Strategic Goal: Goal 3: Advance Translational Research

Genetics and Genomics of Heart Disease

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven ...more »

Submitted by (@wangq2)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven and not hypothesis-driven, so that finding in this area has been extremely low. We recommend that genetics and genomics should be placed as a strong priority for NIH funding for the coming years.

Feasibility and challenges of addressing this CQ or CC :

Feasible

Name of idea submitter and other team members who worked on this idea : Qing Kenneth Wang

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Strategic Goal: Goal 2: Reduce Human Disease

High risk individual’s apparent protection from disease

Can we define the basis for high risk individual’s apparent protection from disease?

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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-7 net votes
8 up votes
15 down votes
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Strategic Goal: Goal 2: Reduce Human Disease

Understand genetic and epigenetic mechanisms underlying cardiac arrhythmias and the biology of the cardiac conduction system.

Critical Challenge

Submitted by (@yong.zhao)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

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-5 net votes
6 up votes
11 down votes
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Strategic Goal: Goal 2: Reduce Human Disease

Predictors of Sickle Cell Disease Severity

Can better predictors of disease severity such as specific biomarkers and/or genetic polymorphisms be identified so as to help understand the course and progression of sickle cell disease in various patients?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The high clinical variability in sickle cell disease (SCD) and the lack of sufficient data to help understand and or predict the course of an individual’s disease warrants the identification of better predictors of disease severity. The identification of predictors of disease severity, such as biomarkers, will be vital in the management and treatment of SCD, especially since more recently several plasma biomarkers and certain genetic polymorphisms have been proposed to influence specific clinical outcomes, including stroke, sickle cell nephropathy, and survival. Furthermore, studies of biomarkers or genetic markers in the context of clinical drug trials may be helpful in predicting response rates, thus allowing for more personalized therapeutic decisions.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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58 net votes
76 up votes
18 down votes
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Strategic Goal: Goal 1: Promote Human Health

Cardiac Gene Networks

What is the level of intra-tissue variation of cardiac development gene regulatory networks at single cell resolution?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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2 net votes
16 up votes
14 down votes
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Strategic Goal: Goal 1: Promote Human Health

Identify genetic variants of sleep/circadian disorders

Most aspects of variation in sleep and circadian rhythm are heritable. Moreover, all common sleep disorders aggregate in families. The response to sleep loss is also a highly heritable trait. Identifying gene variants for these disorders will elaborate new molecular pathways that could be targets for future interventions.

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Addressing this critical challenge would have the following impact. First, the information could be used to help identify these different disorders, including potentially subtypes. Addressing this challenge will lead to identification of new molecular pathways to disease. This will stimulate future research on their role and mechanisms of pathogenesis. Moreover, these pathways may be open to new drug interventions and hence new therapies for disease.

Feasibility and challenges of addressing this CQ or CC :

There is a growing number of cohorts both in the United States and internationally that have sleep phenotype data and DNA. These could be the basis of genetic studies.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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84 net votes
117 up votes
33 down votes
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Strategic Goal: Goal 3: Advance Translational Research

Use isogenic iPS cells to advance Precision Medicine

The goals of Precision Medicine can be achieved if we determine the biological basis of disease-associated variants for NHLBI diseases. Advances in genetic research have yielded hundreds of disease-associated DNA polymorphisms, yet we lack robust methods to experimentally test their functional relevance in human cells. Determining the molecular and cellular basis of human phenotypic variation is one of the great challenges ...more »

Submitted by (@bconklin)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Identifying how disease mutations result in cellular phenotypes will provide an experimental basis for Precision Medicine. Advances in genome engineering and iPS cell technology now offer a unique opportunity for NHLBI researchers to make a focused effort to produce isogenic disease models, to determining the function of putative disease loci. Just a few years ago, the barriers to this type of project seemed insurmountable, as iPS cells were made with damaging DNA insertions, designer nucleases were difficult to make, complex material-transfer agreements (MTAs) inhibited the open sharing of reagents, and cell-engineering methods were cumbersome. Remarkably, all of these barriers have fallen substantially in recent years, to reveal strategic new opportunities. The phenotypes are determined in isogenic human iPS-models, these observations can be applied to animal models, and human clinical studies.

Feasibility and challenges of addressing this CQ or CC :

Progress towards this goal is being made, but slow pace does not meet opportunity that the NHLBI community has. The NHLBI has a much larger opportunity than other institutes because so many genetic variants have already been determined via excellent genetic studies using robust physiological phenotypes. The genetic variants provide hypotheses that are ripe for direct experimental testing in isogenic iPS cell models. Fortunately, many diseases of interest to NHLBI can be modeled in iPS-derived tissues. Other part of NIH (e.g. NIMH, NIDA, NIAAA ) lack abundance of high probability genetic "hits" that NHLBI now has. NHLBI should take advantage of this opportunity.

Name of idea submitter and other team members who worked on this idea : Bruce Conklin

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-19 net votes
8 up votes
27 down votes
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Strategic Goal: Goal 2: Reduce Human Disease

Assessing gene knockout humans more effectively

What insights can be gathered from patients with single gene functional mutations to improve our understanding of the pathobiology of human disease?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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-9 net votes
5 up votes
14 down votes
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Strategic Goal: Goal 3: Advance Translational Research

Translating cardiac development/genetics knowledge into therapy

What is needed to translate our knowledge of cardiac development and congenital heart disease genetics into novel diagnostic and/or therapeutic strategies for congenital or acquired heart disease?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Develop new therapies for congenital or acquired heart disease.

Feasibility and challenges of addressing this CQ or CC :

We are poised to take advantage of the incredible advances in our understanding of cardiac development and genetics which have resulted from the development of high throughput technologies.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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10 net votes
21 up votes
11 down votes
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Strategic Goal: Goal 2: Reduce Human Disease

Improving the phenotyping of the major (chronic) heart, lung, and blood diseases

Which phenotypic and molecular characteristics predict differential responses to therapy in individuals with chronic heart, lung, blood, and sleep (HLBS) diseases?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

• Enable pathophysiologically targeted therapies and prevention

• Enable subgroup assessment of intervention

• Better define gene-gene and gene-environment interactions

• Improve risk stratification

• Understand those who are protected against disease

• Inform development of better in vitro and in vivo models to assess disease and response

Feasibility and challenges of addressing this CQ or CC :

Advances in –omics, diagnostics, cell biology, imaging are ready to be applied

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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30 net votes
42 up votes
12 down votes
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Strategic Goal: Goal 2: Reduce Human Disease

Does lowering circulating lipoprotein(a) levels influence cardiovascular outcomes?

A comprehensive research strategy and plan is needed to determine the most efficient, safe, cost-effective and widely applicable strategy to decrease circulating levels of lipoprotein(a) and to determine whether lowering circulating lipoprotein(a) levels will reduce the risk of developing cardiovascular disease such as a heart attack or a stroke as well as the progression of atherosclerosis or aortic stenosis.

Submitted by (@serevill)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Approximately 20% of the population are characterized by elevated circulating levels of lipoprotein(a), regardless of age, gender or blood cholesterol levels. Estimates suggest that up to 90% of the variation in plasma lipoprotein(a) levels could be due to genetic factors, which makes lipoprotein(a) the most prevalent inherited risk factor for cardiovascular diseases (CVD). Large-scale genetic studies have shown that Lipoprotein(a) was the strongest genetic determinant of CVD such as atherosclerosis and aortic stenosis. Lipoprotein(a) is one of the strongest predictors of residual CVD risk and has been shown to improve CVD risk prediction in several population-based studies. Lipoprotein(a) is also one of the strongest known risk factors for spontaneous ischemic stroke in childhood.

A comprehensive research strategy aiming at identifying, evaluating interaction with other risk factors, treating and educating patients with elevated lipoprotein(a) levels would result in substantial reductions of health care costs in the US and around the globe by reducing the burden of CVD while simultaneously improving the quality of life of these patients.

Feasibility and challenges of addressing this CQ or CC :

The list of pharmaceutical agents that reduce lipoprotein(a) levels is steadily increasing. There are approximately half a dozen strategies that have been shown to significantly and safely lower lipoprotein(a) levels. One of the challenges of this research strategy will be to determine which of these strategies represent the most efficient, safe, cost-effective and widely applicable approach to lower lipoprotein(a) levels and CVD outcomes.

Increasing awareness on lipoprotein(a) and CVD will also be of utmost importance for this effort as relatively few physicians perform lipoprotein(a) testing and even fewer patients are aware of their lipoprotein(a) level. The first sign of high lipoprotein(a) is often a heart attack or stroke. Our challenge will be to identify patients with high lipoprotein(a) that could be enrolled in trials of risk characterization and lipoprotein(a)-lowering.

Name of idea submitter and other team members who worked on this idea : Sandra Revill Tremulis on behalf of the Lipoprotein(a) Foundation Scientific Advisory Board

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235 net votes
297 up votes
62 down votes
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Strategic Goal: Goal 3: Advance Translational Research

Can We Successfully Reduce the Risk Factor Burden and Atherosclerosis in Younger Individuals?

There is growing evidence that risk factors beginning in childhood and young adult life, e.g. from such studies as CARDIA, Bogalusa, etc., are primary determinants of risk of CHD in adults.

Submitted by (@kullerl)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The levels of BP, lipoproteins, ApoB, obviously obesity, cigarette smoking, and growing risk of early age type 2 diabetes, are epidemic in the young United States population. This may result in a continued high burden of CHD in future generations in the United States. Unless something is done about controlling risk factors in younger individuals, a continued epidemic of CHD is likely.

Feasibility and challenges of addressing this CQ or CC :

The NHLBI should begin clinical trials to determine the best approaches to reducing risk factors in the younger United States population. This should include various studies of environmental modifications, better nutrition studies, improved exercise programs, and identification of host genetic susceptibility. To date, the programs have been remarkably unsuccessful and different approaches are required, especially in lower income and minority populations. The NHLBI should also begin to consider the evaluation of drug therapies for elevated lipids and BP, new drug therapies for obesity and even bariatric surgery in high risk young individuals with initial evaluation of the reduction of subclinical atherosclerotic disease, evidence of myocardial injury, e.g. elevated hs-cTnT, NT-proBNP, etc., in these high risk populations. There is little that the current approaches are very effective.

Name of idea submitter and other team members who worked on this idea : Lewis H. Kuller, MD, DrPH

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21 net votes
46 up votes
25 down votes
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