Abstract
Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with increased risk of stroke, heart failure and death. In the general population, the estimated prevalence of AF is of approximately 2%, with a greater prevalence in elderly persons. The Cooperative Health Research in South Tyrol (CHRIS) study is an ongoing longitudinal population-based study1, with phenotypic and genotypic data currently available for 10,518 participants. The large sample size guarantees the possibility to identify a large number of AF cases and so studying AF in a general-population context.
Purpose: The aim of the project is to explore the genetic determinants for AF in the CHRIS Study.
Methods: We defined AF as having a p-wave duration equal to zero in a 10 second electrocardiogram or by reporting the use of anti-AF drugs in specific dosage and intake patterns. Study samples were genotyped on about 1 million single nucleotide polymorphisms (SNPs) with the Illumina Human Omni Express Exome Bead Chip and supplemented by imputation based on the Haplotype Reference Consortium Panel2. To identify possible underlying genetic contributors of AF, we conducted a genome-wide association study (GWAS) using linear mixed models. The study is compliant to the principles of the Declaration of Helsinki and current Italian and EU regulation.
Results: We identified 110 putative AF cases (1%). Among them, 5 (4.5%) individuals were younger than 40 years old when diagnosed and 32 (29%) individuals belong to 19 families. We identified two novel genome-wide significant loci (p-value<5e-8; Figure 1), whose most significant SNPs were the rs528903211, rs573729400 and rs745582874 next to the PBX1 gene, and the rs768476991 within the PCCA gene. The expression of PBX1 was previously reported to be up regulated in AF patients in a genome-wide whole blood transcriptomic study3. Furthermore, mutations in PCCA gene lead to an enzyme deficiency resulting in cardiac dysfunction4. Only one AF case, belonging to a family with two other AF cases, carries all 4 SNPs and showed a very early onset of AF at the age of 31 years.
Conclusions: While the validation of imputed variants by Sanger sequencing and replication studies to confirm the identified loci in an independent population sample are ongoing, these preliminary findings show a possible involvement of PBX1 and PCCA genes in AF and a potential synergistic effect of these 2 loci.