Abstract
Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.
Highlights
This article is an open access articleAtrial fibrillation (AF) is a common cardiac arrhythmia that can cause severe stroke and heart failure and is associated with premature mortality [1]
We used the R/Bioconductor FamAgg package [20] to investigate if CHRIS participants with AF were aggregated within clusters of close relatives. We considered for this analysis all 10,518 CHRIS participants whose quality-controlled data were available on
Responded positively to the question of whether they had been diagnosed with AF by a physician
Summary
Atrial fibrillation (AF) is a common cardiac arrhythmia that can cause severe stroke and heart failure and is associated with premature mortality [1]. AF is characterized by a progressive atrial remodeling, which results in electrical dissociation and local conduction heterogeneities, favoring re-entry and perpetuation of the arrhythmia, with irregular and often abnormally fast heart rate [2]. Multiple risk factors have been implicated for AF, distributed under the terms and conditions of the Creative Commons. Biomolecules 2021, 11, 1663 including valvular heart disease, diabetes mellitus, coronary artery disease, chronic kidney disease, hypertension, obesity, and smoking [3]. Family-based studies indicate that AF has a clear genetic predisposition [5,6]: the risk to develop AF is ~40% larger in first-degree relatives of an AF case [6]. Genome-wide association studies (GWAS) have identified >160 gene loci for AF [7]
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