NHLBI GO-ESP: Family Studies: (Familial Atrial Fibrillation)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Large epidemiological studies have demonstrated a significant heritable component in atrial fibrillation (AF), especially the Lone forms, suggesting a monogenic syndrome. Although substantial genetic contribution has been made to the etiology of AF, the specific genes have not yet been identified. The familial form of this disease remains poorly characterized and largely undetermined. Here we seek to identify, characterize and determine the natural course of AF in our clinical practice. We identified four large multi-generation families (FAF 1-4). In FAF 1-2, most family members have symptomatic paroxysmal Atrial Fibrillation (AF) and were adequately treated with a combination of rate and rhythm therapies. By contrast, the AF substrate in FAF 3 and 4 was resistant to anti-arrhythmic drugs and ablation therapies.]]>
Exclusion criteria: Individuals less than 18 years old, have no atrial fibrillation, have had a bone marrow transplant or cardiac transplant, or if atrial fibrillation was diagnosed within 90 days of cardiac surgery. Inclusion criteria: Individuals must be 18 years old or older, with diagnosis of atrial fibrillation confirmed by ECG, who presented with symptoms or were diagnosed during routine physical examinations. Criteria for Lone AF inclusion: Individuals must be 65 years or younger at the time of diagnosis, in the absence of coronary disease or valvular disease, hypertension, hyperthyroidism, diabetes mellitus, obstructive sleep apnea and body mass index must be under 30.]]>
Over an 8-year period, 2,095 patients were enrolled in the Vanderbilt Atrial Fibrillation (AF) Registry, of which 1,657 (80%) were probands. From the 1,657 probands, 325 (20%) were identified as having lone AF and 133 of those with lone AF (40%) have a positive family history. Recruited members had a physical examination and detailed history to identify the following: past medical conditions, medications, symptoms while in AF and the medical history of all first-degree relatives. Each subject was evaluated by 12-lead ECG, echocardiogram and laboratory studies including one for thyroid-stimulating hormone. The proband and relatives were clinically classified using a consistently applied set of definitions. AF was defined as replacement of sinus P waves by rapid oscillations or fibrillatory waves that varied in size, shape and timing and were associated with an irregular ventricular response when atrioventricular conduction was intact. Documentation of AF on an ECG, rhythm strip, event or Holter monitor was required. We defined as affected those individuals with ECG documented AF. We defined as unaffected only those individuals >65 years of age with no personal history of AF or having no offspring with a history of AF. All other family members were defined as unknown for the purpose of initial genetic analyses.]]>