A Missense Variant in PLEC Increases Risk of Atrial Fibrillation

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:70

Article

Thorolfsdottir, Rosa B.¹  Sveinbjornsson, Gardar¹  Sulem, Patrick¹  Helgadottir, Anna¹  Gretarsdottir, Solveig¹  Benonisdottir, Stefania¹  Magnusdottir, Audur¹  Davidsson, Olafur B.¹  Rajamani, Sridharan¹  Roden, Dan M.^2,3,4  Darbar, Dawood⁵  Pedersen, Terje R.^6,7  Sabatine, Marc S.^8,9  Jonsdottir, Ingileif^1,10,11  Arnar, David O.^1,10,12  Thorsteinsdottir, Unnur^1,10  Gudbjartsson, Daniel F.^1,13  Holm, Hilma¹  Stefansson, Kari^1,10 

[1] deCODE Genet Amgen Inc, Sturlugata 8, IS-101 Reykjavik, Iceland

[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA

[3] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37235 USA

[5] Univ Illinois, Dept Med, Div Cardiol, Chicago, IL USA

[6] Univ Oslo, Ctr Prevent Med, Oslo Univ Hosp, Oslo, Norway

[7] Univ Oslo, Med Fac, Oslo, Norway

[8] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, Boston, MA 02115 USA

[9] Harvard Med Sch, Boston, MA USA

[10] Univ Iceland, Fac Med, Reykjavik, Iceland

[11] Landspitali Univ Hosp, Dept Immunol, Reykjavik, Iceland

[12] Landspitali Univ Hosp, Dept Med, Reykjavik, Iceland

[13] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

关键词: arrhythmia;    atrial fibrillation;    electrocardiogram;    plectin;   

DOI  :  10.1016/j.jacc.2017.09.005

来源: Elsevier

【 摘 要 】

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 x 10(-18)), and the missense variant p. Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 x 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. (C) 2017 by the American College of Cardiology Foundation.

【 授权许可】

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