心电图和心率变异性特征的全基因组关联研究：弗雷明汉心脏研究
Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study.
作者信息
Newton-Cheh Christopher, Guo Chao-Yu, Wang Thomas J, O'donnell Christopher J, Levy Daniel, Larson Martin G
机构信息
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
出版信息
BMC Med Genet. 2007 Sep 19;8 Suppl 1(Suppl 1):S7. doi: 10.1186/1471-2350-8-S1-S7.
BACKGROUND
Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits.
METHODS
Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency > or = 0.10, call rate > or = 80%, Hardy-Weinberg p-value > or = 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN).
RESULTS
Associations at p < 10(-3) were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10(-3); lowest p-value, rs6683968, p = 1 x 10(-4)) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.
CONCLUSION
In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.
背景
可遗传的心电图（ECG）和心率变异性（HRV）指标反映了心脏的起搏、传导、复极化和自主神经功能，与心律失常风险相关。虽然已经注意到几种具有极端表型的罕见单基因疾病，但很少有常见遗传因素导致ECG和HRV指标的个体间差异被确定。我们报告了一项基于社区的全基因组关联研究的结果，该研究针对六个ECG和HRV中间性状。
方法
使用Affymetrix 100K基因芯片对1345名弗雷明汉心脏研究原始队列和后代队列的相关参与者进行基因分型。我们分析了1175名有ECG数据的原始队列和后代参与者（平均年龄为52岁，52%为女性）以及548名有HRV数据的后代参与者（平均年龄为48岁，51%为女性），这些数据与70987个次要等位基因频率≥0.10、检出率≥80%、哈迪-温伯格p值≥0.001的单核苷酸多态性（SNP）相关。我们使用广义估计方程来测试SNP等位基因与QT、RR和PR间期、低频与高频功率比（LF/HFP）、总功率（TP）以及正常RR间期标准差（SDNN）的多变量调整残差之间的关联。
结果
在p<10⁻³水平发现117个（QT）、105个（RR）、111个（PR）、102个（LF/HF）、121个（TP）和102个（SDNN）SNP存在关联。NOS1AP中的几个常见变异（4个SNP的p值<10⁻³；最低p值，rs6683968，p = 1×10⁻⁴）与调整后的QT残差相关，这与我们之前在弗雷明汉心脏研究后代的无关样本和其他队列中关于NOS1AP的发现一致。所有结果均可在NCBI的dbGaP上公开获取，网址为http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 。
结论
在基于社区的弗雷明汉心脏研究中，没有一个ECG和HRV结果单独达到全基因组显著性。然而，QT持续时间的前117个结果中存在真正与QT相关的SNP，这支持了对所报告扫描的顶级结果进行验证的重要性。发现与ECG和HRV定量性状相关的遗传变异可能会识别出与心律失常发生相关的新基因和途径，并有助于更好地识别普通人群中患心律失常高风险的个体。
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