Precision medicine, most simply, is when clinical medicine uses or leverages genetic and genomic knowledge for risk prediction and intervention.  The National Institute of Health defines precision medicine as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”.  Our work on the genetic contributors to DCM will expand precision medicine for cardiology.

A Project Description similar to that of the submitted NIH application, is provided here. The numbers of probands and family members have been modified due in part to supplemental funding from the NHGRI.

Dilated cardiomyopathy of unknown cause (DCM), known clinically as idiopathic dilated cardiomypathy, is the most common cardiomyopathy and is the leading cause of heart transplantation. By our estimates DCM affects approximately one million individuals, and so has a major impact on US public health. DCM is commonly asymptomatic until very late in its course when it causes heart failure, disability, and death. Because of its clinical course, any means to identify patients at risk for DCM or to detect DCM in its asymptomatic phase could provide enormous opportunity for intervention to extend lives and prevent late-stage disease. Within this paradigm precision medicine for DCM could greatly impact health care outcomes and costs. Recent advances in DCM genetics have introduced these possibilities, but unresolved questions of familial recurrence risk, genetic etiology, racial differences, and family-based screening must be addressed to move ahead. Our central hypothesis, based on our published studies, states that DCM has substantial genetic basis. For this study we hypothesize that: (a) 35% of probands of both European and African ancestry (EA/AA) will be classified as familial in a cohort recruited in a multicenter US consortium and given explicit recommendations and assistance to achieve the clinical screening of relatives; (b) approximately 40% of DCM probands, whether categorized as familial or non-familial, or as EA or AA, will have pathogenic or likely pathogenic variants in genes previously implicated in DCM; and (c) a tailored intervention to help DCM probands communicate DCM risk to their family members will improve the uptake and impact of necessary clinical and genetic testing. To test these hypotheses, we propose to: (1) estimate and compare the frequencies of EA and AA DCM probands classified as having familial DCM; (2) estimate and compare the proportions of probands with an identifiable genetic cause of DCM in groups defined by proband classification (familial/non-familial) and ancestry (EA/AA); and (3) evaluate the impact of a randomized intervention to aid and direct family communication on participation of at-risk family members in clinical screening and appropriate follow-up surveillance for DCM. These aims will be accomplished by recruiting a cohort of 1300 DCM probands (600 EA, AA, 100 of Hispanic ethnicity), performing cardiovascular clinical screening of 2600 family members, performing genetic testing of probands and affected family members by exome sequencing, returning genetic results, and randomizing probands to an intervention to improve family communication regarding DCM risk. Proving these hypotheses would be transformative for the field: rather than viewing DCM as only a clinical diagnosis, we would understand DCM as a genetic disease that should be managed using genetic diagnostic and family-based preventive strategies. Our study results would make precision medicine for DCM a reality.

 

The DCM Precision Medicine Study receives its main funding from the National Heart Lung and Blood Institute (NHLBI). However, we have been fortunate to receive supplemental funding from the National Human Genome Research Institute (NHGRI), which will enable us to add 100 probands of Hispanic ethnicity and their 200 family members to the 600 probands and 1200 family members of both European and African ancestry already planned for the study.

Our funding comes from the National Institutes of Health (NIH), a part of the United States federal government dedicated to biomedical research of human health and disease.

For this study we received a grant of $10.7 million from National Heart Lung and Blood Institute (NHLBI). The NHLBI is an Institute dedicated to understanding and preventing heart disease and stroke. Additional information regarding the invaluable work of the NHLBI is available.

We also received $1.7 million in supplemental funding from the National Human Genome Research Institute (NHGRI) to recruit additional patients of Hispanic ethnicity and their families. Please see the section above NHGRI Hispanic Supplement for additional details.