1. Whole Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized with Early-Onset Myocardial Infarction
- Author
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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, and Kathiresan, Sekar
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Health Sciences ,Clinical Sciences ,Sports Science and Exercise ,Genetics ,Clinical Research ,Atherosclerosis ,Human Genome ,Prevention ,Digestive Diseases ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Aged ,Cholesterol ,LDL ,Female ,Genetic Predisposition to Disease ,Genome ,Human ,Humans ,Hyperlipoproteinemia Type II ,Male ,Middle Aged ,Multifactorial Inheritance ,Myocardial Infarction ,Whole Genome Sequencing ,genetics ,humans ,hypercholesterolemia ,myocardial infarction ,risk ,Cardiorespiratory Medicine and Haematology ,Public Health and Health Services ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences ,Sports science and exercise - Abstract
BackgroundThe 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.MethodsWe 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.ResultsThe 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; P3-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 registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.
- Published
- 2019