Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery

BMC Medical Genomics

Brian J Bennett²  Aldons J Lusis¹  Pamela M Quizon²  Jody Albright² 

[1] Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA;Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 2808, USA

关键词: inflammation;    Co-expression network;    Atherosclerosis;   

Others  :  1090563
DOI  :  10.1186/1755-8794-7-51

 received in 2014-04-08, accepted in 2014-07-17,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Albright et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman M, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, et al.: Executive summary: heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation 2013, 127:143-152.
• [2]Lusis AJ, Mar R, Pajukanta P: Genetics of atherosclerosis. Annu Rev Genomics Hum Genet 2004, 5:189-218.
• [3]Homma S, Ishii T, Malcom GT, Zieske AW, Strong JP, Tsugane S, Hirose N: Histopathological modifications of early atherosclerotic lesions by risk factors–findings in PDAY subjects. Atherosclerosis 2001, 156:389-399.
• [4]Yan ZQ, Hansson GK: Innate immunity, macrophage activation, and atherosclerosis. Immunol Rev 2007, 219:187-203.
• [5]Kolodgie FD, Narula J, Burke AP, Haider N, Farb A, Hui-Liang Y, Smialek J, Virmani R: Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 2000, 157:1259-1268.
• [6]Ross R: Atherosclerosis–an inflammatory disease. N Engl J Med 1999, 340:115-126.
• [7]Libby P: Inflammation in atherosclerosis. Nature 2002, 420:868-874.
• [8]Glass CK, Witztum JL: Atherosclerosis. the road ahead. Cell 2001, 104:503-516.
• [9]Falk E: Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006, 47:C7-C12.
• [10]Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM: Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000, 20:1262-1275.
• [11]Hansson GK, Libby P: The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006, 6:508-519.
• [12]Qiao JH, Tripathi J, Mishra NK, Cai Y, Tripathi S, Wang XP, Imes S, Fishbein MC, Clinton SK, Libby P, Lusis AJ, Rajavashisth TB: Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 1997, 150:1687-1699.
• [13]Smith JD, 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, 92:8264-8268.
• [14]Trogan E, Feig JE, Dogan S, Rothblat GH, Angeli V, Tacke F, Randolph GJ, Fisher EA: Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in Apoe-deficient mice. Proc Natl Acad Sci U S A 2006, 103:3781-3786.
• [15]Bennett BJ, Wang SS, Wang XP, Wu X, Lusis AJ: Genetic regulation of atherosclerotic plaque size and morphology in the innominate artery of hyperlipidemic mice. Arterioscler Thromb Vasc Biol 2009, 29:348-355.
• [16]Wang SS, Schadt EE, Wang H, Wang X, Ingram-Drake L, Shi W, Drake TA, Lusis AJ: Identification of pathways for atherosclerosis in mice: integration of quantitative trait locus analysis and global gene expression data. Circ Res 2007, 101:e11-e30.
• [17]Paigen B, Mitchell D, Reue K, Morrow A, Lusis AJ, LeBoeuf RC: Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci U S A 1987, 84:3763-3767.
• [18]Wang SS, Shi W, Wang X, Velky L, Greenlee S, Wang MT, Drake TA, Lusis AJ: Mapping, genetic isolation, and characterization of genetic loci that determine resistance to atherosclerosis in C3H mice. Arterioscler Thromb Vasc Biol 2007, 12:2671-2676.
• [19]Zhao L, Hall JA, Levenkova N, Lee E, Middleton MK, Zukas AM, Rader DJ, Rux JJ, Pure E: CD44 regulates vascular gene expression in a proatherogenic environment. Arterioscler Thromb Vasc Biol 2007, 27:886-892.
• [20]Zhao L, Lee E, Zukas AM, Middleton MK, Kinder M, Acharya PS, Hall JA, Rader DJ, Pure E: CD44 expressed on both bone marrow-derived and non-bone marrow-derived cells promotes atherogenesis in Apoe-deficient mice. Arterioscler Thromb Vasc Biol 2008, 28:1283-1289.
• [21]Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E, Henson PM, Noble PW: Resolution of lung inflammation by CD44. Science 2002, 296:155-158.
• [22]Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, Drake TA, Lusis AJ: Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 2006, 16:995-1004.
• [23]Langfelder P, Horvath S: WGCNA: an R package for weighted gene co-expression network analysis. BMC Bioinform 2008, 9:559.
• [24]Plaisier CL, Horvath S, Huertas-Vazquez A, Cruz-Bautista I, Herrera MF, Tusie-Luna T, Aguilar-Salinas C, Pajukanta P: A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. PLoS Genet 2009, 5:e1000642.
• [25]Gargalovic PS, Imura M, Zhang B, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Patel S, Nelson SF, Horvath S, Berliner JA, Kirchgessner TG, Lusis AJ: Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids. Proc Natl Acad Sci U S A 2006, 103:12741-12746.
• [26]Oldham MC, Horvath S, Geschwind DH: Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc Natl Acad Sci U S A 2006, 103:17973-17978.
• [27]van Nas A, Guhathakurta D, Wang SS, Yehya N, Horvath S, Zhang B, Ingram-Drake L, Chaudhuri G, Schadt EE, Drake TA, Arnold AP, Lusis AJ: Elucidating the role of gonadal hormones in sexually dimorphic gene coexpression networks. Endocrinology 2009, 150:1235-1249.
• [28]Park CC, Gale GD, de Jong S, Ghazalpour A, Bennett BJ, Farber CR, Langfelder P, Lin A, Khan AH, Eskin E, Horvath S, Lusis AJ, Ophoff RA, Smith DJ: Gene networks associated with conditional fear in mice identified using a systems genetics approach. BMC Syst Biol 2011, 5:43.
• [29]Yang X, Peterson L, Thieringer R, Deignan JL, Wang X, Zhu J, Wang S, Zhong H, Stepaniants S, Beaulaurier J, Wang IM, Rosa R, Cumiskey AM, Luo JM, Luo Q, Shah K, Xiao J, Nickle D, Plump A, Schadt EE, Lusis AJ, Lum PY: Identification and validation of genes affecting aortic lesions in mice. J Clin Invest 2010, 120:2414-2422.
• [30]Zhang B, Horvath S: A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 2005, 4:17.
• [31]Langfelder P, Zhang B, Horvath S: Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics 2008, 24:719-720.
• [32]Saito R, Smoot ME, Ono K, Ruscheinski J, Wang PL, Lotia S, Pico AR, Bader GD, Ideker T: A travel guide to Cytoscape plugins. Nat Methods 2012, 9:1069-1076.
• [33]da Huang W, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC, Lempicki RA: DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 2007, 35:W169-W175.
• [34]Aten JE, Fuller TF, Lusis AJ, Horvath S: Using genetic markers to orient the edges in quantitative trait networks: the NEO software. BMC Syst Biol 2008, 2:34.
• [35]Farber CR, van Nas A, Ghazalpour A, Aten JE, Doss S, Sos B, Schadt EE, Ingram-Drake L, Davis RC, Horvath S, Smith DJ, Drake TA, Lusis AJ: An integrative genetics approach to identify candidate genes regulating BMD: combining linkage, gene expression, and association. J Bone Miner Res 2009, 24:105-116.
• [36]Orozco LD, Bennett BJ, Farber CR, Ghazalpour A, Pan C, Che N, Wen P, Qi HX, Mutukulu A, Siemers N, Neuhaus I, Yordanova R, Gargalovic P, Pellegrini M, Kirchgessner T, Lusis AJ: Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell 2012, 151:658-670.
• [37]Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW: 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, 92:1355-1374.
• [38]Flint J, Valdar W, Shifman S, Mott R: Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 2005, 6:271-286.
• [39]Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK, Leonardson A, Castellini LW, Wang S, Champy MF, Zhang B, Emilsson V, Doss S, Ghazalpour A, Horvath S, Drake TA, Lusis AJ, Schadt EE: Variations in DNA elucidate molecular networks that cause disease. Nature 2008, 452:429-435.
• [40]Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM: Advanced atherosclerotic lesions in the innominate artery of the Apoe knockout mouse. Arterioscler Thromb Vasc Biol 2000, 20:2587-2592.
• [41]Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma'ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ, Immunological Genome Consortium: Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 2012, 13:1118-1128.
• [42]Yang X, Deignan JL, Qi H, Zhu J, Qian S, Zhong J, Torosyan G, Majid S, Falkard B, Kleinhanz RR, Karlsson J, Castellani LW, Mumick S, Wang K, Xie T, Coon M, Zhang C, Estrada-Smith D, Farber CR, Wang SS, van Nas A, Ghazalpour A, Zhang B, Macneil DJ, Lamb JR, Dipple KM, Reitman ML, Mehrabian M, Lum PY, Schadt EE, et al.: Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat Genet 2009, 41:415-423.
• [43]Calabrese G, Bennett BJ, Orozco L, Kang HM, Eskin E, Dombret C, De Backer O, Lusis AJ, Farber CR: Systems genetic analysis of osteoblast-lineage cells. PLoS Genet 2012, 8:e1003150.
• [44]Park H, Chan MM, Iritani BM: Hem-1: putting the "WAVE" into actin polymerization during an immune response. FEBS Lett 2010, 584:4923-4932.
• [45]Medrano-Fernandez I, Reyes R, Olazabal I, Rodriguez E, Sanchez-Madrid F, Boussiotis VA, Reche PA, Cabanas C, Lafuente EM: RIAM (Rap1-interacting adaptor molecule) regulates complement-dependent phagocytosis. Cell Mol Life Sci CMLS 2013, 70:2395-2410.
• [46]Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV: A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med 2009, 15(3):313-318.
• [47]Sancho-Shimizu V, Malo D: Sequencing, expression, and functional analyses support the candidacy of Ncf2 in susceptibility to Salmonella typhimurium infection in wild-derived mice. J Immunol 2006, 176:6954-6961.
• [48]Santoni G, Farfariello V, Liberati S, Morelli MB, Nabissi M, Santoni M, Amantini C: The role of transient receptor potential vanilloid type-2 ion channels in innate and adaptive immune responses. Front Immunol 2013, 4:34.
• [49]Szollosi AG, Olah A, Toth IB, Papp F, Czifra G, Panyi G, Biro T: Transient receptor potential vanilloid-2 mediates the effects of transient heat shock on endocytosis of human monocyte-derived dendritic cells. FEBS Lett 2013, 587:1440-1445.
• [50]Giguere PM, Billard MJ, Laroche G, Buckley BK, Timoshchenko RG, McGinnis MW, Esserman D, Foreman O, Liu P, Siderovski DP, Tarrant TK: G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis. Mol Immunol 2013, 54:193-198.
• [51]Imai K, Nonoyama S, Ochs HD: WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol 2003, 3:427-436.
• [52]Mao D, Epple H, Uthgenannt B, Novack DV, Faccio R: PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest 2006, 116:2869-2879.
• [53]Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A, Martins MS, Bunney TD, Santich BH, Moir S, Kuhns DB, Long Priel DA, Ombrello A, Stone D, Ombrello MJ, Khan J, Milner JD, Kastner DL, Aksentijevich I: A hypermorphic missense mutation in PLCG2, encoding phospholipase Cgamma2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet 2012, 91:713-720.
• [54]van Nas A, Pan C, Ingram-Drake LA, Ghazalpour A, Drake TA, Sobel EM, Papp JC, Lusis AJ: The systems genetics resource: a web application to mine global data for complex disease traits. Front Genet 2013, 4:84.
• [55]Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL: Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 1992, 71:343-353.
• [56]Dansky HM, Shu P, Donavan M, Montagno J, Nagle DL, Smutko JS, Roy N, Whiteing S, Barrios J, McBride TJ, Smith JD, Duyk G, Breslow JL, Moore KJ: A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. Genetics 2002, 160:1599-1608.
• [57]Smith JD, Bhasin JM, 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 2006, 26:597-603.
• [58]Zhao L, Hall JA, Levenkova N, Lee E, Middleton MK, Zukas AM, Rader DJ, Rux JJ, Pure E: CD44 regulates vascular gene expression in a proatherogenic environment. Arterioscler Thromb Vasc Biol 2007, 27:886-892.
• [59]Raines EW, Ferri N: Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J Lipid Res 2005, 46:1081-1092.