Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.
Circulation
; 139(13): 1593-1602, 2019 03 26.
Article
en En
| MEDLINE
| ID: mdl-30586733
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 21 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.Palabras clave
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Genoma Humano
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Predisposición Genética a la Enfermedad
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Herencia Multifactorial
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Hiperlipoproteinemia Tipo II
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Infarto del Miocardio
Tipo de estudio:
Clinical_trials
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Prognostic_studies
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Risk_factors_studies
Límite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2019
Tipo del documento:
Article