Chromosome 4q25 Variants Are Genetic Modifiers of Rare Ion Channel

Study Questions:

What is the contribution of two common polymorphisms in the chromosome 4q25 region to the variable penetrance of familial atrial fibrillation (AF)?

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:

The authors concluded that common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with familial AF.

Perspective:

This study suggests that two common AF-associated polymorphisms act as genetic modifiers of the clinical expression of latent cardiac ion channel and signaling gene mutations associated with familial AF. Furthermore, it supports the idea that AF inheritance is complex and non-Mendelian and common variants may act as significant modifiers of the effects of rare variants, and that the genetic architecture of common human phenotypes includes both rare and common variants. Given that the risks of misinterpretation are high and the therapeutic value is quite low for genetic testing for AF at this time, larger studies demonstrating clear utility are indicated prior to consideration in routine clinical practice.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, EP Basic Science, Lipid Metabolism

Keywords: Mutation, Polymorphism, Genetic, Family, Ion Channels, Chromosomes


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