Dataset Information

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

ABSTRACT:

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.

SUBMITTER: Jones GT

PROVIDER: S-EPMC5253231 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Jones Gregory T GT Tromp Gerard G Kuivaniemi Helena H Gretarsdottir Solveig S Baas Annette F AF Giusti Betti B Strauss Ewa E Van't Hof Femke N G FN Webb Thomas R TR Erdman Robert R Ritchie Marylyn D MD Elmore James R JR Verma Anurag A Pendergrass Sarah S Kullo Iftikhar J IJ Ye Zi Z Peissig Peggy L PL Gottesman Omri O Verma Shefali S SS Malinowski Jennifer J Rasmussen-Torvik Laura J LJ Borthwick Kenneth M KM Smelser Diane T DT Crosslin David R DR de Andrade Mariza M Ryer Evan J EJ McCarty Catherine A CA Böttinger Erwin P EP Pacheco Jennifer A JA Crawford Dana C DC Carrell David S DS Gerhard Glenn S GS Franklin David P DP Carey David J DJ Phillips Victoria L VL Williams Michael J A MJ Wei Wenhua W Blair Ross R Hill Andrew A AA Vasudevan Thodor M TM Lewis David R DR Thomson Ian A IA Krysa Jo J Hill Geraldine B GB Roake Justin J Merriman Tony R TR Oszkinis Grzegorz G Galora Silvia S Saracini Claudia C Abbate Rosanna R Pulli Raffaele R Pratesi Carlo C Saratzis Athanasios A Verissimo Ana R AR Bumpstead Suzannah S Badger Stephen A SA Clough Rachel E RE Cockerill Gillian G Hafez Hany H Scott D Julian A DJ Futers T Simon TS Romaine Simon P R SP Bridge Katherine K Griffin Kathryn J KJ Bailey Marc A MA Smith Alberto A Thompson Matthew M MM van Bockxmeer Frank M FM Matthiasson Stefan E SE Thorleifsson Gudmar G Thorsteinsdottir Unnur U Blankensteijn Jan D JD Teijink Joep A W JA Wijmenga Cisca C de Graaf Jacqueline J Kiemeney Lambertus A LA Lindholt Jes S JS Hughes Anne A Bradley Declan T DT Stirrups Kathleen K Golledge Jonathan J Norman Paul E PE Powell Janet T JT Humphries Steve E SE Hamby Stephen E SE Goodall Alison H AH Nelson Christopher P CP Sakalihasan Natzi N Courtois Audrey A Ferrell Robert E RE Eriksson Per P Folkersen Lasse L Franco-Cereceda Anders A Eicher John D JD Johnson Andrew D AD Betsholtz Christer C Ruusalepp Arno A Franzén Oscar O Schadt Eric E EE Björkegren Johan L M JL Lipovich Leonard L Drolet Anne M AM Verhoeven Eric L EL Zeebregts Clark J CJ Geelkerken Robert H RH van Sambeek Marc R MR van Sterkenburg Steven M SM de Vries Jean-Paul JP Stefansson Kari K Thompson John R JR de Bakker Paul I W PI Deloukas Panos P Sayers Robert D RD Harrison Seamus C SC van Rij Andre M AM Samani Nilesh J NJ Bown Matthew J MJ

Circulation research 20161129 2

<h4>Rationale</h4>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.<h4>Objective</h4>To identify additional AAA risk loci using data from all available genome-wide association studies.<h4>Methods and results</h4>Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 contr ...[more]

PMID: 27899403

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Project description:BackgroundUnderstanding the hemodynamics of an abdominal aortic aneurysm (AAA) is crucial for risk assessment and treatment planning. This study introduces a low-cost, patient-specific in vitro AAA model to investigate hemodynamics using particle image velocimetry (PIV) and flow-simulating circuit, validated through fluid-structure interaction (FSI) simulations.MethodsIn this study, 3D printing was employed to manufacture a flexible patient-specific AAA phantom using a lost-core casting technique. A pulsatile flow circuit was constructed using off-the-shelf components. A particle image velocimetry (PIV) setup was built using an affordable laser source and global shutter camera, and finally, the flow field inside the AAA was analyzed using open-source software. Fluid-structure interaction (FSI) simulations were performed to enhance our understanding of the flow field, and the results were validated by PIV analysis. Both steady-state and transient flow conditions were investigated.ResultsOur experimental setup replicated physiological conditions, analyzing arterial wall deformations and flow characteristics within the aneurysm. Under constant flow, peak wall deformations and flow velocities showed deviations within - 12% to + 27% and - 7% to + 5%, respectively, compared to FSI simulations. Pulsatile flow conditions further demonstrated a strong correlation (Pearson coefficient 0.85) in flow velocities and vectors throughout the cardiac cycle. Transient phenomena, particularly the formation and progression of vortex structures during systole, were consistently depicted between experimental and numerical models.ConclusionsBy bridging high-fidelity experimental observations with comprehensive computational analyses, this study underscores the potential of integrated methodologies in enhancing our understanding of AAA pathophysiology. The convergence of realistic AAA phantoms, precise PIV measurements at affordable cost point, and validated FSI models heralds a new paradigm in vascular research, with significant implications for personalized medicine and bioengineering innovations.

Project description:BackgroundAbdominal aortic aneurysm (AAA) is life-threatening, surgical treatment is currently the only clinically available intervention for the disease. Mesenchymal stem cells (MSCs) have presented eligible immunomodulatory and regenerative abilities which showed favorable therapeutic efficacy in various cardiovascular diseases. However, current evidence summarizing the effectiveness of MSCs for AAA is lacking. Thus, a meta-analysis and systematic review was necessary to be performed to assess the therapeutic efficacy of MSCs for AAA in preclinical studies.MethodsComprehensive literature search restricted in English was conducted in PubMed, Cochrane Library, EBSCO, EMBASE and Web of Science from inception to Oct 2021. The primary outcomes were parameters about aortic diameter change during MSCs intervention. The secondary outcomes included elastin content and expression level of inflammatory cytokines, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Data were extracted and analyzed independently by two authors. The meta package with random effects model was used to calculate the pooled effect size and 95% confidence intervals in R (version 4.0.2).ResultsMeta-analysis of 18 included studies demonstrated that MSCs intervention has significant therapeutic effects on suppressing aortic diameter enlargement compared with the control group (diameter, SMD = - 1.19, 95% CI [- 1.47, - 0.91]; diameter change ratio, SMD = - 1.36, 95% CI [- 1.72, - 1.00]). Subgroup analysis revealed differences between MSCs and control group regarding to cell type, intervention route and cell compatibility. Moreover, the meta-analysis also showed that MSCs intervention had a significant effect on preserving aortic elastin content, reducing MCP-1, TNF-α, IL-6, MMP-2/9 and increasing TIMP-1/2 expression level compared with control group.ConclusionOur results suggested that MSC intervention is effective in AAA by suppressing aortic diameter enlargement, reducing elastin degradation, and modulating local immunoinflammatory reactions. These results are important for the systemic application of MSCs as a potential treatment candidate for AAA in further animal experiments and clinical trials.

Dataset Information

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Rationale

Objective

Methods and results

Conclusions

Publications

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Similar Datasets

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