Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.
Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.
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DOI：
10.1161/circulationaha.114.009892
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发表时间：
2014-10-07
期刊：
影响因子：
37.8
通讯作者：
Ellinor PT
中科院分区：
文献类型：
--
作者：
Sinner MF;Tucker NR;Lunetta KL;Ozaki K;Smith JG;Trompet S;Bis JC;Lin H;Chung MK;Nielsen JB;Lubitz SA;Krijthe BP;Magnani JW;Ye J;Gollob MH;Tsunoda T;Müller-Nurasyid M;Lichtner P;Peters A;Dolmatova E;Kubo M;Smith JD;Psaty BM;Smith NL;Jukema JW;Chasman DI;Albert CM;Ebana Y;Furukawa T;Macfarlane PW;Harris TB;Darbar D;Dörr M;Holst AG;Svendsen JH;Hofman A;Uitterlinden AG;Gudnason V;Isobe M;Malik R;Dichgans M;Rosand J;Van Wagoner DR;METASTROKE Consortium;AFGen Consortium;Benjamin EJ;Milan DJ;Melander O;Heckbert SR;Ford I;Liu Y;Barnard J;Olesen MS;Stricker BH;Tanaka T;Kääb S;Ellinor PT
心房颤动 (AF) 影响着全球超过 3000 万人，并与中风、心力衰竭和死亡风险增加相关。房颤具有高度遗传性，但心律失常的遗传基础仍不完全清楚。为了识别新的 AF 相关基因，我们采用了多方面的方法，结合了两个不同种族人群的大规模基因分型、cis-eQTL 作图和功能验证。在欧洲血统个体中，在基因 NEURL（rs12415501，RR=1.18，95%CI 1.13 – 1.23，p=6.5×10−16）、GJA1（rs13216675，RR=1.10，95%CI 1.06 – 1.14）附近发现了四个新位点。 p=2.2×10−8)、TBX5 (rs10507248、RR=1.12、95%CI 1.08 – 1.16、p=5.7×10−11) 和 CAND2 (rs4642101、RR=1.10、95%CI 1.06 – 1.14、p=9.8×10−9)。在日语中，在 NEURL（rs6584555，RR=1.32，95%CI 1.26–1.39，p=2.0×10−25）和 CUX2（rs6490029，RR=1.12，95%CI 1.08–1.16，p=3.9×10−9）附近发现了新的位点。顶级 SNP 或其代理被确定为基因 CAND2 (p=2.6×10−19)、GJA1 (p=2.66×10−6) 和 TBX5 (p=1.36×10−05) 的顺式 eQTL。敲低 NEURL 和 CAND2 的斑马鱼直系同源物导致心房动作电位持续时间延长（分别为 17% 和 45%）。我们已经确定了 AF 的 5 个新位点。我们的研究结果进一步扩大了房颤相关遗传途径的多样性，并为未来的生物学和药理学研究提供了新的分子靶点。
Atrial fibrillation (AF) affects over 30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. To identify new AF-related genes, we utilized a multifaceted approach, combining large-scale genotyping in two ethnically distinct populations, cis-eQTL mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501, RR=1.18, 95%CI 1.13 – 1.23, p=6.5×10−16), GJA1 (rs13216675, RR=1.10, 95%CI 1.06 – 1.14, p=2.2×10−8), TBX5 (rs10507248, RR=1.12, 95%CI 1.08 – 1.16, p=5.7×10−11), and CAND2 (rs4642101, RR=1.10, 95%CI 1.06 – 1.14, p=9.8×10−9). In Japanese, novel loci were identified near NEURL (rs6584555, RR=1.32, 95%CI 1.26–1.39, p=2.0×10−25) and CUX2 (rs6490029, RR=1.12, 95%CI 1.08–1.16, p=3.9×10−9). The top SNPs or their proxies were identified as cis-eQTLs for the genes CAND2 (p=2.6×10−19), GJA1 (p=2.66×10−6), and TBX5 (p=1.36×10−05). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). We have identified five novel loci for AF. Our results further expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.