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Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.
Circulation Research ( IF 16.5 ) Pub Date : 2016-11-29 , DOI: 10.1161/circresaha.116.308765 Gregory T Jones 1 , Gerard Tromp 1 , Helena Kuivaniemi 1 , Solveig Gretarsdottir 1 , Annette F Baas 1 , Betti Giusti 1 , Ewa Strauss 1 , Femke N G Van't Hof 1 , Thomas R Webb 1 , Robert Erdman 1 , Marylyn D Ritchie 1 , James R Elmore 1 , Anurag Verma 1 , Sarah Pendergrass 1 , Iftikhar J Kullo 1 , Zi Ye 1 , Peggy L Peissig 1 , Omri Gottesman 1 , Shefali S Verma 1 , Jennifer Malinowski 1 , Laura J Rasmussen-Torvik 1 , Kenneth M Borthwick 1 , Diane T Smelser 1 , David R Crosslin 1 , Mariza de Andrade 1 , Evan J Ryer 1 , Catherine A McCarty 1 , Erwin P Böttinger 1 , Jennifer A Pacheco 1 , Dana C Crawford 1 , David S Carrell 1 , Glenn S Gerhard 1 , David P Franklin 1 , David J Carey 1 , Victoria L Phillips 1 , Michael J A Williams 1 , Wenhua Wei 1 , Ross Blair 1 , Andrew A Hill 1 , Thodor M Vasudevan 1 , David R Lewis 1 , Ian A Thomson 1 , Jo Krysa 1 , Geraldine B Hill 1 , Justin Roake 1 , Tony R Merriman 1 , Grzegorz Oszkinis 1 , Silvia Galora 1 , Claudia Saracini 1 , Rosanna Abbate 1 , Raffaele Pulli 1 , Carlo Pratesi 1 , Athanasios Saratzis 1 , Ana R Verissimo 1 , Suzannah Bumpstead 1 , Stephen A Badger 1 , Rachel E Clough 1 , Gillian Cockerill 1 , Hany Hafez 1 , D Julian A Scott 1 , T Simon Futers 1 , Simon P R Romaine 1 , Katherine Bridge 1 , Kathryn J Griffin 1 , Marc A Bailey 1 , Alberto Smith 1 , Matthew M Thompson 1 , Frank M van Bockxmeer 1 , Stefan E Matthiasson 1 , Gudmar Thorleifsson 1 , Unnur Thorsteinsdottir 1 , Jan D Blankensteijn 1 , Joep A W Teijink 1 , Cisca Wijmenga 1 , Jacqueline de Graaf 1 , Lambertus A Kiemeney 1 , Jes S Lindholt 1 , Anne Hughes 1 , Declan T Bradley 1 , Kathleen Stirrups 1 , Jonathan Golledge 1 , Paul E Norman 1 , Janet T Powell 1 , Steve E Humphries 1 , Stephen E Hamby 1 , Alison H Goodall 1 , Christopher P Nelson 1 , Natzi Sakalihasan 1 , Audrey Courtois 1 , Robert E Ferrell 1 , Per Eriksson 1 , Lasse Folkersen 1 , Anders Franco-Cereceda 1 , John D Eicher 1 , Andrew D Johnson 1 , Christer Betsholtz 1 , Arno Ruusalepp 1 , Oscar Franzén 1 , Eric E Schadt 1 , Johan L M Björkegren 1 , Leonard Lipovich 1 , Anne M Drolet 1 , Eric L Verhoeven 1 , Clark J Zeebregts 1 , Robert H Geelkerken 1 , Marc R van Sambeek 1 , Steven M van Sterkenburg 1 , Jean-Paul de Vries 1 , Kari Stefansson 1 , John R Thompson 1 , Paul I W de Bakker 1 , Panos Deloukas 1 , Robert D Sayers 1 , Seamus C Harrison 1 , Andre M van Rij 1 , Nilesh J Samani 1 , Matthew J Bown 1
Circulation Research ( IF 16.5 ) Pub Date : 2016-11-29 , DOI: 10.1161/circresaha.116.308765 Gregory T Jones 1 , Gerard Tromp 1 , Helena Kuivaniemi 1 , Solveig Gretarsdottir 1 , Annette F Baas 1 , Betti Giusti 1 , Ewa Strauss 1 , Femke N G Van't Hof 1 , Thomas R Webb 1 , Robert Erdman 1 , Marylyn D Ritchie 1 , James R Elmore 1 , Anurag Verma 1 , Sarah Pendergrass 1 , Iftikhar J Kullo 1 , Zi Ye 1 , Peggy L Peissig 1 , Omri Gottesman 1 , Shefali S Verma 1 , Jennifer Malinowski 1 , Laura J Rasmussen-Torvik 1 , Kenneth M Borthwick 1 , Diane T Smelser 1 , David R Crosslin 1 , Mariza de Andrade 1 , Evan J Ryer 1 , Catherine A McCarty 1 , Erwin P Böttinger 1 , Jennifer A Pacheco 1 , Dana C Crawford 1 , David S Carrell 1 , Glenn S Gerhard 1 , David P Franklin 1 , David J Carey 1 , Victoria L Phillips 1 , Michael J A Williams 1 , Wenhua Wei 1 , Ross Blair 1 , Andrew A Hill 1 , Thodor M Vasudevan 1 , David R Lewis 1 , Ian A Thomson 1 , Jo Krysa 1 , Geraldine B Hill 1 , Justin Roake 1 , Tony R Merriman 1 , Grzegorz Oszkinis 1 , Silvia Galora 1 , Claudia Saracini 1 , Rosanna Abbate 1 , Raffaele Pulli 1 , Carlo Pratesi 1 , Athanasios Saratzis 1 , Ana R Verissimo 1 , Suzannah Bumpstead 1 , Stephen A Badger 1 , Rachel E Clough 1 , Gillian Cockerill 1 , Hany Hafez 1 , D Julian A Scott 1 , T Simon Futers 1 , Simon P R Romaine 1 , Katherine Bridge 1 , Kathryn J Griffin 1 , Marc A Bailey 1 , Alberto Smith 1 , Matthew M Thompson 1 , Frank M van Bockxmeer 1 , Stefan E Matthiasson 1 , Gudmar Thorleifsson 1 , Unnur Thorsteinsdottir 1 , Jan D Blankensteijn 1 , Joep A W Teijink 1 , Cisca Wijmenga 1 , Jacqueline de Graaf 1 , Lambertus A Kiemeney 1 , Jes S Lindholt 1 , Anne Hughes 1 , Declan T Bradley 1 , Kathleen Stirrups 1 , Jonathan Golledge 1 , Paul E Norman 1 , Janet T Powell 1 , Steve E Humphries 1 , Stephen E Hamby 1 , Alison H Goodall 1 , Christopher P Nelson 1 , Natzi Sakalihasan 1 , Audrey Courtois 1 , Robert E Ferrell 1 , Per Eriksson 1 , Lasse Folkersen 1 , Anders Franco-Cereceda 1 , John D Eicher 1 , Andrew D Johnson 1 , Christer Betsholtz 1 , Arno Ruusalepp 1 , Oscar Franzén 1 , Eric E Schadt 1 , Johan L M Björkegren 1 , Leonard Lipovich 1 , Anne M Drolet 1 , Eric L Verhoeven 1 , Clark J Zeebregts 1 , Robert H Geelkerken 1 , Marc R van Sambeek 1 , Steven M van Sterkenburg 1 , Jean-Paul de Vries 1 , Kari Stefansson 1 , John R Thompson 1 , Paul I W de Bakker 1 , Panos Deloukas 1 , Robert D Sayers 1 , Seamus C Harrison 1 , Andre M van Rij 1 , Nilesh J Samani 1 , Matthew J Bown 1
Affiliation
RATIONALE
Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA.
OBJECTIVE
To identify additional AAA risk loci using data from all available genome-wide association studies.
METHODS AND RESULTS
Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9.
CONCLUSIONS
The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
中文翻译：
腹主动脉瘤全基因组关联研究的荟萃分析确定了四个新的疾病特异性风险位点。
基本原理 腹主动脉瘤 (AAA) 是一种具有遗传和环境风险因素的复杂疾病。总之，先前确定的 6 个风险位点仅解释了 AAA 遗传力的一小部分。目的使用来自所有可用的全基因组关联研究的数据来识别额外的 AAA 风险基因座。方法和结果 通过对 6 个全基因组关联研究数据集的荟萃分析和总计 10 204 例病例和 107 766 例对照的验证研究，我们确定了 4 个新的 AAA 风险基因座：1q32.3 (SMYD2)、13q12.11 (LINC00540 )、20q13.12（靠近 PCIF1/MMP9/ZNF335）和 21q22.2 (ERG)。在各种数据库搜索中，我们观察到前导 AAA 单核苷酸多态性与冠状动脉疾病、血压、血脂或糖尿病之间没有新的关联。网络分析确定了 ERG、IL6R、和 LDLR 作为 MMP9 的修饰剂，ERG 和 MMP9 之间存在直接相互作用。结论 与其他心血管疾病和相关特征相比，AAA 的 4 个新风险位点似乎对 AAA 具有特异性，这表明传统的心血管风险因素管理在预防动脉瘤疾病进展方面的价值可能有限。
更新日期：2019-11-01
中文翻译：
腹主动脉瘤全基因组关联研究的荟萃分析确定了四个新的疾病特异性风险位点。
基本原理 腹主动脉瘤 (AAA) 是一种具有遗传和环境风险因素的复杂疾病。总之，先前确定的 6 个风险位点仅解释了 AAA 遗传力的一小部分。目的使用来自所有可用的全基因组关联研究的数据来识别额外的 AAA 风险基因座。方法和结果 通过对 6 个全基因组关联研究数据集的荟萃分析和总计 10 204 例病例和 107 766 例对照的验证研究，我们确定了 4 个新的 AAA 风险基因座：1q32.3 (SMYD2)、13q12.11 (LINC00540 )、20q13.12（靠近 PCIF1/MMP9/ZNF335）和 21q22.2 (ERG)。在各种数据库搜索中，我们观察到前导 AAA 单核苷酸多态性与冠状动脉疾病、血压、血脂或糖尿病之间没有新的关联。网络分析确定了 ERG、IL6R、和 LDLR 作为 MMP9 的修饰剂，ERG 和 MMP9 之间存在直接相互作用。结论 与其他心血管疾病和相关特征相比，AAA 的 4 个新风险位点似乎对 AAA 具有特异性，这表明传统的心血管风险因素管理在预防动脉瘤疾病进展方面的价值可能有限。
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