Chromosome 4q25 Variants Are Genetic Modifiers of Rare Ion Channel Mutations Associated With Familial Atrial Fibrillation

• Published in: Journal of the American College of Cardiology Vol. 60; no. 13; pp. 1173 - 1181
• Main Authors: Ritchie, Marylyn D., Rowan, Shane, Kucera, Gayle, Stubblefield, Tanya, Blair, Marcia, Carter, Shannon, Roden, Dan M., Darbar, Dawood
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 25.09.2012; Elsevier; Elsevier Limited
• Subjects: Adult; Age; Aged; atrial fibrillation; Atrial Fibrillation - genetics; Atrial Natriuretic Factor - genetics; Biological and medical sciences; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Chromosomes; Chromosomes, Human, Pair 4 - genetics; Cohort Studies; Confidence intervals; Genes; Genetic Predisposition to Disease; genetics; Genotype; Genotype & phenotype; Heart; Heart surgery; Homeobox Protein Nkx-2.5; Homeodomain Proteins - genetics; Humans; Ion Channels - genetics; KCNQ1 Potassium Channel - genetics; Kv1.5 Potassium Channel - genetics; Medical sciences; Middle Aged; Mutation - genetics; mutations; NAV1.5 Voltage-Gated Sodium Channel - genetics; Pedigree; Polymorphism, Single Nucleotide - genetics; polymorphisms; Prospective Studies; Registries; Transcription Factors - genetics; atrial fibrillation; genetics; mutations; OR; SNP; AF; DNA; polymorphisms; deoxyribonucleic acid; single nucleotide polymorphism; odds ratio; Arrhythmia; Family study; Heart disease; Atrial fibrillation; Cardiovascular disease; Chromosome; Genetics; Ionic channel; Circulatory system; Mutation; Cardiology; Excitability disorder
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2012.04.030

The aim of this study was to test the hypothesis that 2 common polymorphisms in the chromosome 4q25 region that have been associated with atrial fibrillation (AF) contribute to the variable penetrance of familial AF. Although mutations in ion channels, gap junction proteins, and signaling molecules have been described for Mendelian forms of AF, penetrance is highly variable. Recent studies have consistently identified 2 common single-nucleotide polymorphisms in the chromosome 4q25 region as independent AF susceptibility alleles. Eleven families in which AF was present in ≥2 members who also shared a candidate gene mutation were studied. These mutations were identified in all subjects with familial lone AF (n = 33) as well as apparently unaffected family members (age >50 years with no AF; n = 17). Mutations were identified in SCN5A (n = 6), NPPA (n = 2), KCNQ1 (n = 1), KCNA5 (n = 1), and NKX2.5 (n = 1). In genetic association analyses, unstratified and stratified according to age of onset of AF and unaffected age >50 years, there was a highly statistically significant association between the presence of both common (rs2200733 and rs10033464) and rare variants and AF (unstratified p = 1 × 10−8, stratified [age of onset <50 years and unaffected age >50 years] p = 7.6 × 10−5) (unstratified p < 0.0001, stratified [age of onset <50 years and unaffected age >50 years] p < 0.0001). Genetic association analyses showed that the presence of common 4q25 risk alleles predicted whether carriers of rare mutations developed AF (p = 2.2 × 10−4). Common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with familial AF. These findings support the idea that the genetic architecture of AF is complex and includes both rare and common genetic variants.