Genetic Network Identifies Novel Pathways Contributing to Atherosclerosis Susceptibility in the Innominate Artery

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2014 Aug 14

PMID 25115202

Citations 6

Authors

Jody Albright

Pamela M Quizon

Aldons J Lusis

Brian J Bennett

Affiliations

Soon will be listed here.

Abstract

Background: Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors.

Methods: In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies.

Results: We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice.

Conclusion: These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes.

Citing Articles

Signature transcriptome analysis of stage specific atherosclerotic plaques of patients.

Verma S, Kumar A, Narang R, Bisoi A, Mitra D BMC Med Genomics. 2022; 15(1):99.

PMID: 35488341 PMC: 9055692. DOI: 10.1186/s12920-022-01250-8.

Obesogenic and diabetic effects of CD44 in mice are sexually dimorphic and dependent on genetic background.

VerHague M, Albright J, Barron K, Kim M, Bennett B Biol Sex Differ. 2022; 13(1):14.

PMID: 35410390 PMC: 8996418. DOI: 10.1186/s13293-022-00426-2.

Weighted Gene Co-expression Network Analysis Identifies Crucial Genes Mediating Progression of Carotid Plaque.

Chen M, Chen S, Yang D, Zhou J, Liu B, Chen Y Front Physiol. 2021; 12:601952.

PMID: 33613306 PMC: 7894049. DOI: 10.3389/fphys.2021.601952.

Macrophage Trafficking, Inflammatory Resolution, and Genomics in Atherosclerosis: JACC Macrophage in CVD Series (Part 2).

Moore K, Koplev S, Fisher E, Tabas I, Bjorkegren J, Doran A J Am Coll Cardiol. 2018; 72(18):2181-2197.

PMID: 30360827 PMC: 6522246. DOI: 10.1016/j.jacc.2018.08.2147.

Analytical Strategy to Prioritize Alzheimer's Disease Candidate Genes in Gene Regulatory Networks Using Public Expression Data.

Kawalia S, Raschka T, Naz M, De Matos Simoes R, Senger P, Hofmann-Apitius M J Alzheimers Dis. 2017; 59(4):1237-1254.

PMID: 28800327 PMC: 5611835. DOI: 10.3233/JAD-170011.

References

Medrano-Fernandez I, Reyes R, Olazabal I, Rodriguez E, Sanchez-Madrid F, Boussiotis V . RIAM (Rap1-interacting adaptor molecule) regulates complement-dependent phagocytosis. Cell Mol Life Sci. 2013; 70(13):2395-410. PMC: 5474120. DOI: 10.1007/s00018-013-1268-6. View

Smith J, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M . Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995; 92(18):8264-8. PMC: 41137. DOI: 10.1073/pnas.92.18.8264. View

Flint J, Valdar W, Shifman S, Mott R . Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet. 2005; 6(4):271-86. DOI: 10.1038/nrg1576. View

Gargalovic P, Imura M, Zhang B, Gharavi N, Clark M, Pagnon J . Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids. Proc Natl Acad Sci U S A. 2006; 103(34):12741-6. PMC: 1568918. DOI: 10.1073/pnas.0605457103. View

Smith J, Bhasin J, Baglione J, Settle M, Xu Y, Barnard J . Atherosclerosis susceptibility loci identified from a strain intercross of apolipoprotein E-deficient mice via a high-density genome scan. Arterioscler Thromb Vasc Biol. 2005; 26(3):597-603. DOI: 10.1161/01.ATV.0000201044.33220.5c. View

Malinin N, Zhang L, Choi J, Ciocea A, Razorenova O, Ma Y . A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009; 15(3):313-8. PMC: 2857384. DOI: 10.1038/nm.1917. View

Rosenfeld M, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz S . Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000; 20(12):2587-92. DOI: 10.1161/01.atv.20.12.2587. View

Langfelder P, Horvath S . WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9:559. PMC: 2631488. DOI: 10.1186/1471-2105-9-559. View

STARY H, Chandler A, Dinsmore R, Fuster V, Glagov S, INSULL Jr W . A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995; 92(5):1355-74. DOI: 10.1161/01.cir.92.5.1355. View

10.

Zhou Q, Lee G, Brady J, Datta S, Katan M, Sheikh A . A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012; 91(4):713-20. PMC: 3484656. DOI: 10.1016/j.ajhg.2012.08.006. View

11.

Mao D, Epple H, Uthgenannt B, Novack D, Faccio R . PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest. 2006; 116(11):2869-79. PMC: 1616195. DOI: 10.1172/JCI28775. View

12.

Szollosi A, Olah A, Toth I, Papp F, Czifra G, Panyi G . Transient receptor potential vanilloid-2 mediates the effects of transient heat shock on endocytosis of human monocyte-derived dendritic cells. FEBS Lett. 2013; 587(9):1440-5. DOI: 10.1016/j.febslet.2013.03.027. View

13.

Imai K, Nonoyama S, Ochs H . WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol. 2003; 3(6):427-36. DOI: 10.1097/00130832-200312000-00003. View

14.

Plump A, Smith J, Hayek T, Aalto-Setala K, Walsh A, Verstuyft J . Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992; 71(2):343-53. DOI: 10.1016/0092-8674(92)90362-g. View

15.

Park H, Chan M, Iritani B . Hem-1: putting the "WAVE" into actin polymerization during an immune response. FEBS Lett. 2010; 584(24):4923-32. PMC: 3363972. DOI: 10.1016/j.febslet.2010.10.018. View

16.

Raines E, Ferri N . Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J Lipid Res. 2005; 46(6):1081-92. DOI: 10.1194/jlr.R500004-JLR200. View

17.

Yang X, Peterson L, Thieringer R, Deignan J, Wang X, Zhu J . Identification and validation of genes affecting aortic lesions in mice. J Clin Invest. 2010; 120(7):2414-22. PMC: 2898611. DOI: 10.1172/JCI42742. View

18.

Hansson G, Libby P . The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6(7):508-19. DOI: 10.1038/nri1882. View

19.

Yang X, Schadt E, Wang S, Wang H, Arnold A, Ingram-Drake L . Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 2006; 16(8):995-1004. PMC: 1524872. DOI: 10.1101/gr.5217506. View

20.

Plaisier C, Horvath S, Huertas-Vazquez A, Cruz-Bautista I, Herrera M, Tusie-Luna T . A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. PLoS Genet. 2009; 5(9):e1000642. PMC: 2730565. DOI: 10.1371/journal.pgen.1000642. View