Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.
Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.
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DOI：
10.1371/journal.pgen.1002158
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发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Chugh SS
中科院分区：
文献类型：
--
作者：
Arking DE;Junttila MJ;Goyette P;Huertas-Vazquez A;Eijgelsheim M;Blom MT;Newton-Cheh C;Reinier K;Teodorescu C;Uy-Evanado A;Carter-Monroe N;Kaikkonen KS;Kortelainen ML;Boucher G;Lagacé C;Moes A;Zhao X;Kolodgie F;Rivadeneira F;Hofman A;Witteman JC;Uitterlinden AG;Marsman RF;Pazoki R;Bardai A;Koster RW;Dehghan A;Hwang SJ;Bhatnagar P;Post W;Hilton G;Prineas RJ;Li M;Köttgen A;Ehret G;Boerwinkle E;Coresh J;Kao WH;Psaty BM;Tomaselli GF;Sotoodehnia N;Siscovick DS;Burke GL;Marbán E;Spooner PM;Cupples LA;Jui J;Gunson K;Kesäniemi YA;Wilde AA;Tardif JC;O'Donnell CJ;Bezzina CR;Virmani R;Stricker BH;Tan HL;Albert CM;Chakravarti A;Rioux JD;Huikuri HV;Chugh SS
心源性猝死（SCD）仍然是全球死亡的主要原因之一，在美国每年的发病率估计为250，000 - 300，000，并且绝大多数发生在冠状动脉疾病的情况下。我们对来自5项研究的1，283例SCD病例和> 20，000名欧洲血统对照个体进行了全基因组关联荟萃分析，并对来自11项欧洲血统研究的3，119例SCD病例和11，146名对照进行了随访基因分型，并确定BAZ 2B基因座与SCD相关（P = 1.8×10−10）。 该风险等位基因虽然是祖先，但其频率为1.4%，表明强烈的负选择，每个等位基因使SCD风险增加1.92倍（95%CI 1.57-2.34）。我们还测试了49个SNPs的作用，这些SNPs以前参与调节心电图特征（QRS，QT和RR间期）。流行病学研究显示，随着QRS/QT间期延长，SCD风险增加，与此一致，间期延长等位基因与SCD风险增加相关（P = 0.006）。 家族研究已经清楚地证明了基因在改变心脏性猝死（SCD）风险中的作用，然而遗传研究受到可用样本的限制。在这里，我们收集了超过4，400例SCD病例，其中> 30，000例对照，均为欧洲血统，并采用两阶段研究设计。在第一阶段，我们对1，283名SCD病例和> 20，000名对照进行了无偏倚的全基因组扫描，然后对其余样本进行了后续基因分型。我们证明了与先前未涉及SCD的基因组区域（BAZ 2B基因座）的强关联，该基因座包含3个先前不知道在心脏生物学中发挥作用的基因。此外，我们使用全基因组扫描数据来检验一个集中的假设，即调节与SCD相关的ECG特征（QT，QRS和RR间期）的遗传变异也会改变SCD的风险，并且我们证明QT和QRS延长等位基因作为一个组与SCD风险增加相关。综上所述，这些发现开始阐明遗传因素对SCD易感性的贡献，并为功能研究提供重要靶点，以调查SCD的病因和发病机制。
Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006). Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.
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影响因子：
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McAnulty, J
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Abecasis, Goncalo R.
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