Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. Issue 13 (26th March 2019)

• Record Type: Journal Article
• Authors: Khera, Amit V.; Chaffin, Mark; Zekavat, Seyedeh M.; Collins, Ryan L.; Roselli, Carolina; Natarajan, Pradeep; Lichtman, Judith H.; D'Onofrio, Gail; Mattera, Jennifer; Dreyer, Rachel; Spertus, John A.; Taylor, Kent D.; Psaty, Bruce M.; Rich, Stephen S.; Post, Wendy; Gupta, Namrata; Gabriel, Stacey; Lander, Eric; Ida Chen, Yii-Der; Talkowski, Michael E.; Rotter, Jerome I.; Krumholz, Harlan M.; Kathiresan, Sekar
• Is Part Of: Circulation. Volume 139:Issue 13(2019)
• Publication Date: 2019-03-26
• Subjects: genetics -- humans -- hypercholesterolemia -- myocardial infarction -- risk; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.118.035658
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : Background: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ⩽55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations. Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1–6.8; P <0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1–4.6; P <0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008). Conclusions: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction. Clinical Trial Registration: URL:https://www.clinicaltrials.gov . Unique identifier: NCT00597922. Abstract : Supplemental Digital Content is available in the text.