Second common genetic variant in AF identified

Friday, July 17, 2009

by Marlene Busko

Reykjavik, Iceland - Researchers report that a new genetic variant—in the ZFHX3 gene—is linked with an increased risk of atrial fibrillation (AF) in people of European ancestry [1].

More than one-third of individuals of European ancestry carry one copy of the newly identified variant in the ZFHX3 gene, and they have about a 20% greater risk of AF and cardioembolic stroke than individuals without this variant.

Previously, the researchers, led by Dr Daniel F Gudbjartsson (deCODE Genetics, Reykjavik, Iceland), identified that sequence variants on chromosome 4q25 near gene PITX2 confer risk of AF, which was confirmed by others.

"As with our 4q25 variant, this latest discovery has been replicated in numerous populations by us and others, and the connection to cardioembolic stroke is yet further evidence that we are putting our finger on an important pathway involved in AF and stroke risk," author Dr Kari Stefansson, deCODE CEO, said in a press release.

The study is published online July 14, 2009 in Nature Genetics.

Pathway in AF and stroke

AF accounts for 10% to 15% of all ischemic strokes and is a major risk for cardioembolic stroke, the group writes. Their initial study in Iceland showed that sequence variants on chromosome 4q25 close to the PITX2 gene, a gene critical for heart development, are linked to risk of AF.

To search for more gene variants associated with AF, they first genotyped samples from many more patients with AF or atrial flutter and control individuals in Iceland.

After testing hundreds of thousands of single-nucleotide polymorphisms (SNPs) for an association with AF or atrial flutter, they identified three SNPs outside the 4q25 region, which were not previously associated with AF.

The researchers then performed genotyping of the three SNPs in case-control cohorts of people with European ancestry from Iceland, Norway, and the US. A variant in the ZFHX3 gene on chromosome 16222, rs7193343-T, emerged as being significantly associated with AF (odds ratio [OR] 1.21).

This variant was also associated with a nonsignificant increased risk for atrial flutter.

In the Icelandic sample set, presence of the ZFHX3 gene variant did not correlate with obesity, hypertension, or CAD. "This suggests that the association between rs7193343 and AF is not mediated through these known risk factors for AF," the authors write.

Presence of this genetic variant in a Han Chinese population from Hong Kong—a population where this variant is more frequently found—was not linked with increased risk of AF.

In five cohorts of stroke patients and controls—from Iceland, western Germany, southern Germany, Sweden, and the UK—the ZFHX3 gene variant was significantly associated with ischemic stroke (OR 1.11) and especially cardioembolic stroke (OR 1.22).

These research findings will be integrated into the company's DNA-based risk-assessment test for AF, Stefansson said.

Important finding

In a comment to heartwire, Dr Eric J Topol (Scripps Translational Science Institute, La Jolla, CA) said that this is "certainly an important finding—only the second common gene variant that is a susceptibility marker for atrial fibrillation."

The presence of the ZFHX3 gene variant is common, although it does not predict nearly as high an increased risk of AF as the presence of the variant near the PITX2 gene, he noted. Interestingly, as the investigators also point out, both genes may work via the same pathway, Topol added.

"At the moment, these markers [could] be useful to identify patients who are at risk for AF, such as patients with cryptogenic stroke . . . but the lag before such new data get incorporated into practice is unfortunately much longer than it need be," he said.

Cryptogenic stroke due to undiagnosed AF

Dr Jeffrey Gulcher, deCODE chief scientific officer and study author, told heartwire that the magnitude of the increased risk for AF conferred by the new variant on 16q22 is lower than for the two variants on chromosome 4q25: 20% vs 72% and 39% for individuals who carry one copy of these variants and double that for individuals who carry two copies of these variants. The three markers confer independent, additive risk.

The deCODE test, which uses a blood or cheek-swab sample, detects the markers with an accuracy of 99.9% he said. ECG or cardiac monitoring is then required to make a diagnosis of AF.

"AF is widely underdiagnosed, even in patients who have had a recent ischemic stroke," he added. A multicenter study by deCODE researchers published in 2008 in Annals of Neurology estimated that as much as 30% of cryptogenic stroke and 25% of carotid stroke are really due to undiagnosed AF. Patients found to have intermittent AF may benefit from warfarin for prevention of another stroke rather than remaining on an antiplatelet agent, which has little effect on risk of AF-related strokes, Gulcher said.


  1. Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009: DOI:10.1038/ng.417. Available at:


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