and help personalize treatment to reduce DM complications and
hypoglycemia – and support discovery of new therapies to mitigate the underlying processes.
糖尿病(DM)并发症是其发病率、死亡率和费用的主要原因。 MVP009有
对潜在遗传学的深入了解。由于 DM 护理没有利用进展
遗传学,我们建议使用遗传学来支持临床转化和机制发现。
在 MVP009 中,我们在全基因组关联研究 (GWAS) 中利用了高度特异性的表型
(i) 射血分数保留与降低的心力衰竭 (HF); (ii) 低血糖 – 严重(紧急就诊)
和偶然的(门诊就诊); (iii) 肾脏疾病; (iv) 眼部疾病。我们还发现,虽然很典型,
“青少年发病的 1 型糖尿病 (T1D)”不包括服兵役,至少 10% 的退伍军人被推定患有 T2D
MVP 中的患者可能患有“成人发病的 T1D”——很大程度上未被识别。我们现在建议扩展这些发现。
与糖尿病精准医学共识报告一致,我们的目标是精准治疗
(i) 诊断(遗传性 T1D 与 T2D),(ii) 治疗 [结合遗传与传统危险因素 (RF)],以及 (iii)
预后(表观基因组对并发症的贡献)——将遗传学纳入其中,以便护理可以更加准确
准确和个性化,并确定可以导致新疗法发现的机制。
目标 1:评估 T1D 和 T2D 遗传负荷对临床特征的贡献
以及推测患有 T2D 的人的疾病轨迹。我们将用 T1D 来模拟多种族遗传风险
T2D 多基因风险评分(PRS,包含来自近期大型研究的多种族数据);每个 MVP 老将都会
同时拥有 T1D 和 T2D PRS。结果将包括糖尿病事件和疾病轨迹:年龄和体重指数
发病时、胰岛素注射时间、酮症酸中毒和低血糖。我们将评估 PRS 的实用性
确定患有 DM 的退伍军人,他们将受益于明确的 T1D 检测和/或早期使用胰岛素。
目标 2:评估遗传/非遗传 RF 对发育的综合贡献
并发症。 (子目标 a)确定 RF 和并发症之间的影响变化。遗传
交互分析将包括生活方式、人口统计数据和合并症(例如血压、HbA1c),如
疾病位点和 PRS 赋予并发症风险的修饰因子。我们将使用假设检验
已知基因座和 PRS 的方法,以及假设生成方法(使用全基因组 G×E
模型)来检查与糖尿病眼病(DED)、肾病(DKD)、心衰和糖尿病相关的相互作用
使用最先进的孟德尔随机化 (MR) 来确定低血糖和因果关系,包括
多变量和中介 MR。 (子目标 b)开发和测试预测模型。我们将使用摘要
来自 MVP GWAS 和文献的统计数据,使用最近的“最佳实践”开发单独的 PRS
方法,针对 DED、DKD、HF 和低血糖,以及 PheWAS 和 PRS,以阐明以前未知的情况
RF。利用 PRS、PheWAS、SubAim (a) 的信息、临床 RF 和治疗,我们将开发
基于基因组的预测模型将在 eMERGE 和最近的 MVP 参与者中进行评估。
目标 3:识别 DM 并发症背后的表观基因组标记和分子系统。
表观基因组变化调节基因表达,可以介导环境和生理效应,并具有
与 T2D 和相关血糖特征相关。我们假设差异甲基化也将是
与 DM 并发症相关。使用 EPIC 芯片(>850,000 个位点)的甲基化信息将被
可用于超过 30,000 名退伍军人,并且可以推算到其他退伍军人中,从而实现表观基因组和多组学分析
聚合分析和全表观基因组关联研究等方法,以(i)确定与
糖尿病并发症和低血糖,以及 (ii) 确定相关基因和途径。
影响:诊断遗传学、G×E、表观基因组学和预测模型都应该有所帮助
翻译——识别个人风险,帮助个性化治疗,以减少糖尿病并发症和
低血糖——并支持发现新疗法以减轻潜在的过程。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LAWRENCE S PHILLIPS其他文献
LAWRENCE S PHILLIPS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('LAWRENCE S PHILLIPS', 18)}}的其他基金
Diabetic Complications and Genetic Variants in the Million Veterans Program
百万退伍军人计划中的糖尿病并发症和遗传变异
- 批准号:
10368695 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Assessing Barriers and Facilitators for Participating Structured Lifestyle Intervention and its Real-world Effectiveness and Cost-Effectiveness among US Veterans
评估美国退伍军人参与结构化生活方式干预的障碍和促进因素及其现实世界的有效性和成本效益
- 批准号:
10554732 - 财政年份:2022
- 资助金额:
-- - 项目类别:
CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES – “CHANGE” STUDY
改变 2 型糖尿病的自然病史 — — — 变化 — 研究
- 批准号:
10437877 - 财政年份:2021
- 资助金额:
-- - 项目类别:
CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES – “CHANGE” STUDY
改变 2 型糖尿病的自然病史 — — — 变化 — 研究
- 批准号:
10619451 - 财政年份:2021
- 资助金额:
-- - 项目类别:
CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES – “CHANGE” STUDY
改变 2 型糖尿病的自然病史 — — — 变化 — 研究
- 批准号:
10298826 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Diabetic Complications and Genetic Variants in the Million Veterans Program
百万退伍军人计划中的糖尿病并发症和遗传变异
- 批准号:
9483196 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Diabetic Complications and Genetic Variants in the Million Veterans Program
百万退伍军人计划中的糖尿病并发症和遗传变异
- 批准号:
10908985 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Diabetic Complications and Genetic Variants in the Million Veterans Program
百万退伍军人计划中的糖尿病并发症和遗传变异
- 批准号:
10439613 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Diabetic Complications and Genetic Variants in the Million Veterans Program
百万退伍军人计划中的糖尿病并发症和遗传变异
- 批准号:
10268156 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Reach, Outcomes and System Impacts of the VA's National Weight Loss Program, MOVE
退伍军人管理局国家减肥计划 MOVE 的范围、成果和系统影响
- 批准号:
8878249 - 财政年份:2014
- 资助金额:
-- - 项目类别:
相似海外基金
Developing a Young Adult-Mediated Intervention to Increase Colorectal Cancer Screening among Rural Screening Age-Eligible Adults
制定年轻人介导的干预措施,以增加农村符合筛查年龄的成年人的结直肠癌筛查
- 批准号:
10653464 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Doctoral Dissertation Research: Estimating adult age-at-death from the pelvis
博士论文研究:从骨盆估算成人死亡年龄
- 批准号:
2316108 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
Determining age dependent factors driving COVID-19 disease severity using experimental human paediatric and adult models of SARS-CoV-2 infection
使用 SARS-CoV-2 感染的实验性人类儿童和成人模型确定导致 COVID-19 疾病严重程度的年龄依赖因素
- 批准号:
BB/V006738/1 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Research Grant
Transplantation of Adult, Tissue-Specific RPE Stem Cells for Non-exudative Age-related macular degeneration (AMD)
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 (AMD)
- 批准号:
10294664 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Sex differences in the effect of age on episodic memory-related brain function across the adult lifespan
年龄对成人一生中情景记忆相关脑功能影响的性别差异
- 批准号:
422882 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Operating Grants
Modelling Age- and Sex-related Changes in Gait Coordination Strategies in a Healthy Adult Population Using Principal Component Analysis
使用主成分分析对健康成年人群步态协调策略中与年龄和性别相关的变化进行建模
- 批准号:
430871 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Studentship Programs
Transplantation of Adult, Tissue-Specific RPE Stem Cells as Therapy for Non-exudative Age-Related Macular Degeneration AMD
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 AMD
- 批准号:
9811094 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Doctoral Dissertation Research: Literacy Effects on Language Acquisition and Sentence Processing in Adult L1 and School-Age Heritage Speakers of Spanish
博士论文研究:识字对西班牙语成人母语和学龄传统使用者语言习得和句子处理的影响
- 批准号:
1823881 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Standard Grant
Adult Age-differences in Auditory Selective Attention: The Interplay of Norepinephrine and Rhythmic Neural Activity
成人听觉选择性注意的年龄差异:去甲肾上腺素与节律神经活动的相互作用
- 批准号:
369385245 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Research Grants














{{item.name}}会员




