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Are toll-like receptors potential drug targets for atherosclerosis? Evidence from genetic studies to date

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Abstract

Low-density lipoprotein cholesterol lowering, most notably via statin therapy, has successfully reduced the burden of coronary artery disease (CAD) in recent decades. However, the residual risk remaining even after aggressive lipid lowering has renewed interest in alternative targets. Anti-inflammatory drugs are thought to have much potential in this context, but side effects associated with long-term use of conventional anti-inflammatories, such as NSAIDs and glucocorticoids, preclude their use as preventive agents for CAD. Evidence from epidemiological studies and murine models of atherosclerosis suggests that toll-like receptors (TLRs) may have utility as targets for more focused anti-inflammatories, but it remains unclear if this pathway is causally related to CAD in man. Here, we review recent insight into this question gained from genetic studies of cardiovascular risk and innate immune function, focussing on the potential of Mendelian randomisation approaches based on intracellular-signalling pathways to identify and prioritise targets for drug development.

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References

  • Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191

    Article  CAS  PubMed  Google Scholar 

  • Ashida K, Miyazaki K, Takayama E, Tsujimoto H, Ayaori M, Yakushiji T, Iwamoto N, Yonemura A, Isoda K, Mochizuki H, Hiraide H, Kusuhara M, Ohsuzu F (2005) Characterization of the expression of TLR2 (toll-like receptor 2) and TLR4 on circulating monocytes in coronary artery disease. J Atheroscler Thromb 12:53–60

    Article  CAS  PubMed  Google Scholar 

  • Bronson PG, Chaivorapol C, Ortmann W, Behrens TW, Graham RR (2012) The genetics of type I interferon in systemic lupus erythematosus. Curr Opin Immunol 24:530–537

    Article  CAS  PubMed  Google Scholar 

  • Cole JE, Navin TJ, Cross AJ, Goddard ME, Alexopoulou L, Mitra AT, Davies AH, Flavell RA, Feldmann M, Monaco C (2011) Unexpected protective role for toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A 108:2372–2377

    Article  PubMed  PubMed Central  Google Scholar 

  • de Craen AJ, Posthuma D, Remarque EJ, van den Biggelaar AH, Westendorp RG, Boomsma DI (2005) Heritability estimates of innate immunity: an extended twin study. Genes Immun 6:167–170

    Article  CAS  PubMed  Google Scholar 

  • Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, Pellikka N, Wallaschofski H, Kettunen J, Henneman P, Baumert J, Strachan DP, Fuchsberger C, Vitart V, Wilson JF, Paré G, Naitza S, Rudock ME, Surakka I, de Geus EJC, Alizadeh BZ, Guralnik J, Shuldiner A, Tanaka T, Zee RYL, Schnabel RB, Nambi V, Kavousi M, Ripatti S, Nauck M, Smith NL, Smith AV, Sundvall J, Scheet P, Liu Y, Ruokonen A, Rose LM, Larson MG, Hoogeveen RC, Freimer NB, Teumer A, Tracy RP, Launer LJ, Buring JE, Yamamoto JF, Folsom AR, Sijbrands EJG, Pankow J, Elliott P, Keaney JF, Sun W, Sarin AP, Fontes JD, Badola S, Astor BC, Hofman A, Pouta A, Werdan K, Greiser KH, Kuss O, Meyer zu Schwabedissen HE, Thiery J, Jamshidi Y, Nolte IM, Soranzo N, Spector TD, Völzke H, Parker AN, Aspelund T, Bates D, Young L, Tsui K, Siscovick DS, Guo X, Rotter JI, Uda M, Schlessinger D, Rudan I, Hicks AA, Penninx BW, Thorand B, Gieger C, Coresh J, Willemsen G, Harris TB, Uitterlinden AG, Järvelin MR, Rice K, Radke D, Salomaa V, Willems van Dijk K, Boerwinkle E, Vasan RS, Ferrucci L, Gibson QD, Bandinelli S, Snieder H, Boomsma DI, Xiao X, Campbell H, Hayward C, Pramstaller PP, van Duijn CM, Peltonen L, Psaty BM, Gudnason V, Ridker PM, Homuth G, Koenig W, Ballantyne CM, Witteman JCM, Benjamin EJ, Perola M, Chasman DI (2011) Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123:731–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, den Hertog HM, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkilä K, Hyppönen E, Isaacs A, Jackson AU, Johansson Å, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J’, Lyytikäinen LP, Magnusson PKE, Mangino M, Mihailov E, Montasser ME, Müller-Nurasyid M, Nolte IM, O’Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney ASF, Döring A, Elliott P, Epstein SE, Eyjolfsson GI, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJP, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimäki T, Lin SY, Lindström J, Loos RJF, Mach F, McArdle WL, Meisinger C, Mitchell BD, Müller G, Nagaraja R, Narisu N, Nieminen TVM, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stančáková A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YDI, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrières J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Järvelin MR, Jula A, Kähönen M, Kaprio J, Kesäniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, März W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njølstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PEH, Sheu WHH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BHR, Altshuler D, Ordovas JM, Boerwinkle E, Palmer CNA, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Mohlke KL, Ingelsson E, Abecasis GR, Daly MJ, Neale BM, Kathiresan S (2013) Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 45:1345–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, Erdmann J, Braund P, Engert JC, Bennett D, Coin L, Ashby D, Tzoulaki I, Brown IJ, Mt-Isa S, McCarthy MI, Peltonen L, Freimer NB, Farrall M, Ruokonen A, Hamsten A, Lim N, Froguel P, Waterworth DM, Vollenweider P, Waeber G, Jarvelin MR, Mooser V, Scott J, Hall AS, Schunkert H, Anand SS, Collins R, Samani NJ, Watkins H, Kooner JS (2009) Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302:37–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elsenberg EH, Sels JE, Hillaert MA, Schoneveld AH, van den Dungen NA, van Holten TC, Roest M, Jukema JW, van Zonneveld AJ, de Groot PG, Pijls N, Pasterkamp G, Hoefer IE (2013) Increased cytokine response after toll-like receptor stimulation in patients with stable coronary artery disease. Atherosclerosis 231:346–351

    Article  CAS  PubMed  Google Scholar 

  • Erridge C (2008) The roles of pathogen-associated molecular patterns in atherosclerosis. Trends Cardiovasc Med 18:52–56

    Article  CAS  PubMed  Google Scholar 

  • Erridge C, Stewart J, Poxton IR (2003) Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the toll-like receptor 4 gene show no deficit in LPS signalling. J Exp Med 197:1787–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fairfax BP, Humburg P, Makino S, Naranbhai V, Wong D, Lau E, Jostins L, Plant K, Andrews R, McGee C, Knight JC (2014) Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343:1246949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferwerda B, McCall MB, Verheijen K, Kullberg BJ, van der Ven AJ, Van der Meer JW, Netea MG (2008) Functional consequences of toll-like receptor 4 polymorphisms. Mol Med 14:346–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of toll-like receptor signalling complexes. Nat Rev Immunol 14:546–558

    Article  CAS  PubMed  Google Scholar 

  • Gerstein MB, Kundaje A, Hariharan M, Landt SG, Yan KK, Cheng C, Mu XJ, Khurana E, Rozowsky J, Alexander R, Min R, Alves P, Abyzov A, Addleman N, Bhardwaj N, Boyle AP, Cayting P, Charos A, Chen DZ, Cheng Y, Clarke D, Eastman C, Euskirchen G, Frietze S, Fu Y, Gertz J, Grubert F, Harmanci A, Jain P, Kasowski M, Lacroute P, Leng JJ, Lian J, Monahan H, O’Geen H, Ouyang Z, Partridge EC, Patacsil D, Pauli F, Raha D, Ramirez L, Reddy TE, Reed B, Shi M, Slifer T, Wang J, Wu L, Yang X, Yip KY, Zilberman-Schapira G, Batzoglou S, Sidow A, Farnham PJ, Myers RM, Weissman SM, Snyder M (2012) Architecture of the human regulatory network derived from ENCODE data. Nature 489:91–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh S, Vivar J, Nelson CP, Willenborg C, Segrè AV, Mäkinen VP, Nikpay M, Erdmann J, Blankenberg S, O’Donnell C, März W, Laaksonen R, Stewart AF, Epstein SE, Shah SH, Granger CB, Hazen SL, Kathiresan S, Reilly MP, Yang X, Quertermous T, Samani NJ, Schunkert H, Assimes TL, McPherson R (2015) Systems genetics analysis of genome-wide association study reveals novel associations between key biological processes and coronary artery disease. Arterioscler Thromb Vasc Biol 35:1712–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabási AL (2007) The human disease network. Proc Natl Acad Sci U S A 104:8685–8690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goossens P, Gijbels MJ, Zernecke A, Eijgelaar W, Vergouwe MN, van der Made I, Vanderlocht J, Beckers L, Buurman WA, Daemen MJ, Kalinke U, Weber C, Lutgens E, de Winther MP (2010) Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab 12:142–153

    Article  CAS  PubMed  Google Scholar 

  • Hawn TR, Scholes D, Li SS, Wang H, Yang Y, Roberts PL, Stapleton AE, Janer M, Aderem A, Stamm WE, Zhao LP, Hooton TM (2009) Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One 4:e5990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmes MV, Simon T, Exeter HJ, Folkersen L, Asselbergs FW, Guardiola M, Cooper JA, Palmen J, Hubacek JA, Carruthers KF, Horne BD, Brunisholz KD, Mega JL, van Iperen EPA, Li M, Leusink M, Trompet S, Verschuren JJW, Hovingh GK, Dehghan A, Nelson CP, Kotti S, Danchin N, Scholz M, Haase CL, Rothenbacher D, Swerdlow DI, Kuchenbaecker KB, Staines-Urias E, Goel A, van ‘t Hooft F, Gertow K, de Faire U, Panayiotou AG, Tremoli E, Baldassarre D, Veglia F, Holdt LM, Beutner F, Gansevoort RT, Navis GJ, Mateo Leach I, Breitling LP, Brenner H, Thiery J, Dallmeier D, Franco-Cereceda A, Boer JMA, Stephens JW, Hofker MH, Tedgui A, Hofman A, Uitterlinden AG, Adamkova V, Pitha J, Onland-Moret NC, Cramer MJ, Nathoe HM, Spiering W, Klungel OH, Kumari M, Whincup PH, Morrow DA, Braund PS, Hall AS, Olsson AG, Doevendans PA, Trip MD, Tobin MD, Hamsten A, Watkins H, Koenig W, Nicolaides AN, Teupser D, Day INM, Carlquist JF, Gaunt TR, Ford I, Sattar N, Tsimikas S, Schwartz GG, Lawlor DA, Morris RW, Sandhu MS, Poledne R, Maitland-van der Zee AH, Khaw KT, Keating BJ, van der Harst P, Price JF, Mehta SR, Yusuf S, Witteman JCM, Franco OH, Jukema JW, de Knijff P, Tybjaerg-Hansen A, Rader DJ, Farrall M, Samani NJ, Kivimaki M, Fox KAA, Humphries SE, Anderson JL, Boekholdt SM, Palmer TM, Eriksson P, Paré G, Hingorani AD, Sabatine MS, Mallat Z, Casas JP, Talmud PJ (2013) Secretory phospholipase A2-IIA and cardiovascular disease: a Mendelian randomization study. J Am Coll Cardiol 62:1966–1976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (2006) Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332:1302–1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J (2001) Chronic infections and the risk of carotid atherosclerosis prospective results from a large population study. Circulation 103:1064–1070

    Article  CAS  PubMed  Google Scholar 

  • Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347:185–192

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Becker J, Bechheim M, Kaiser V, Noursadeghi M, Fricker N, Beier E, Klaschik S, Boor P, Hess T, Hofmann A, Holdenrieder S, Wendland JR, Fröhlich H, Hartmann G, Nöthen MM, Müller-Myhsok B, Pütz B, Hornung V, Schumacher J (2014) Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes. Nat Commun 5:5236

    Article  CAS  PubMed  Google Scholar 

  • Koulis C, Chen YC, Hausding C, Ahrens I, Kyaw TS, Tay C, Allen T, Jandeleit-Dahm K, Sweet MJ, Akira S, Bobik A, Peter K, Agrotis A (2014) Protective role for toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 34:516–525

    Article  CAS  PubMed  Google Scholar 

  • Larsen MH, Albrechtsen A, Thørner LW, Werge T, Hansen T, Gether U, Haastrup E, Ullum H (2013) Genome-wide association study of genetic variants in LPS-stimulated IL-6, IL-8, IL-10, IL-1ra and TNF-α cytokine response in a Danish cohort. PLoS One 8:e66262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee MN, Ye C, Villani AC, Raj T, Li W, Eisenhaure TM, Imboywa SH, Chipendo PI, Ran FA, Slowikowski K, Ward LD, Raddassi K, McCabe C, Lee MH, Frohlich IY, Hafler DA, Kellis M, Raychaudhuri S, Zhang F, Stranger BE, Benoist CO, De Jager PL, Regev A, Hacohen N (2014) Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343:1246980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levy Z, Rachmani R, Trestman S, Dvir A, Shaish A, Ravid M, Harats D (2003) Low-dose interferon-alpha accelerates atherosclerosis in an LDL receptor-deficient mouse model. Eur J Intern Med 14:479–483

    Article  CAS  PubMed  Google Scholar 

  • Lewis SJ (2010) Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology. Circ Cardiovasc Genet 3:109–117

    Article  PubMed  Google Scholar 

  • Li Y, Oosting M, Deelen P, Ricaño-Ponce I, Smeekens S, Jaeger M, Matzaraki V, Swertz MA, Xavier RJ, Franke L, Wijmenga C, Joosten LA, Kumar V, Netea MG (2016) Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi. Nat Med 22:952–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linsel-Nitschke P, Götz A, Erdmann J, Braenne I, Braund P, Hengstenberg C, Stark K, Fischer M, Schreiber S, El Mokhtari NE, Schaefer A, Schrezenmeir J, Rubin D, Hinney A, Reinehr T, Roth C, Ortlepp J, Hanrath P, Hall AS, Mangino M, Lieb W, Lamina C, Heid IM, Doering A, Gieger C, Peters A, Meitinger T, Wichmann HE, König IR, Ziegler A, Kronenberg F, Samani NJ, Schunkert H, Wellcome Trust Case Control Consortium (WTCCC); Cardiogenics Consortium (2008) Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian randomisation study. PLoS One 3:e2986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mäkinen VP, Civelek M, Meng Q, Zhang B, Zhu J, Levian C, Huan T, Segrè AV, Ghosh S, Vivar J, Nikpay M, Stewart AF, Nelson CP, Willenborg C, Erdmann J, Blakenberg S, O’Donnell CJ, März W, Laaksonen R, Epstein SE, Kathiresan S, Shah SH, Hazen SL, Reilly MP, Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium, Lusis AJ, Samani NJ, Schunkert H, Quertermous T, McPherson R, Yang X, Assimes TL (2014) Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet 10:e1004502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malik TH, Cortini A, Carassiti D, Boyle JJ, Haskard DO, Botto M (2010) The alternative pathway is critical for pathogenic complement activation in endotoxin- and diet-induced atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 122:1948–1956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayerle J, den Hoed CM, Schurmann C, Stolk L, Homuth G, Peters MJ, Capelle LG, Zimmermann K, Rivadeneira F, Gruska S, Völzke H, de Vries AC, Völker U, Teumer A, van Meurs JB, Steinmetz I, Nauck M, Ernst F, Weiss FU, Hofman A, Zenker M, Kroemer HK, Prokisch H, Uitterlinden AG, Lerch MM, Kuipers EJ (2013) Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA 309:1912–1920

    Article  CAS  PubMed  Google Scholar 

  • Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J (2005) Expansion of circulating toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation 111:2654–2661

    Article  CAS  PubMed  Google Scholar 

  • Michelson KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) Lack of toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A 101:10679–10684

    Article  Google Scholar 

  • Mikacenic C, Reiner AP, Holden TD, Nickerson DA, Wurfel MM (2013) Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses. Genes Immun 14:52–57

    Article  CAS  PubMed  Google Scholar 

  • Mullick AE, Tobias PS, Curtiss LK (2005) Modulation of atherosclerosis in mice by toll-like receptor 2. J Clin Invest 115:3149–3156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nabel EG, Braunwald E (2012) A tale of coronary artery disease and myocardial infarction. N Engl J Med 366:54–63

    Article  CAS  PubMed  Google Scholar 

  • Nelson CP, Schunkert H, Samani NJ, Erridge C (2015) Genetic analysis of leukocyte type-I interferon production and risk of coronary artery disease. Arterioscler Thromb Vasc Biol 35:1456–1462

    Article  CAS  PubMed  Google Scholar 

  • Nelson CP, Goel A, Butterworth AS, Kanoni S, Webb TR, Marouli E, Zeng L, Ntalla I, Lai FY, Hopewell JC, Giannakopoulou O, Jiang T, Hamby SE, di Angelantonio E, Assimes TL, Bottinger EP, Chambers JC, Clarke R, Palmer CNA, Cubbon RM, Ellinor P, Ermel R, Evangelou E, Franks PW, Grace C, Gu D, Hingorani AD, Howson JMM, Ingelsson E, Kastrati A, Kessler T, Kyriakou T, Lehtimäki T, Lu X, Lu Y, März W, McPherson R, Metspalu A, Pujades-Rodriguez M, Ruusalepp A, Schadt EE, Schmidt AF, Sweeting MJ, Zalloua PA, AlGhalayini K, Keavney BD, Kooner JS, Loos RJF, Patel RS, Rutter MK, Tomaszewski M, Tzoulaki I, Zeggini E, Erdmann J, Dedoussis G, Björkegren JLM, EPIC-CVD Consortium, CARDIoGRAMplusC4D., UK Biobank CardioMetabolic Consortium CHD working group, Schunkert H, Farrall M, Danesh J, Samani NJ, Watkins H, Deloukas P (2017) Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nat Genet 49:1385–1391

    Article  CAS  PubMed  Google Scholar 

  • Netea MG, van de Veerdonk FL, van Deuren M, van der Meer JW (2011) Defects of pattern recognition: primary immunodeficiencies of the innate immune system. Curr Opin Pharmacol 11:412–422

    Article  CAS  PubMed  Google Scholar 

  • Netea MG, Joosten LA, Li Y, Kumar V, Oosting M, Smeekens S, Jaeger M, Ter Horst R, Schirmer M, Vlamakis H, Notebaart R, Pavelka N, Aguirre-Gamboa RR, Swertz MA, Tunjungputri RN, van de Heijden W, Franzosa EA, Ng A, Graham D, Lassen K, Schraa K, Netea-Maier R, Smit J, de Mast Q, van de Veerdonk F, Kullberg BJ, Tack C, van de Munckhof I, Rutten J, van der Graaf J, Franke L, Hofker M, Jonkers I, Platteel M, Maatman A, Fu J, Zhernakova A, van der Meer JW, Dinarello CA, van der Ven A, Huttenhouwer C, Koenen H, Joosten I, Xavier RJ, Wijmenga C (2016) Understanding human immune function using the resources from the Human Functional Genomics Project. Nat Med 22:831–833

    Article  CAS  PubMed  Google Scholar 

  • Pérez-Zafrilla B, Carmona L, Gómez-Reino JJ (2012) Infections in patients with rheumatic diseases treated with TNF antagonists. Curr Pharm Biotechnol 13:1418–1425

    Article  PubMed  Google Scholar 

  • Reilly M, Miller RM, Thomson MH, Patris V, Ryle P, McLoughlin L, Mutch P, Gilboy P, Miller C, Broekema M, Keogh B, McCormack W, van de Wetering de Rooij J (2013) Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody. Clin Pharmacol Ther 94:593–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group (2017) Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131

    Article  CAS  PubMed  Google Scholar 

  • Rocha VZ, Libby P (2009) Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 6:399–409

    Article  CAS  PubMed  Google Scholar 

  • Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson AD, Teumer A, Reiner AP, Folkersen L, Basu S, Rudnicka AR, Trompet S, Mälarstig A, Baumert J, Bis JC, Guo X, Hottenga JJ, Shin SY, Lopez LM, Lahti J, Tanaka T, Yanek LR, Oudot-Mellakh T, Wilson JF, Navarro P, Huffman JE, Zemunik T, Redline S, Mehra R, Pulanic D, Rudan I, Wright AF, Kolcic I, Polasek O, Wild SH, Campbell H, Curb JD, Wallace R, Liu S, Eaton CB, Becker DM, Becker LC, Bandinelli S, Räikkönen K, Widen E, Palotie A, Fornage M, Green D, Gross M, Davies G, Harris SE, Liewald DC, Starr JM, Williams FM, Grant PJ, Spector TD, Strawbridge RJ, Silveira A, Sennblad B, Rivadeneira F, Uitterlinden AG, Franco OH, Hofman A, van Dongen J, Willemsen G, Boomsma DI, Yao J, Swords Jenny N, Haritunians T, McKnight B, Lumley T, Taylor KD, Rotter JI, Psaty BM, Peters A, Gieger C, Illig T, Grotevendt A, Homuth G, Völzke H, Kocher T, Goel A, Franzosi MG, Seedorf U, Clarke R, Steri M, Tarasov KV, Sanna S, Schlessinger D, Stott DJ, Sattar N, Buckley BM, Rumley A, Lowe GD, McArdle W, Chen MH, Tofler GH, Song J, Boerwinkle E, Folsom AR, Rose LM, Franco-Cereceda A, Teichert M, Ikram MA, Mosley TH, Bevan S, Dichgans M, Rothwell PM, Sudlow CL, Hopewell JC, Chambers JC, Saleheen D, Kooner JS, Danesh J, Nelson CP, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Morange PE, Ferrucci L, Eriksson JG, Jacobs D, Deary IJ, Soranzo N, Witteman JC, de Geus EJ, Tracy RP, Hayward C, Koenig W, Cucca F, Jukema JW, Eriksson P, Seshadri S, Markus HS, Watkins H, Samani NJ, VTE Consortium., STROKE Consortium., Wellcome Trust Case Control Consortium 2 (WTCCC2)., C4D Consortium., CARDIoGRAM Consortium, Wallaschofski H, Smith NL, Tregouet D, Ridker PM, Tang W, Strachan DP, Hamsten A, O’Donnell CJ (2013) Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 128:1310–1324

    Article  CAS  PubMed  Google Scholar 

  • Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators (2017) Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 376:1713–1722

    Article  CAS  PubMed  Google Scholar 

  • Salagianni M, Galani IE, Lundberg AM, Davos CH, Varela A, Gavriil A, Lyytikäinen LP, Lehtimäki T, Sigala F, Folkersen L, Gorgoulis V, Lenglet S, Montecucco F, Mach F, Hedin U, Hansson GK, Monaco C, Andreakos E (2012) TLR7 protects from atherosclerosis by constraining ‘Inflammatory’ macrophage activation. Circulation 126:952–962

    Article  CAS  PubMed  Google Scholar 

  • Schurz H, Daya M, Möller M, Hoal EG, Salie M (2015) TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: a systematic review and meta-analysis. PLoS One 10:e0139711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Den Biggelaar AH, De Craen AJ, Gussekloo J, Huizinga TW, Heijmans BT, Frölich M, Kirkwood TB, Westendorp RG (2004) Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming. FASEB J 18:1022–1024

    Article  CAS  Google Scholar 

  • van Meurs JB, Pare G, Schwartz SM, Hazra A, Tanaka T, Vermeulen SH et al (2013) Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nutr 98:668–676

    Article  PubMed  PubMed Central  Google Scholar 

  • Versteeg D, Hoefer IE, Schoneveld AH, de Kleijn DP, Busser E, Strijder C, Emons M, Stella PR, Doevendans PA, Pasterkamp G (2008) Monocyte toll-like receptor 2 and 4 responses and expression following percutaneous coronary intervention: association with lesion stenosis and fractional flow reserve. Heart 94:770–776

    Article  CAS  PubMed  Google Scholar 

  • Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13:227–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiedermann CI, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J (1999) Association of endotoxaemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol 34:1975–1981

    Article  CAS  PubMed  Google Scholar 

  • Zhang LN, Velichko S, Vincelette J, Fitch RM, Vergona R, Sullivan ME, Croze E, Wang YX (2008) Interferon-beta attenuates angiotensin II-accelerated atherosclerosis and vascular remodeling in apolipoprotein E deficient mice. Atherosclerosis 197:204–211

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiovascular Sciences, University of Leicester, Leicester, LE3 9QP, UK

    Christopher P. Nelson & Clett Erridge

  2. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK

    Christopher P. Nelson

  3. Department of Biomedical and Forensic Sciences, Anglia Ruskin University, East Rd, Cambridge, CB1 1PT, UK

    Clett Erridge

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Nelson, C.P., Erridge, C. Are toll-like receptors potential drug targets for atherosclerosis? Evidence from genetic studies to date. Immunogenetics 71, 1–11 (2019). https://doi.org/10.1007/s00251-018-1092-0

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