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JAMA. 2018 Dec 11;320(22):2354-2364. doi: 10.1001/jama.2018.18179.

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

Author information

1
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
2
Cardiovascular Research Center, Massachusetts General Hospital, Boston.
3
National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham, Massachusetts.
4
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
5
Department of Imaging Science and Innovation, Geisinger, Danville, Pennsylvania.
6
Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
7
Departments of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
8
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
9
Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
10
Divisions of Preventive and Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
11
Departments of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio.
12
Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston.
13
Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle.
14
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
15
Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
16
Department of Bioengineering, School of Pharmacy, University of California, San Francisco.
17
Department of Biostatistics, University of Washington, Seattle.
18
Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor.
19
Department of Molecular and Functional Genomics, Geisinger, Danville, Pennsylvania.
20
Regeneron Genetics Center, Tarrytown, New York.
21
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
22
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle.
23
Departments of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio.
24
Kaiser Permanente Washington Health Research Institute, Seattle, Washington.
25
Department of Health Services, University of Washington, Seattle.
26
Division of Cardiology, Department of Medicine, University of Illinois, Chicago.
27
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
28
Departments of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
29
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
30
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.
31
Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
32
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
33
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston.

Abstract

Importance:

Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood.

Objective:

To perform large-scale whole-genome sequencing to identify genetic variants related to AF.

Design, Setting, and Participants:

The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants).

Exposures:

Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome.

Main Outcomes and Measures:

Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3.

Results:

Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01).

Conclusions and Relevance:

In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

PMID:
30535219
DOI:
10.1001/jama.2018.18179
[Indexed for MEDLINE]

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