Using A Large Electronic Medical Record To Validate 4q25 Variants Conferring Risk For Atrial Fibrillation

Background : Genome-wide association studies, largely in research populations, have identified susceptibility single-nucleotide polymorphisms (SNPs) for a broad range of human diseases, including variants at 4q25 associated with atrial fibrillation (AF). However, no studies have evaluated the applicability of these data to practice-based settings. Methods : This study was conducted in the Vanderbilt DNA Databank, a repository that accrues 500 –900 new samples/week from routine outpatient blood draws, and included 37,335 samples as of June 2, 2008. The Databank is linked to a de-identified derivative of the electronic medial record (EMR), which includes data for the last 15 years on 1.4 million subjects. We used natural language processing techniques and billing code queries to extract AF cases and controls without AF from the first 10,000 subjects entering the Databank. Cases had AF recorded in the cardiologist report of an electrocardiogram (ECG). Controls had at least one ECG and no AF, other abnormal atrial rhythms, or atrioventricular nodal ablation in any portion of the EMR, including text documents, billing codes, and ECGs. We excluded subjects with heart transplants and non-Caucasian ethnicity. Subjects were genotyped at rs2200733 and rs10033464, both located at 4q25, previously associated with AF with odds ratios (ORs) of 1.75 and 1.42, respectively. Results : We identified 168 cases with AF and 1695 controls. The electronic algorithms had an accuracy of 98% for identifying cases and 100% for controls over a random sample of 100 subjects each. The minor allele frequencies (MAF) for rs2200733 were 0.1419 for cases and 0.1032 for controls; the MAF for rs10033464 were 0.1019 for cases and 0.908 for controls. rs2200733 was significantly associated with AF (OR [95% confidence interval], 1.44 [1.01–2.03], p=0.04). The effect of rs10033464 on AF was not significant (OR, 1.14 [0.78 –1.67], p=0.52); however, power calculations indicate that 993 cases with AF were needed to replicate this effect. Conclusion : This practice-based study replicated an association identified in research datasets between a 4q25 SNP and AF. These findings support the utility of Electronic Medical Records coupled to DNA collections as resources for genomic research.