Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.
Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.
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DOI：
10.1161/jaha.115.002603
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发表时间：
2016-07-14
影响因子：
5.4
通讯作者：
de Bakker PI
中科院分区：
文献类型：
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作者：
van 't Hof FN;Ruigrok YM;Lee CH;Ripke S;Anderson G;de Andrade M;Baas AF;Blankensteijn JD;Böttinger EP;Bown MJ;Broderick J;Bijlenga P;Carrell DS;Crawford DC;Crosslin DR;Ebeling C;Eriksson JG;Fornage M;Foroud T;von Und Zu Fraunberg M;Friedrich CM;Gaál EI;Gottesman O;Guo DC;Harrison SC;Hernesniemi J;Hofman A;Inoue I;Jääskeläinen JE;Jones GT;Kiemeney LA;Kivisaari R;Ko N;Koskinen S;Kubo M;Kullo IJ;Kuivaniemi H;Kurki MI;Laakso A;Lai D;Leal SM;Lehto H;LeMaire SA;Low SK;Malinowski J;McCarty CA;Milewicz DM;Mosley TH;Nakamura Y;Nakaoka H;Niemelä M;Pacheco J;Peissig PL;Pera J;Rasmussen-Torvik L;Ritchie MD;Rivadeneira F;van Rij AM;Santos-Cortez RL;Saratzis A;Slowik A;Takahashi A;Tromp G;Uitterlinden AG;Verma SS;Vermeulen SH;Wang GT;Aneurysm Consortium; Vascular Research Consortium of New Zealand;Han B;Rinkel GJ;de Bakker PI
颅内动脉瘤（IA）、腹主动脉瘤（AAA）和胸主动脉瘤（TAA）均具有家族易感性。鉴于已知动脉瘤类型可同时发生，我们假设IA、AAA和TAA可能存在共同的遗传风险因素。我们对4个先前发表的动脉瘤队列的1000个基因组项目插补的全基因组关联研究（GWAS）数据进行了大规模分析：2个IA队列（共1516例病例，4305例对照），1个AAA队列（818例病例，3004例对照）和1个TAA队列（760例病例，2212例对照），并观察到4个已知IA，AAA和/或TAA风险位点（9 p21，18 q11，15 q21和2 q33）在所有4个队列中具有一致的效应方向。我们根据IA、AAA和TAA相关SNP计算多基因评分，并在其他动脉瘤队列中检验这些评分与病例对照状态的相关性;这表明没有共同的多基因效应。同样，连锁不平衡评分回归分析也未显示任何一对动脉瘤亚型之间存在显著相关性。最后，我们通过在扩展的动脉瘤队列中的合作，评估了14个先前发表的动脉瘤风险单核苷酸多态性的证据，共有6548例病例和16843例对照（IA）以及4391例病例和37904例对照（AAA），发现RBBP 8附近的IA风险位点18 q11与AAA存在名义上的显著相关性。（比值比[OR]=1.11; P=4.1×10−5），TAA风险位点15 q21接近FBN 1至AAA（OR=1.07; P=1.1×10−3）。虽然没有证据表明IA，AAAs和TAAs之间的多基因重叠，我们发现两个既定的风险位点的IA和TAAs在AAAs的名义上显着的影响。这两个位点需要进一步复制。
Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.