Uncovering an Intermediate Phenotype Associated With rs2200733 at 4q25 in Lone Atrial Fibrillation

Study Questions:

What are the potential relations between rs2200733 versus clinical and electrocardiographic traits in a cohort of patients with early-onset atrial fibrillation (AF) who lack traditional risk factors?


From November 2000 to June 2009, patients referred to a single center and diagnosed with lone AF were identified. The investigators recruited 219 unrelated subjects with lone AF and procured whole blood for genomic deoxyribonucleic acid extraction and analysis. Genotyping of the rs2200733 polymorphism was performed by restriction fragment length polymorphism analysis. Associations between the three genotypes and continuous variables were tested using one-way analysis of variance; chi-square or Fisher’s exact tests were used to compare associations between genotypes and categorical variables. Statistical significance was accepted for p values < 0.05.


Congruent with previous reports, the minor T allele was overrepresented in subjects with lone AF. All genotype groups were statistically similar for age at diagnosis, gender distribution, family history, body mass index, AF type, ventricular rate, QRS duration, corrected QT interval, and use of PR interval–prolonging medications. However, a novel association was identified between the TT genotype and duration of the PR interval. The TT group had a mean PR interval of 189.5 ± 35.8 ms in comparison to mean PR intervals of 172.0 ± 29.0 and 171.0 ± 27.1 ms for the CT and CC groups, respectively (p = 0.013 and p = 0.0056).


The authors concluded that PR interval length, an established risk factor for AF, represents an rs2200733-associated intermediate phenotype.


Genotype distribution in this lone AF cohort corroborated previous studies, demonstrating overrepresentation of the T allele in AF compared to reported frequencies of rs2200733T in controls. The study suggests that the TT genotype group had statistically significant longer PR intervals compared to the other genotypes. Although the mechanism by which rs2200733 modulates PR interval is not clear, the finding of an association between the TT genotype and an intermediate AF trait may provide a biologic link between rs2200733 and AF, and help our understanding of AF susceptibility.

Keywords: DNA, Polymorphism, Genetic, Phenotype, Electrocardiography, Genotype

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