Polymorphisms and atrial fibrillation: sorting the wheat from the chaff.

In the last 5 years, we have gained an increasing appreciation for the genetic contribution to atrial fibrillation (AF). While Mendelian families with AF have been reported, they have typically been considered rare. Studies from Framingham and Iceland have demonstrated a genetic basis for AF in the general population. Family members of those with AF have an odds ratios of 1.8 for developing the arrhythmia. This risk is considerably greater for younger patients and those with lone AF. One approach to identify common genetic determinants of a disease in a population is to perform an association study between a single nucleotide polymorphism (SNP) and the condition of interest. Such a study can be performed using one to many hundreds of thousands of SNPs across the genome. In the case of AF, numerous prior associations have been reported between AF and variants in the cardiac sodium and potassium channels, gap junction proteins, and inflammatory markers, among others. However, the studies to date have generally been underpowered, have not been replicated, and have a low pre-test probability of the SNP actually causing AF. Sinner et al. have described the relationship between the K897T SNP in KCNH2/HERG and AF in .1200 affected individuals and 2400 controls. Based on the well-known relationship between variation in KCNH2/HERG and ventricular repolarization, the authors hypothesized that this gene may also be associated with alterations in atrial repolarization, and thus AF. Starting with 40 SNPs across the KCNH2 gene, they determined the frequency of each SNP in 671 cases and 694 controls and found five associated with AF. These five SNPs were then analysed in an additional 531 cases with AF and 1781 control subjects, and one, the well-known K897T polymorphism, emerged. This SNP had an odds ratio of 1.25 [95% confidence interval (CI) 1.11–1.41, P 1⁄4 3.3 10] with the 897K allele being associated with an increased risk of AF, while the 897T allele had a reduced risk. This association remained after correction for the age and sex of the subjects. With such a large, well-powered cohort, these investigators have raised the standard for future association studies on AF. However, this study was subject to some limitations. It would have been interesting to know the relationship between AF and ventricular repolarization in this population; unfortunately electrocardiograms were unavailable from the control subjects. This study is also limited by the lack of information on other covariates associated with AF, such as congestive heart failure and hypertension. Further, all of the subjects in the study were of European descent so the results many not be applicable to other races and ethnicities. Finally, with an odds ratio of 1.25, this variant in KCNH2 has a relatively modest overall effect in the population, implying that additional genetic variants for AF remain to be identified. What do we know of the K897T polymorphism? This SNP has a minor allele frequency of 23% in Caucasians and is therefore common in the general population. As summarized in Table 1, it has been extensively studied for its role in ventricular repolarization. In 2002, Pietila and colleagues described the association between the QT interval and K897T in 413 individuals. They found that the minor allele, 897T, was associated with QT prolongation but only in the subset of 187 women. The following year, Bezzina et al. reported the opposite, that 897T was associated with QT shortening in 1382 subjects and was more predictive in females. This result was replicated by investigators from the KORA study who found that 897T is associated with a 1.9 ms reduction in the QT interval per allele and with a greater decrease in women than men. Recently, a similar result was noted in the Framingham Heart Study, with a reduction in the corrected QT interval by 1.6 ms per 897T allele. Thus, while there is some inconsistency, on the whole the preponderance of epidemiological data supports the association between the QT shortening effect and the 897T allele.