Common Variants in KCNN3 are Associated with Lone Atrial Fibrillation

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Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. A subset of patients with lone AF have no overt heart disease and an increased heritability of AF. We sought to identify common genetic variants underlying lone AF. Cases were from the German AF Network, Heart and Vascular Health Study, Atherosclerosis Risk in Communities Study, Cleveland Clinic, and Massachusetts General Hospital. Subjects were genotyped, HapMap SNPs imputed, and age- sex- and hypertension-adjusted analyses performed. A meta-analysis was conducted using 1,335 cases of lone AF and 12,844 referents. A novel locus on chromosome 1q21 was identified, and the most significant SNP, rs13376333, had an adjusted odds ratio of 1.56 ( P=6.3×10 ⁻¹²). This association was replicated in two cohorts with lone AF for an overall odds ratio of 1.52 ( P=1.83×10 ⁻²¹). Rs13376333 is intronic to KCNN3, a potassium channel involved in atrial repolarization. KCNN3 represents a novel potential therapeutic target in the treatment of AF.

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Most cited references 26

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The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.

Greta Splansky, Diane Corey, Qiong Yang … (2007)

For nearly 60 years, the Framingham Heart Study has examined the natural history, risk factors, and prognosis of cardiovascular, lung, and other diseases. Recruitment of the Original Cohort began in 1948. Twenty-three years later, 3,548 children of the Original Cohort, along with 1,576 of their spouses, enrolled in the Offspring Cohort. Beginning in 2002, 4,095 adults having at least one parent in the Offspring Cohort enrolled in the Third Generation Cohort, along with 103 parents of Third Generation Cohort participants who were not previously enrolled in the Offspring Cohort. The objective of new recruitment was to complement phenotypic and genotypic information obtained from prior generations, with priority assigned to larger families. From a pool of 6,553 eligible individuals, 1,912 men and 2,183 women consented and attended the first examination (mean age: 40 (standard deviation: 9) years; range: 19-72 years). The examination included clinical and laboratory assessments of vascular risk factors and imaging for subclinical atherosclerosis, as well as assessment of cardiac structure and function. The comparison of Third Generation Cohort data with measures previously collected from the first two generations will facilitate investigations of genetic and environmental risk factors for subclinical and overt diseases, with a focus on cardiovascular and lung disorders.

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An investigation of coronary heart disease in families. The Framingham offspring study.

W Kannel, M Feinleib, P McNamara … (1979)

The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.

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Variants conferring risk of atrial fibrillation on chromosome 4q25.

Daniel Fannar Gudbjartsson, David O Arnar, Anna Helgadottir … (2007)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 15 March 2010

Publication date (Electronic): 21 February 2010

Publication date (Print): March 2010

Publication date PMC-release: 1 September 2010

Volume: 42

Issue: 3

Pages: 240-244

Affiliations

[1 ]Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA

[2 ]Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA

[3 ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA

[4 ]Department of Biostatistics, School of Public Health, Boston University, Boston, MA

[5 ]National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA

[6 ]Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA

[7 ]Institute of Human Genetics, Klinikum Rrchts der Isar Technische Universität München, Munich, Germany

[8 ]Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany

[9 ]Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN

[10 ]Department of Cardiovascular Medicine, Heart and Vascular Institute, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH

[11 ]Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany

[12 ]Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

[13 ]Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA

[14 ]Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

[15 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

[16 ]Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA

[17 ]Department of Medicine, University of Mississippi Medical Center, Jackson, MS

[18 ]Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN

[19 ]Department of Epidemiology, University of Washington, Seattle, WA

[20 ]Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington

[21 ]Department of Cell Biology, Lerner Research Institute, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH

[22 ]Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston Salem, NC

[23 ]Department of Biostatistics, University of Washington, Seattle, WA

[24 ]Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

[25 ]Dutch Medicines Evaluation Board, The Hague, The Netherlands

[26 ]Netherlands Consortium on Healthy Aging (NCHA) Leiden, The Netherlands

[27 ]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

[28 ]Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA

[29 ]Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH

[30 ]Icelandic Heart Association, Kópavogur, Iceland

[31 ]University of Iceland, Reykjavik, Iceland

[32 ]Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD

[33 ]Estonian Biocenter, Genotyping Core Facility, Tartu, Estonia

[34 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

[35 ]Institute for Biological and Medical Imaging, Helmholtz Zentrum München, Germany

[36 ]German Research Center for Environmental Health, Neuherberg, Germany

[37 ]Estonian Genome Center, University of Tartu, Tartu, Estonia

[38 ]Department of Epidemiology, Johns Hopkins University, Baltimore, MD

[39 ]Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany

[40 ]Cardiology Division, Massachusetts General Hospital, Boston, MA

[41 ]Department of Cardiology, West German Heart Center Essen, University Duisburg-Essen, Essen, Germany

[42 ]Departments of Medicine, Preventive Medicine and Cardiology sections, Boston University School of Medicine

[43 ]Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center Bonn, D-53127 Bonn

[44 ]Cardiovascular Division, Brigham and Woman's Hospital, Boston, MA

[45 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

[46 ]Inspectorate for Health Care, The Hague, The Netherlands

[47 ]Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands

[48 ]Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, MD

[49 ]University of Texas Health Science Center at Houston, Human Genetics Center and Institute for Molecular Medicine, Houston, TX

[50 ]Scripps Translational Science Institute, The Scripps Research Institute, Scripps Health, La Jolla, CA

[51 ]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

[52 ]Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, and Group Health Research Institute, Group Health, Seattle, WA

[53 ]Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

[54 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

[55 ]Klinikum Grosshadern, Munich, Germany

[56 ]Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH

[57 ]Department of Epidemiology, School of Public Health, Boston University, Boston, MA

[58 ]Cardiology and Preventive Medicine Division, Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA

[59 ]Department of Epidemiology, University of Washington, and Group Health Research Institute, Group Health, Seattle, WA

Author notes

[60]

These authors contributed equally to the manuscript.

Current address: Cardiology Center, Geneva University Hospital, Geneva, Switzerland

Corresponding Authors:Patrick T. Ellinor, MD, PhD, Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA; Phone 617-724-8729, FAX: 617-726-5806, pellinor@ 123456partners.org

Stefan Kääb, MD, PhD, LMU München, Klinikum Großhadern, Department of Medicine I, 81366 München, Germany; Phone: +49-89-70-95-6049, FAX: +49-89-7095-6076 Stefan.Kaab@ 123456med.uni-muenchen.de .

Article

Manuscript ID: nihpa172759

DOI: 10.1038/ng.537

PMC ID: 2871387

PubMed ID: 20173747

SO-VID: 7561a62f-7317-458b-8200-37d1a8463b39

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Funded by: National Institute on Aging : NIA

Funded by: National Center for Research Resources : NCRR

Funded by: National Human Genome Research Institute : NHGRI

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Common Variants in KCNN3 are Associated with Lone Atrial Fibrillation

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The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.

An investigation of coronary heart disease in families. The Framingham offspring study.

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