title: Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation.
abstract: OBJECTIVE
  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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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)).
  
  
  CONCLUSIONS
  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.
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Marylyn D
authors: MD
authors: Ritchie
authors: Shane
authors: S
authors: Rowan
authors: Gayle
authors: G
authors: Kucera
authors: Tanya
authors: T
authors: Stubblefield
authors: Marcia
authors: M
authors: Blair
authors: Shannon
authors: S
authors: Carter
authors: Dan M
authors: DM
authors: Roden
authors: Dawood
authors: D
authors: Darbar
mesh_terms: D000328:Adult; D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D051666:Kv1.5 Potassium Channel / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012042:Registries; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D007473:Ion Channels; C496981:KCNA5 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D051666:Kv1.5 Potassium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; C095552:NKX2-5 protein, human; C472955:NPPA protein, human; C568320:SCN5A protein, human; D014157:Transcription Factors; D009320:Atrial Natriuretic Factor