Verweij Niek, Mateo Leach Irene, van den Boogaard Malou, van Veldhuisen Dirk J, Christoffels Vincent M, Hillege Hans L, van Gilst Wiek H, Barnett Phil, de Boer Rudolf A, van der Harst Pim
From the Department of Cardiology (N.V., I.M.L., D.J.v.V., H.L.H., W.H.v.G., R.A.d.B., P.v.d.H.) and Department of Genetics (P.v.d.H.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (M.v.d.B., V.M.C., P.B.); and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (P.v.d.H.).
Circ Cardiovasc Genet. 2014 Aug;7(4):475-81. doi: 10.1161/CIRCGENETICS.113.000373. Epub 2014 May 21.
The PR interval on the ECG reflects atrial depolarization and atrioventricular nodal delay which can be partially differentiated by P wave duration and PR segment, respectively. Genome-wide association studies have identified several genetic loci for PR interval, but it remains to be determined whether this is driven by P wave duration, PR segment, or both.
We replicated 7 of the 9 known PR interval loci in 16 468 individuals of European ancestry. Four loci were unambiguously associated with PR segment, while the others were shared for P wave duration and PR segment. Next, we performed a genome-wide analysis on P wave duration and PR segment separately and identified 5 novel loci. Single-nucleotide polymorphisms in KCND3 (P=8.3×10(-11)) and FADS2 (P=2.7×10(-8)) were associated with P wave duration, whereas single-nucleotide polymorphisms near IL17D (P=2.3×10(-8)), in EFHA1 (P=3.3×10(-10)), and in LRCH1 (P=2.1×10(-8)) were associated with PR segment. Analysis on DNA elements indicated that genome-wide significant single-nucleotide polymorphisms were enriched at genomic regions suggesting active gene transcription in the human right atrium. Quantitative polymerase chain reaction showed that genes were significantly higher expressed in the right atrium and atrioventricular node compared with left ventricle (P=5.6×10(-6)).
Genetic associations of PR interval seem to be mainly driven by genetic determinants of the PR segment. Some of the PR interval associations are strengthened by a directional consistent effect of genetic determinants of P wave duration. Through genome-wide association we also identified genetic variants specifically associated with P wave duration which might be relevant for cardiac biology.
心电图上的PR间期反映心房去极化和房室结延迟，这可分别通过P波时限和PR段部分区分。全基因组关联研究已确定了几个与PR间期相关的基因位点，但尚需确定这是由P波时限、PR段还是两者共同驱动。
我们在16468名欧洲血统个体中重复验证了9个已知PR间期基因位点中的7个。4个基因位点与PR段明确相关，而其他基因位点在P波时限和PR段中共有。接下来，我们分别对P波时限和PR段进行全基因组分析，并确定了5个新的基因位点。KCND3（P = 8.3×10⁻¹¹）和FADS2（P = 2.7×10⁻⁸）中的单核苷酸多态性与P波时限相关，而IL17D附近（P = 2.3×10⁻⁸）、EFHA1（P = 3.3×10⁻¹⁰）和LRCH1（P = 2.1×10⁻⁸）中的单核苷酸多态性与PR段相关。对DNA元件的分析表明，全基因组显著的单核苷酸多态性在提示人类右心房活跃基因转录的基因组区域富集。定量聚合酶链反应显示，与左心室相比，这些基因在右心房和房室结中的表达显著更高（P = 5.6×10⁻⁶）。
PR间期的遗传关联似乎主要由PR段的遗传决定因素驱动。P波时限的遗传决定因素的方向一致效应增强了一些PR间期关联。通过全基因组关联研究，我们还确定了与P波时限特异性相关的遗传变异，这可能与心脏生物学相关。
