The PITX2 variant M207V is associated with early-onset lone atrial fibrillation and co-segregates within a family

Purpose: Genetic variants play an important role in lone atrial fibrillation (AF). Ten genetic loci have been associated with AF in genome-wide association (GWA) studies. Variants identified so far can only explain a small proportion of familial clustering, leading to a search for the sources of "missing" heritability. In all of these studies, the single nucleotide polymorphism (SNP) rs2200733 was the top hit. Recently a meta-analysis of all association studies performed on this SNP confirmed its independent association with AF. It is located upstream of PITX2, a gene important in the cardiogenesis, specifically in the atria, suggesting a potential role in AF. We hypothesized that genetic variants in PITX2 could predispose to early-onset of lone AF. Methods: The coding region of PITX2 was sequenced in 342 cases with early-onset lone AF. 750 controls free of AF were screened for variants identified in the cases. The genotype at the locus rs2200733 was assessed in all cases carrying novel variants in PITX2. Results: Two genetic variants were identified: M207V in four patients, and the previously described A188T in six patients. The frequency of M207V was significantly higher in patients vs. controls (0.58% vs. 0.00%; p=0.01) and in patients vs. the NHLBI Exome Variant Server (0.58% vs. 0.03%; p=0.001), which holds SNP-data on 8,600 European American alleles. M207V co-segregated with both AF and the risk allele of the SNP rs2200733 in one family. All variant-carriers had no mutations in other genes previously associated with AF. Conclusion: This is the first report of 1) an association between a variant in PITX2 and early-onset lone AF, and 2) co-segregation of the SNP rs2200733 with a non-synonymous genetic variant within the coding region of PITX2. This supports the hypothesis of the 4q25 locus being a marker of genetic variation in PITX2 in patients with AF, and suggests that this gene may be involved in AF, independent of major structural abnormalities in the heart.