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. 2022 Aug;1(3):100068.
doi: 10.1016/j.jacadv.2022.100068. Epub 2022 Aug 16.

Clinical Implementation of Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease

Dimitri J Maamari  1   2   3 , Deanna G Brockman  1   2 , Krishna Aragam  2   4   5 , Renée C Pelletier  1   2 , Emma Folkerts  1 , Cynthia L Neben  6 , Sydney Okumura  6 , Leland E Hull  5   7 , Anthony A Philippakis  2 , Pradeep Natarajan  1   2   4   5   8 , Patrick T Ellinor  2   4   5   8 , Kenney Ng  9 , Alicia Y Zhou  6 , Amit V Khera  1   2   4   5   8   10 , Akl C Fahed  1   2   4   5   8
Affiliations

Clinical Implementation of Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease

Dimitri J Maamari et al. JACC Adv. 2022 Aug.

Abstract

Background: State-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants-such as those related to familial hypercholesterolemia-as well as the cumulative impact of many common variants, as quantified by a polygenic score.

Objectives: The objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management.

Methods: Study participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine. Digital postdisclosure surveys and chart review evaluated the impact of disclosure.

Results: There were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging.

Conclusions: Combined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.

Keywords: coronary artery disease; genetics; genomic medicine; polygenic score; precision medicine; preventive cardiology.

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Conflict of interest statement

Funding support was provided by grants 1K08HG010155 and 1U01HG011719 (to Dr Khera) from the National Human Genome Research Institute, a Hassenfeld Scholar Award from Massachusetts General Hospital (to Dr Khera), a Merkin Institute Fellowship, and institutional SPARC award from the Broad Institute of MIT and Harvard (to Dr Khera), and a sponsored research agreement from IBM Research (to Dr Khera). Dr Ng is an employee of IBM Research. Drs Zhou and Neben and Mr Okumura are employed by and may have an equity interest in Color Health. Dr Philippakis has received research support from Bayer AG, IBM, Intel, and Verily; and has consulted for Novartis and Rakuten. Dr Natarajan has received grant support from Amgen, Apple, AstraZeneca, Novartis, and Boston Scientific; consulting income from Apple, AstraZeneca, Genentech/Roche, Blackstone Life Sciences, Foresite Labs, Novartis, and TenSixteen Bio; is a member of the scientific advisory board and shareholder of TenSixteen Bio and geneXwell; and spousal employment and equity in Vertex, all unrelated to the present work. Dr Ellinor has received sponsored research support from Bayer AG and IBM Research; and has consulted for Bayer AG, Novartis, and MyoKardia. Dr Khera is an employee and holds equity in Verve Therapeutics; has served as a scientific advisor to Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Novartis, Silence Therapeutics, Korro Bio, Veritas International, Color Health, Third Rock Ventures, Foresite Labs, and Columbia University (National Institute of Health); received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; and received a sponsored research agreement from IBM Research. Dr Fahed is a consultant and owns shares in Goodpath. All other authors have reported that they have no relationships relevant to the contents of this paper.

Figures

None
Graphical abstract
Figure 1
Figure 1
Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease (A) Results of combined monogenic and polygenic risk assessment for coronary artery disease; a high polygenic score is defined as being in the 80th to 99th percentile, an intermediate polygenic score as being in the 20th to 79th percentile, and a low polygenic score as being in the 0 to 19th percentile of the population distribution of polygenic scores. (B) Illustration of genomic risk for coronary artery disease by polygenic score category and familial hypercholesterolemia variant carrier status. The arrows and black dots indicate the participants’ genetic risk, and the larger arrows highlight the participants with both high polygenic scores and familial hypercholesterolemia variants. B is partially reproduced from Fahed et al. CAD = coronary artery disease; FH = familial hypercholesterolemia.
Central Illustration
Central Illustration
Combined Monogenic and Polygenic Risk Assessment and Disclosure Can Identify Individuals at High Inherited Risk for Coronary Artery Disease, Encourage Intent to Have a Healthier Lifestyle, and Guide Initiation of Preventive Therapy A clinical test inclusive of both monogenic and polygenic risk for coronary artery disease was returned to participants. Three percent of participants had a monogenic variant pathogenic for familial hypercholesterolemia and 32% had a polygenic score in the top quintile of the population distribution. Participants were also asked to complete 2 surveys, 1 at baseline and 1 following disclosure of genetic test results. In the postdisclosure survey, Participants expressed intent to make positive lifestyle changes. Most participants stated that they learned something valuable about their health. Nearly half of participants without coronary artery disease had a change in management including statin initiation, statin intensification, or coronary imaging following the Disclosure of Results. CAD = coronary artery disease.
Figure 2
Figure 2
Impact of Combined Monogenic and Polygenic Risk Assessment on Clinical Management (N = 42) Figure showing the proportion of participants without coronary artery disease who had a change in clinical management following the disclosure visit. Of the 42 participants without CAD, 17 had a change in management, including changes in pharmacotherapy and diagnostic testing. Of the 26 not on a statin at baseline, 10 (38%) were recommended to initiate statin therapy. Of the 10 on a moderate-intensity statin at baseline, 2 (20%) were recommended to increase their statin dosage. Of the 32 who did not have a coronary imaging scan in the last 5 years, 6 (19%) were recommended to undergo a coronary imaging scan. Percentages are based on the respective eligible population size. The polygenic score range shows the scores of the participants who had the respective intervention proposed. FH = familial hypercholesterolemia.
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Comment in

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