Chromosome 4q25 Variants Are Genetic Modifiers of Rare Ion Channel Mutations Associated With Familial Atrial Fibrillation
Key result
Common chromosome 4q25 variants linked to increased AF risk in rare cardiac mutation carriers.
- P 2.2×10−4
- n=50
Why the study?
Penetrance of familial atrial fibrillation caused by ion channel and signaling molecule mutations is highly variable, and the role of common 4q25 polymorphisms as modifiers was unclear.
Do common chromosome 4q25 polymorphisms modify the penetrance and clinical expression of atrial fibrillation in carriers of rare familial ion channel mutations?
Key Points
- To test whether two common chromosome 4q25 single nucleotide polymorphisms contribute to the variable penetrance of rare mutations associated with familial atrial fibrillation.
- Evaluated 11 families exhibiting atrial fibrillation in 2 or more individuals who shared a candidate gene mutation.
- Analyzed genetic data from 33 affected individuals with familial lone atrial fibrillation and 17 unaffected mutation carriers aged older than 50 years.
- Performed unstratified and stratified genetic association analyses evaluating common variants (rs2200733 and rs10033464) alongside rare mutations in cardiac genes.
- Identified rare mutations across 11 families in SCN5A (n=6), NPPA (n=2), KCNQ1 (n=1), KCNA5 (n=1), and NKX2.5 (n=1).
- Observed a significant association between atrial fibrillation and the presence of both common (rs2200733, rs10033464) and rare variants in unstratified (P = 1×10⁻⁸ and P < 0.0001) and age-stratified analyses (P = 7.6×10⁻⁵ and P < 0.0001).
- Demonstrated that common 4q25 risk alleles predicted whether carriers of rare mutations developed atrial fibrillation (P = 2.2×10⁻⁴).
Study Design
Type
Observational (n=50)
Structured PICO
Do common chromosome 4q25 polymorphisms modify the penetrance and clinical expression of atrial fibrillation in carriers of rare familial ion channel mutations?
P
Population
50 subjects from 11 families with shared candidate gene mutations, including 33 with familial lone AF and 17 unaffected family members over age 50.
E
Exposure
Presence of common chromosome 4q25 polymorphisms (single nucleotide polymorphisms rs2200733, rs10033464)
C
Comparator
Absence of the common chromosome 4q25 risk alleles
O
Outcome
Development (clinical expression) of atrial fibrillation
Main Result
p-value: p=2.2×10−4
Common genetic variants at chromosome 4q25 modify the penetrance of rare familial ion channel mutations, explaining the variable clinical expression of atrial fibrillation in affected families.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“One reasonable view is that "genetic background," captured by single-nucleotide variants (SNVs) across multiple susceptibility pathways, can itself predispose to AF or modulate penetrance of rarer high-effect size variants captured by family studies”
Implication
4q25 alleles were associated with AF penetrance in rare-mutation carriers; hypothesis-generating and should not yet change genetic counseling or testing.
Abstract
Objectives This study tested the hypothesis that two 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 (SNPs) in the chromosome 4q25 region as independent AF susceptibility alleles. Methods We studied 11 families in which AF was present in ≥2 individuals who also shared a candidate gene mutation. These mutations were identified in all subjects with familial lone AF (n=33) as well as apparently unaffected family members (age >50 yrs 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, un-stratified and stratified according to age of onset of AF and unaffected age > 50 yrs, there was a highly statistically significant association between the presence of both common (rs2200733, rs10033464) as well as rare variants and AF (un-stratified P=1×10−8; stratified [age of onset <50 yrs and unaffected age >50 yrs], P=7.6×10−5) (un-stratified P<0.0001; stratified [age of onset <50 yrs and unaffected age >50 yrs], 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.
Discussion
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Cite This Study
Ritchie et al. (2012) conducted an observational in Familial Atrial Fibrillation (n=50). Common chromosome 4q25 polymorphisms (rs2200733, rs10033464) vs. Absence of risk alleles was evaluated on Development of atrial fibrillation in carriers of rare mutations (p=2.2×10−4). The presence of common chromosome 4q25 risk alleles significantly predicted the development of atrial fibrillation in carriers of rare cardiac gene mutations (P=2.2x10-4).