Icelandic researchers ID genetic variant that increases risk of AFib

Icelandic researchers have uncovered two novel genetic variants of atrial fibrillation (AFib), one of which could increase the risk of developing AFib for susceptible patients.

Kari Stefansson, MD, PhD, and colleagues detailed their recent findings in the Journal of the American College of Cardiology. They launched the study following the relatively new discovery of variants in the sarcomere genes MYH6 and MYL4, which are involved in maintaining myocardial structure. The variants identified in this study—known as rs72700114 and p.Gly4098Ser—possess similar traits. In particular, the latter variant, which is found in the gene PLEC, was identified as a low-frequency missense variant that encodes plectin, a cytoskeletal cross-linking protein that’s partially responsible for the integrity of cardiac tissue.

The other novel variant, rs72700114, is a common intergenic variant that can be found on the chromosome 1q24.

Stefansson and co-authors wrote that in addition to uncovering the two new variants, they confirmed 29 variants which had been previously reported.

“Of the 31 variants we assessed, 29 are in noncoding regions,” the authors wrote. “For most, the genes and molecular mechanisms linking these noncoding variants to risk of AFib have not been established. However, many of them are located in or close to genes with a known role in cardiovascular function or development, giving rise to theories on how they affect AFib risk.”

Many of these rare sequence variants have been found in familial AFib, including coding variants in ion channels, signaling molecules, structural proteins and transcription factors, according to Stefansson et al’s research. While these variants provide insight into the inner workings of AFib, they only explain a sliver of arrhythmia cases.

The researchers used data from 14,255 AFib patients who were treated for the condition at Iceland’s two largest hospitals between 1987 and 2015. They contrasted the results of tests in the study cohort with those of a control group of 374,939 Icelanders recruited through genetic research projects across the country.

Stefansson and colleagues focused on whole-genome sequencing and testing for AFib variants in the patients, looking for associations between variants and related phenotypes like sick sinus syndrome and ischemic stroke. After testing around 32.5 million sequence variants for AFib associations, resulting variants were then tested for associations with electrocardiogram traits.

The scientists found p.Gly4098Ser to be a predictor of increased AFib risk in patients who carry the variant.

David J. Milan, MD, wrote in an accompanying JACC editorial that Stefansson and co-authors’ findings are so interesting in part because the p.Gly4098Ser variant lies in the coding region of PLEC, which was “previously unsuspected in AFib.”

“In this case, the genetic variant results in a change in the protein composition of plectin,” he wrote. “The implication is that the genetic signal is also the mechanistic link to the disease.”

Milan noted that genome-wide association studies like this one have recently received criticism questioning the ability of the trials to find useful disease links. Indeed, Milan wrote, the PLEC variant “is found in so few people and increases risk in a modest enough fashion that genetic testing for this allele is unlikely to be clinically valuable.”

Still, he said, he thinks these studies are well worth the effort.

“These findings reinforce clinical observations that cardiac structure and function are important in AFib pathogenesis,” he wrote. “Whether as primary myopathy or as a response to hemodynamic stresses, the concept that variants in structural/functional proteins would be important in AFib is intuitive and now has a greater grounding in genetic data. These observations provide a better understanding of pathogenesis and perhaps more importantly the complexities of AFib genetics and mechanisms.”