What you carry at this position in your DNA and what research says about it.
Atrial Fibrillation Risk: 10/10 evidence, 18 publications.
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Sample genotype (not yours): C/C
Typical Atrial Fibrillation Risk
Carrying two copies of the common C allele is associated with a baseline risk of developing atrial fibrillation. This genotype does not carry the risk-elevating T allele.
What this genotype means: Typical baseline risk for atrial fibrillation; Lower risk of cardioembolic stroke compared to T carriers.
Sample genotype (not yours): C/T
Increased Atrial Fibrillation Risk
Carrying one copy of the T allele is associated with a moderately higher risk of developing atrial fibrillation. This variant can affect the heart's electrical pathways and increase susceptibility to irregular heartbeats.
What this genotype means: Moderately increased risk of atrial fibrillation; Slightly higher susceptibility to cardioembolic stroke.
Sample genotype (not yours): T/T
Elevated Atrial Fibrillation Risk
Carrying two copies of the T allele is associated with the highest genetic risk of developing atrial fibrillation at this locus. This genotype is strongly linked to irregular heart rhythms and related cardiovascular complications.
What this genotype means: Highest genetic risk of atrial fibrillation at this locus; Elevated risk of cardioembolic stroke.
Gene function and biological role
Gene Function: The ZFHX3 gene encodes zinc finger homeobox 3, a large transcription factor that plays a critical role in regulating gene expression [1]. It is highly expressed in cardiac tissues and is essential for normal heart development and electrical signaling [2]. ZFHX3 also acts as a key regulator of inflammatory pathways and cellular growth [3]. Alterations in its expression or function can disrupt the heart's electrical stability, making it a major focus in cardiovascular genetics [1].
Variant Impact: The rs2106261 variant is an intronic change located within the ZFHX3 gene on chromosome 16 [1]. Although it does not alter the protein sequence directly, it is thought to influence how the gene is transcribed and expressed in cardiac cells [2]. This specific genetic change is one of the most well-replicated markers associated with heart rhythm variations across diverse global populations [4]. By modulating ZFHX3 activity, it alters susceptibility to abnormal electrical activity in the upper chambers of the heart [1].
Key Insight: Although the T allele increases the risk of developing atrial fibrillation, carriers of this variant actually show a lower rate of arrhythmia recurrence after undergoing catheter ablation therapy.
Location: ZFHX3. Chromosome 16 · 16q22.3 · 73.0 Mb
Estimated prevalence by population
Global 62.5%; European 68.2%; African 54.9%; East Asian 46.9%; South Asian 58.8%; Americas 62.7%; Ashkenazi 74.4%; Finnish 58.7%; Middle Eastern 77.0%; Amish 66.1%.
Estimated CC genotype frequency.
Global 32.9%; European 28.8%; African 38.4%; East Asian 43.2%; South Asian 35.7%; Americas 33.0%; Ashkenazi 23.7%; Finnish 35.9%; Middle Eastern 21.5%; Amish 30.4%.
Estimated CT genotype frequency.
Global 4.6%; European 3.0%; African 6.7%; East Asian 9.9%; South Asian 5.4%; Americas 4.3%; Ashkenazi 1.9%; Finnish 5.5%; Middle Eastern 1.5%; Amish 3.5%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Cardiovascular & Metabolic
Heart Rhythm & Conduction
Atrial Fibrillation. Evidence: 10/10. Source: PMID 19597492. Typical Risk.
Cardiac Arrhythmia. Evidence: 6/10. Source: PMID 39024449. Typical Risk.
Stroke
Cardioembolic Stroke. Evidence: 8/10. Source: PMID 35872910. Typical Risk.
Coagulation & Clotting
Prothrombin Time. Evidence: 6/10. Source: PMID 39024449. Typical.
Showing effects for C/T genotype
Atrial Fibrillation. Evidence: 10/10. Source: PMID 19597492. ~1.24x Risk.
Cardiac Arrhythmia. Evidence: 6/10. Source: PMID 39024449. Increased Risk.
Cardioembolic Stroke. Evidence: 8/10. Source: PMID 35872910. Increased Risk.
Prothrombin Time. Evidence: 6/10. Source: PMID 39024449. Slightly Longer.
Showing effects for T/T genotype
Atrial Fibrillation. Evidence: 10/10. Source: PMID 19597492. Elevated Risk.
Cardiac Arrhythmia. Evidence: 6/10. Source: PMID 39024449. Elevated Risk.
Cardioembolic Stroke. Evidence: 8/10. Source: PMID 35872910. Elevated Risk.
Prothrombin Time. Evidence: 6/10. Source: PMID 39024449. Longer.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Maintaining two copies of the common C allele represents the baseline genetic profile for heart rhythm stability at this locus [1]. Large-scale genomic studies show that this genotype is associated with a lower risk of developing atrial fibrillation compared to carrying the T allele [2]. It is also linked to a lower risk of cardioembolic stroke, a serious complication often triggered by untreated irregular heartbeats [3]. Normal cardiac electrical conduction and typical prothrombin times are commonly observed with this genetic profile [4]. While this genotype is protective against developing arrhythmias, some clinical studies suggest that if atrial fibrillation does occur, patients with this profile might have a slightly higher rate of recurrence after certain ablation procedures compared to T allele carriers [5]. This difference is thought to be driven by variations in post-procedure inflammatory responses regulated by the ZFHX3 gene [5]. Overall, this genotype represents the standard, lower-risk baseline for general heart rhythm health [1]. Having this baseline profile means that standard lifestyle measures for heart health remain highly effective [2].
Typical baseline risk for atrial fibrillation; Lower risk of cardioembolic stroke compared to T carriers.
Sample genotype: CT (Heterozygous)
Inheriting one copy of the T allele is associated with a moderately increased risk of developing atrial fibrillation [1]. This genetic variation is thought to alter the expression of the ZFHX3 transcription factor, which can disrupt normal electrical signaling in the heart's upper chambers [2]. Clinical data indicate that carriers of this single risk allele have a higher likelihood of experiencing cardiac arrhythmias [3]. This elevation in arrhythmia risk also correlates with an increased susceptibility to cardioembolic stroke, as irregular heartbeats can promote blood clot formation [4]. Additionally, research has linked this variant to subtle differences in prothrombin time, a measure of how quickly blood clots [3]. Interestingly, some studies of patients undergoing catheter ablation for atrial fibrillation show that T allele carriers may experience lower recurrence rates post-procedure [5]. This potential benefit is hypothesized to stem from lower baseline inflammation levels associated with the T allele [5]. Despite this specific procedural nuance, the primary health impact remains an elevated baseline risk for developing heart rhythm disorders [1]. Monitoring heart health and discussing cardiovascular risk factors with a healthcare provider can be beneficial [1].
Moderately increased risk of atrial fibrillation; Slightly higher susceptibility to cardioembolic stroke.
Sample genotype: TT (Homozygous)
Possessing two copies of the T allele is associated with the highest genetic susceptibility to atrial fibrillation at this locus [1]. Multiple international studies have confirmed that this genotype significantly increases the risk of developing irregular heart rhythms [2]. The double dose of the risk allele is believed to impact ZFHX3 expression in cardiac tissue, leading to electrical instability in the atria [3]. Consequently, this genotype is also linked to an increased risk of cardioembolic stroke, which can occur when irregular heartbeats lead to blood clots [4]. Furthermore, genetic analyses show an association with altered prothrombin times, reflecting potential changes in coagulation pathways [5]. In the context of medical interventions, some clinical trials have observed that T/T homozygotes have a lower rate of arrhythmia recurrence after undergoing pulmonary vein isolation [6]. This clinical observation is linked to lower post-procedure inflammation levels in carriers of the minor allele [6]. However, the overriding clinical significance of this genotype is the heightened risk of developing atrial fibrillation and its associated cardiovascular challenges [1]. Proactive management of other cardiovascular risk factors, such as blood pressure and cholesterol, is particularly important for individuals with this genetic profile [2].
Highest genetic risk of atrial fibrillation at this locus; Elevated risk of cardioembolic stroke.
Variants with shared genetic architecture
rs7193343 · ZFHX3 Gene · Chr 16 · Atrial Fibrillation Risk
rs883079 · TBX5 Gene · Chr 12 · Atrial Fibrillation Risk
rs10033464 · Chr 4 · Atrial Fibrillation Risk
Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
Meta-analysis identifies six new susceptibility loci for atrial fibrillation.
Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
Content updated August 2026.
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