Science
Overview of Atrial Fibrillation
Atrial fibrillation (AF) is the most common significant cardiac arrhythmia affecting nearly 3 million Americans. It leads to an increased risk of stroke, congestive heart failure and death. Although most AF is associated with other cardiovascular conditions, 10-30% of patients have isolated or lone AF. Despite the broad socioeconomic impact of AF, relatively little is understood about the molecular mechanisms leading to the arrhythmia.
In recent years we have learned that AF is a heritable condition. Using both families and populations with AF, we and others have identified a number of genes and genetic loci have been implicated in the pathogenesis of AF. The overall goal of our current laboratory work is to use our genetic findings as a basis to develop a greater understanding of the molecular pathways involved in AF.
Laboratory Projects
How do genetic loci identified in genome wide association studies lead to AF?
As a part of the AFGen consortium (below), we have identified multiple genetic loci associated with AF. A large part of our laboratory work is focused on trying to determine the mechanism through which variation in a SNP identified in a GWAS (genome wide association study) leads to AF. We have used a multi-faceted approach including human genetics, assays in cell lines and animal model work in zebrafish and mice. Examples of ongoing projects include:
- Fine mapping genetic loci for AF
- Assessing CNV at AF loci
- Deep resequencing of AF loci to identify rare pathologic variants associated with AF
- Performing GEI analyses
- Screening for enhancers of PITX2 function at the 4q25 locus for AF
- Evaluating mouse lines with gain and loss of function of KCNN3
What can we learn from families with AF? 
Families with AF present a unique opportunity to identify novel genes for AF. As a part of the MGH AF Study (below) we have been collecting families with AF both in the local Boston region and throughout the world. Figure 2 illustrates one family in which we identified and characterized a mutation in the cardiac potassium channel, KCNQ1. We are currently evaluating nearly a dozen large families with autosomal dominant AF. We are using a combination of linkage analysis and exome sequencing to identify the causatives genes for AF.
What if I have a family history of AF?
We welcome families with an extensive history of atrial fibrillation to participate in the study (generally 5 or more people in a family with atrial fibrillation). If you are a patient with any of these conditions and you would like to learn more about our work please contact our research nurse, Marisa Shea, by clicking here.
Collaborative work with the Milan laboratory
Patrick Ellinor's lab is works closely with the David Milan’s lab on animal models of arrhythmias. Postdoctoral fellows and research technicians in both labs regularly work on collaborative projects between the labs. Joint lab meetings are held Wednesday from 12-1.
Clinical Research
MGH AF Study
Since 2001 we have been enrolling patients with lone AF in a study to learn more about the genetic contribution to this arrhythmia. We have currently enrolled over 1,300 patients and family members with early-onset AF. Over the last ten years we have published over 30 manuscripts from the MGH AF Study. We continue to actively enroll patients from the Cardiac Arrhythmia Service at MGH. This year we will be undertaking a 10 year follow up of all patients in the study.
CHARGE AF or AFGen Consortium
 Drs. Ellinor, Benjamin (Framingham), Heckbert (Washington) and Kääb (Munich) co-lead the CHARGE-AF or AFGen consortium. The Consortium involves nearly a dozen cohort studies with genetic and phenotypic data for AF and/or the electrocardiographic measurement of the PR interval, a quantitative intermediate phenotype for AF. Current studies include AGES, ARIC, Cleveland Clinic, CHS, deCODE, Framingham, Gutenberg Heart Study, AFNET/ MONICA/KORA, MGH, Rotterdam, and Women’s Genome Health Study (Figure 3). The Consortium currently includes over 8,600 subjects with AF, 90,000 without AF, and more than 70,000 individuals with PR interval data.
We performed three initial studies. First, we performed a meta-analysis of GWAS for AF observed in the community and identified a novel genetic locus for AF at the transcription factor ZFHX3. Second, in an analysis of the genetics of the PR interval, we identified 9 loci associated with the PR interval, 4 of which were also associated with AF. Finally, we performed a meta-analysis of lone AF from five centers including MGH and identified a novel genetic locus for lone AF at the potassium channel KCNN3. Multiple other projects are currently underway including a larger meta-analysis of AF in all studies.
Framingham Heart Study
Over the past four years we have collaborated closely with Dr. Emelia J. Benjamin of the Framingham Heart Study. In recent years a number of fellows have worked between MGH and the Framingham Heart Study on clinical and genetic projects related to atrial fibrillation.
Familial Arrhythmias
We have also been working to identify the molecular basis of rare familial arrhythmias including:
• Arrhythmogenic Right Ventricular Dysplasia
• Brugada Syndrome
• Long QT syndrome
• Short QT syndrome
• Exercise induced ventricular tachycardia
If you are a patient with any of these conditions and you would like to learn more about this research project please contact our research nurse Marisa Shea by clicking here.
Publications
A complete list of Patrick Ellinor’s publications can be found by clicking here.
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