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:10368695
- 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 OriginEye diseasesGene ExpressionGenesGeneticGenetic LoadGenetic RiskGenetic studyGenomeGlycosylated hemoglobin AGoalsHealthHeart failureHypoglycemiaIndividualInsulinInsulin-Dependent Diabetes MellitusKidney DiseasesLeadLibrariesLife StyleLiteratureMediatingMediationMendelian randomizationMethodsMethylationModelingModificationMolecularMorbidity - disease rateMutationNatural HistoryNon-Insulin-Dependent Diabetes MellitusOutcomeOutpatientsParticipantPathway interactionsPatternPersonsPhenotypePhysiologicalProcessPrognosisProteinuriaRaceReportingRetinal DiseasesRiskRisk FactorsSiteSystemTestingThromboplastinTimeTranslationsVeteransVisitbaseclinical 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 modelingpredictive testpreservationprogramsstatisticstrait
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已经
项目成果
期刊论文数量(0)
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LAWRENCE S PHILLIPS其他文献
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{{ 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:
10655281 - 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:
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