Abstract 11864: Examining Rare and Low-Frequency Genetic Variants Previously Associated With Lone or Familial Forms of Atrial Fibrillation in an Electronic Medical Record System: A Cautionary Note
Introduction: Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and familial atrial fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here we used a cohort of 20,204 patients of European ancestry (EA) or African ancestry (AA) (n=18,424 and n=1,780, respectively) with electronic medical records (EMRs) and exome chip data to compare the frequency of AF among carriers and non-carriers of these rare variants.
Methods and Results: The exome chip included 19/115 rare variants, in 9 genes, previously associated with lone or familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1,056 AF cases (>18 years) and 19,148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt EMR-linked DNA repository, BioVU. While known correlations between AF and common variants at 4q25 were replicated, none of the 19 variants previously associated with AF were overrepresented among AF cases (P >0.1 for all). The frequency of variant carriers among non-AF controls was >0.1% for 14/19 polymorphisms; 9 of 19 polymorphisms were absent in EA AF cases, but were present in 1-35 (0.01-0.2%) non-AF EA controls. The greatest numbers of risk allele carriers among EA AF cases were identified for the following variants: Phe2004Leu in SCN5A (13 [1.3%] AF cases vs. 179 [1.0%] non-AF controls, p=0.42), Gln76Glu in GREM2 (10 [1.0%] vs. 133 [0.8%], p=0.76), Ser64Arg in NPPA (5 [0.5%] vs. 120 [0.7%], p=0.69), and Arg1193Gln in SCN5A (4 [0.4%] vs. 33 [0.2%], p=0.14). Repeat analyses using EA non-AF controls aged >60 (n=14,904) >70 (n=9,670), and >80 (n=4,729) years old did not influence these findings. Analysis among AA yielded similar results.
Conclusion: Rare variants previously implicated in lone or familial forms AF present on the exome chip are detected at low frequencies in a general population but are not associated with AF. These findings emphasize the need for caution when ascribing variants as pathogenic or causative.
Author Disclosures: P. Weeke: None. J.C. Denny: None. L. Basterache: None. C. Shaffer: None. E. Bowton: None. C. Ingram: None. D. Darbar: None. D.M. Roden: None.
- © 2014 by American Heart Association, Inc.