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J Am Coll Cardiol. 2017 Oct 24;70(17):2157-2168. doi: 10.1016/j.jacc.2017.09.005.

A Missense Variant in PLEC Increases Risk of Atrial Fibrillation.

Author information

1
deCODE genetics/Amgen, Inc., Reykjavik, Iceland. Electronic address: rosath@decode.is.
2
deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
3
Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
4
Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
5
Center For Preventive Medicine, Oslo University Hospital and Medical Faculty, University of Oslo, Oslo, Norway.
6
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
7
deCODE genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Immunology, Landspitali University Hospital, Reykjavik, Iceland.
8
deCODE genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.
9
deCODE genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
10
deCODE genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
11
deCODE genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. Electronic address: kstefans@decode.is.

Abstract

BACKGROUND:

Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4.

OBJECTIVES:

The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements.

METHODS:

The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals.

RESULTS:

The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10-18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10-10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive.

CONCLUSIONS:

The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.

KEYWORDS:

arrhythmia; atrial fibrillation; electrocardiogram; plectin

PMID:
29050564
PMCID:
PMC5704994
DOI:
10.1016/j.jacc.2017.09.005
[Indexed for MEDLINE]
Free PMC Article

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