Gene Variants Blur Line Between "Lone" AF and Typical AF Presentation

February 23, 2010

February 23, 2010 (New York, New York) A meta-analysis of genome-wide association studies (GWAS) involving patients with "lone" atrial fibrillation (AF) found a significant connection between the arrhythmia typically seen in younger symptomatic patients without apparent structural heart disease and mutations in a gene likely involved in atrial repolarization but not previously linked to AF [1].

The study's authors, led by Dr Patrick T Ellinor (Massachusetts General Hospital, Boston, MA), then prospectively confirmed those correlations between the arrhythmia and variants in the gene KCNN3, encoded for a calcium-activated potassium-channel protein, in several independent lone-AF cohorts and in the more typical AF setting of older patients with heart disease or other known precipitating conditions.

The findings blur the line between lone AF and more common forms of the arrhythmia. They also indicate that the presence of one or more copies of the KCNN3 mutations could potentially influence future risk of the "big three" clinical consequences of AF--heart failure, stroke, and death--or mediate AF responses to drug or ablation therapy, Ellinor told heartwire .

This particular one turns out to be an intriguing candidate because the electrophysiologic and cellular hallmarks of atrial fibrillation are a shortened action-potential duration and calcium overload.

Moreover, given the physiologic function of KCNN3 and the fact that many antiarrhythmic drugs work by modulating ion channels, the KCNN3 variants and their activity could make tempting targets for therapy, he said. "Those are all fairly logical extensions of what we looked at."

Lone-AF clusters in families have been long observed, and they've been connected to specific gene mutations before, Ellinor noted. "We now have three different genetic loci for atrial fibrillation, and in none of these cases have the genes been on anyone's radar screen. This particular one turns out to be an intriguing candidate because the electrophysiologic and cellular hallmarks of atrial fibrillation are a shortened action-potential duration and calcium overload."

The group's research, appearing online February 21, 2010 in Nature Genetics, included a meta-analysis of GWAS encompassing 1,335 people with lone AF and 12,844 unrelated people without AF (documented by ECG). Lone AF was defined as AF onset at <66 years of age with no preceding history of MI, heart failure, or recognized LV systolic dysfunction.

Definitions of lone AF vary, Ellinor observed. In the current analysis, it was "basically young people without overt heart disease. But we did include people with hypertension, which I think some people would object to." It was done "because of the high lifetime risk of hypertension and also to maximize the power of our study," the report states.

"So we went to great lengths to ensure that the various SNPs [single-nucleotide polymorphisms] we identified were not associated with hypertension by themselves," Ellinor said.

It's just a diagnosis of exclusion. And as people keep identifying new risk factors, such as obesity, alcohol use, and exercise, it's hard to find people who don't have any of these things.

The lone-AF cases and controls consisted of genotyped patients in the German Competence Network on Atrial Fibrillation (AFNET, a large registry of patients with early-onset AF, according to Ellinor), the Heart and Vascular Health (HVH) study, the Atherosclerosis Risk in Communities (ARIC) study, the Framingham Heart Study, and other sources.

In addition to confirming previous associations between AF and a locus on chromosome 4q25, the current analysis identified six SNPs on chromosome 1q21 with significant relations to lone AF. The most significant SNP was rs13376333 in KCNN3, with an odds ratio (OR) of 1.56 (95% CI, 1.38-1.77), according to the group.

They then prospectively replicated their findings for the 1q21 locus in two lone-AF populations. In analyses of 977 cases from the AFNET, who were not included in the previous meta-analysis, and 3042 controls without AF from a Cooperative Health Research in the Region of Augsburg (KORA) cohort, rs13376333 was related to lone AF at an OR of 1.45 (95% CI, 1.26-1.66). Then, in 187 patients with lone AF and 565 controls without AF in the Vanderbilt University Lone AF Registry, the OR was 1.55 (95% CI, 1.19-2.03). All associations were significant at p<0.001.

There was also a relation between rs13376333 and "the more typical forms of AF observed in the community," although, importantly, less of a relation than was seen in the lone-AF groups, in an analysis based on patients from the Age, Gene, Environment Susceptibility Study (AGES). The OR was 1.13 (95% CI, 1.04-1.24; p=0.006).

In the end, the genetic determinants are all there in both populations, but with different strengths, depending on age and other comorbidities people have.

"We saw that it was associated with these more typical forms, but with a much weaker effect," Ellinor said. "That's something we've seen across these genome-wide association studies--many of the same genes are involved but they might be weaker in the older individuals and stronger in the younger individuals."

At the study's outset, according to Ellinor, "we weren't really sure whether or not these were two separate conditions. Certainly the people we see getting ablations are young, they're symptomatic, and their AF often arises from the pulmonary veins. We don't know if they're the same as the 75-year-old who shows up with asymptomatic AF."

In the end, he said, "I think the genetic determinants are all there in both populations, but with different strengths, depending on age and other comorbidities people have."

As to the value of a diagnosis of lone AF, if both can have the genetic underpinnings, Ellinor observed that "it's just a diagnosis of exclusion. And as people keep identifying new risk factors, such as obesity, alcohol use, and exercise, it's hard to find people who don't have any of these things."

But, he said, "it's still useful to me as an electrophysiologist, because the younger and healthier a person is, the more likely they are to have AF that arises from a pulmonary-vein source, and they're more likely to have a successful ablation therapy."

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....