Genetics of Atrial Fibrillation

Large Families With Atrial Fibrillation Are Rare, But Informative

Early attempts to identify the genetic basis of AF used classic linkage analysis to identify monogenic disease loci in families. Linkage analysis relies on the fact that genetic recombination during meiosis shuffles regions of the genome. Assessing genetic markers at known locations of the genome can help determine which loci transmit along with disease.

The first genetic locus for AF was described in 1997 by Brugada and associates who identified an AF susceptibility region on chromosome 10 in a large family with autosomal dominant AF ( Table 47.1 ). Since this initial report, linkage analysis has occasionally been used to identify genetic mutations underlying AF in a number of large families with AF.

Chen and colleagues narrowed an AF susceptibility locus to a region on chromosome 11p15 in a family with autosomal dominant AF spanning four generations. The investigators extended their analysis by sequencing KCNQ1, a candidate gene in the region that encodes a potassium channel α-subunit. In the first transmembrane segment of the channel they discovered a highly conserved serine residue that was mutated to a glycine in all affected family members. Subsequent characterization revealed that the mutant protein increases the repolarizing I _Ks current density when expressed with the KCNE1 subunit. This gain-of-function mutation is expected to result in shortened atrial refractory periods, thereby promoting reentry, a well-founded mechanism underlying AF. Our group led by Das and coworkers used a similar approach to map a mutation in the third transmembrane domain of KCNQ1. The S209P variant demonstrated a similar gain-of-function effect again implicating KCNQ1 as a disease susceptibility gene for AF.

Linkage analysis also has identified mutations in SCN5A that segregate with AF, conduction abnormalities, cardiomyopathy, and possibly early-onset ischemic stroke. SCN5A encodes a sodium channel α-subunit responsible for the depolarizing I _Na current. The D1275N mutation that results in an aspartic acid for asparagine substitution was independently identified by different investigators, and associates with atrial standstill when cosegregating with connexin40 ( GJA5 ) mutations.

In another large multigenerational family with AF, Hodgson-Zingman and colleagues mapped a frameshift mutation to NPPA, which encodes atrial natriuretic peptide. The 2-bp deletion eliminates a stop codon and results in an additional 12 amino acids at the carboxy terminus of the mature 28-residue long ANP protein. Ex vivo rabbit hearts bathed in the mutant peptide demonstrated significantly shortened atrial effective refractory periods compared with those bathed with a wild-type atrial natriuretic peptide, again consistent with reentry as a pathogenic model for AF.

In aggregate, linkage analysis has implicated potassium ( KCNQ1 ^, and KCNJ3 ) and sodium ( SCN5A ) channel mutations, a nuclear envelope protein ( NUP155 ^, ), NPPA, and loci on chromosomes 6 and 10. ^, However, the large multigenerational families needed for linkage analysis remain rare. More often AF is observed in smaller families; thus is it is often hard to establish the causality of apparently disease-causing mutations with such limited genetic information.