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Current Atherosclerosis Reports

Erschienen in:

01.10.2020 | Genetics and Genomics (A.J. Marian, Section Editor)

Immunogenetics of Atherosclerosis—Link between Lipids, Immunity, and Genes

verfasst von: Kuang-Yuh Chyu, Paul C. Dimayuga, Prediman K. Shah

Erschienen in: Current Atherosclerosis Reports | Ausgabe 10/2020

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Abstract

Purpose of Review

Atherosclerosis is a complex disease process with lipid as a traditional modifiable risk factor and therapeutic target in treating atherosclerotic cardiovascular disease (ACVD). Recent evidence indicates that genetic influence and host immune response also are vital in this process. How these elements interact and modify each other and if immune response may emerge as a novel modifiable target remain poorly understood.

Recent Findings

Numerous preclinical studies have clearly demonstrated that hypercholesterolemia is essential for atherogenesis, but genetic variations and host immune-inflammatory responses can modulate the pro-atherogenic effect of elevated LDL-C. Clinical studies also suggest that a similar paradigm may also be operational in atherogenesis in humans. More importantly each element modifies the biological behavior of the other two elements, forming a triangular relationship among the three. Modulating any one of them will have downstream impact on atherosclerosis.

Summary

This brief review summarizes the relationship among lipids, genes, and immunity in atherogenesis and presents evidence to show how these elements affect each other. Modulation of immune response, though in its infancy, has a potential to emerge as a novel clinical strategy in treating ACVD.

Ross R. Atherosclerosis is an inflammatory disease. Am Heart J. 1999;138:S419–20.PubMed

Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832–44.PubMed

Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity. 2013;38(6):1092–104.PubMedPubMedCentral

Schaftenaar F, Frodermann V, Kuiper J, Lutgens E. Atherosclerosis: the interplay between lipids and immune cells. Curr Opin Lipidol. 2016;27(3):209–15.PubMed

Gimbrone MA Jr, Garcia-Cardena G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol. 2013;22(1):9–15.PubMed

Roberts R. Genetics in the prevention and management of coronary artery disease. Curr Opin Cardiol. 2018;33(3):257–68.PubMed

Perez DL, Alonso R, Muniz-Grijalvo O, az-Diaz JL, Zambon D, Miramontes JP, et al. Coronary computed tomographic angiography findings and their therapeutic implications in asymptomatic patients with familial hypercholesterolemia. Lessons from the SAFEHEART study. J Clin Lipidol. 2018;12(4):948–57.

Miname MH, Bittencourt MS, Moraes SR, Alves RIM, Silva PRS, Jannes CE, et al. Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy. JACC Cardiovasc Imaging. 2019;12(9):1797–804.PubMed

Galaska R, Kulawiak-Galaska D, Wegrzyn A, Wasag B, Chmara M, Borowiec J, et al. Assessment of subclinical atherosclerosis using computed tomography calcium scores in patients with familial and nonfamilial hypercholesterolemia. J Atheroscler Thromb. 2016;23(5):588–95.PubMed

10.

Johnson KW, Dudley JT, Bobe JR. A 72-year-old patient with longstanding, untreated familial hypercholesterolemia but no coronary artery calcification: a case report. Cureus. 2018;10(4):e2452.PubMedPubMedCentral

11.

Selathurai A, Deswaerte V, Kanellakis P, Tipping P, Toh BH, Bobik A, et al. Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms. Cardiovasc Res. 2014;102(1):128–37.PubMed

12.

Qiao JH, Tripathi J, Mishra NK, Cai Y, Tripathi S, Wang XP, et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol. 1997;150:1687–99.PubMedPubMedCentral

13.

Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, et al. 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. 2004;101:10679–84.PubMedPubMedCentral

14.

Binder CJ, Shaw PX, Chang MK, Boullier A, Hartvigsen K, Horkko S, et al. The role of natural antibodies in atherogenesis. J Lipid Res. 2005;46(7):1353–63 Epub 2005 May 16 2005; 46:1353–1363.PubMed

15.

Kyaw T, Tipping P, Bobik A, Toh BH. Protective role of natural IgM-producing B1a cells in atherosclerosis. Trends Cardiovasc Med. 2012;22(2):48–53.PubMed

16.

Rosenfeld SM, Perry HM, Gonen A, Prohaska TA, Srikakulapu P, Grewal S, et al. B-1b cells secrete atheroprotective IgM and attenuate atherosclerosis. Circ Res. 2015;117(3):e28–39.PubMedPubMedCentral

17.

Lewis MJ, Malik TH, Ehrenstein MR, Boyle JJ, Botto M, Haskard DO. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation. 2009;120(5):417–26.PubMedPubMedCentral

18.

Tsiantoulas D, Bot I, Ozsvar-Kozma M, Goderle L, Perkmann T, Hartvigsen K, et al. Increased plasma IgE accelerate atherosclerosis in secreted IgM deficiency. Circ Res. 2017;120(1):78–84.PubMed

19.

Kyaw T, Tay C, Hosseini H, Kanellakis P, Gadowski T, Mackay F, et al. Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PLoS One. 2012;7(1):e29371.PubMedPubMedCentral

20.

Sage AP, Tsiantoulas D, Baker L, Harrison J, Masters L, Murphy D, et al. BAFF receptor deficiency reduces the development of atherosclerosis in mice--brief report. Arterioscler Thromb Vasc Biol. 2012;32(7):1573–6.PubMed

21.

Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020. https://doi.org/10.1038/s41569-020-0352-5.

22.

Back M, Yurdagul A Jr, Tabas I, Oorni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16(7):389–406.PubMedPubMedCentral

23.

Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res. 2010;106(2):383–90.PubMed

24.

Liu P, Yu YR, Spencer JA, Johnson AE, Vallanat CT, Fong AM, et al. CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden. Arterioscler Thromb Vasc Biol. 2008;28(2):243–50.PubMed

25.

Tian D, Hong H, Shang W, Ho CC, Dong J, Tian XY. Deletion of Ppard in CD11c(+) cells attenuates atherosclerosis in ApoE knockout mice. FASEB J. 2020;34(2):3367–78.PubMed

26.

Wu H, Gower RM, Wang H, Perrard XY, Ma R, Bullard DC, et al. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation. 2009;119(20):2708–17.PubMedPubMedCentral

27.

Daugherty A, Pure E, Delfel-Butteiger D, Chen S, Leferovich J, Roselaar SE, et al. The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E−/− mice. J Clin Invest. 1997;100:1575–80.PubMedPubMedCentral

28.

Reardon CA, Blachowicz L, White T, Cabana V, Wang Y, Lukens J, et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:1011–6.PubMed

29.

Roselaar SE, Kakkanathu PX, Daugherty A. Lymphocyte populations in atherosclerotic lesions of apoE −/− and LDL receptor −/− mice. Decreasing density with disease progression. Arterioscler Thromb Vasc Biol. 1996;16:1013–8.PubMed

30.

Zhou X, Stemme S, Hansson GK. Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice. Am J Pathol. 1996;149:359–66.PubMedPubMedCentral

31.

Zhou X. CD4+ T cells in atherosclerosis. Biomed Pharmacother. 2003;57(7):287–91.PubMed

32.

Engelbertsen D, Rattik S, Wigren M, Vallejo J, Marinkovic G, Schiopu A, et al. IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis. Cardiovasc Res. 2018;114(1):180–7.PubMed

33.

Buono C, Binder CJ, Stavrakis G, Witztum JL, Glimcher LH, Lichtman AH. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci U S A. 2005;102:1596–601.PubMedPubMedCentral

34.

Elhage R, Gourdy P, Brouchet L, Jawien J, Fouque MJ, Fievet C, et al. Deleting TCR alpha beta+ or CD4+ T lymphocytes leads to opposite effects on site-specific atherosclerosis in female apolipoprotein E-deficient mice. Am J Pathol. 2004;165:2013–8.PubMedPubMedCentral

35.

Kolbus D, Ramos OH, Berg KE, Persson J, Wigren M, Bjorkbacka H, et al. CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe(/) mice. BMC Immunol. 2010;11:58.PubMedPubMedCentral

36.

Kyaw T, Winship A, Tay C, Kanellakis P, Hosseini H, Cao A, et al. Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in ApoE−/− mice. Circulation. 2013;127(9):1028–39.PubMed

37.

Clement M, Guedj K, Andreata F, Morvan M, Bey L, Khallou-Laschet J, et al. Control of the T follicular helper-germinal center B-cell axis by CD8(+) regulatory T cells limits atherosclerosis and tertiary lymphoid organ development. Circulation. 2015;131(6):560–70.PubMed

38.

Kolbus D, Ljungcrantz I, Soderberg I, Alm R, Bjorkbacka H, Nilsson J, et al. TAP1-deficiency does not alter atherosclerosis development in Apoe−/− mice. PLoS One. 2012;7(3):e33932.PubMedPubMedCentral

39.

40.

Major AS, Fazio S, Linton MF. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol. 2002;22(11):1892–8.PubMed

41.

Rao LN, Ponnusamy T, Philip S, Mukhopadhyay R, Kakkar VV, Mundkur L. Hypercholesterolemia induced immune response and inflammation on progression of atherosclerosis in Apob(tm2Sgy) Ldlr(tm1Her)/J mice. Lipids. 2015;50(8):785–97.PubMed

42.

Proto JD, Doran AC, Subramanian M, Wang H, Zhang M, Sozen E, et al. Hypercholesterolemia induces T cell expansion in humanized immune mice. J Clin Invest. 2018;128(6):2370–5.PubMedPubMedCentral

43.

• Dimayuga PC, Zhao X, Yano J, Lio WM, Zhou J, Mihailovic PM, et al. Identification of apoB-100 Peptide-Specific CD8+ T Cells in Atherosclerosis. J Am Heart Assoc. 2017;6(7). https://doi.org/10.1161/JAHA.116.005318Characterization of apoB-100 peptide related immune responses in atherosclerosis.

44.

Chyu KY, Lio WM, Dimayuga PC, Zhou J, Zhao X, Yano J, et al. Cholesterol lowering modulates T cell function in vivo and in vitro. PLoS One. 2014;9(3):e92095.PubMedPubMedCentral

45.

Armstrong AJ, Gebre AK, Parks JS, Hedrick CC. ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation. J Immunol. 2010;184(1):173–83.PubMed

46.

Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008;134(1):97–111.PubMedPubMedCentral

47.

Muldoon MF, Marsland A, Flory JD, Rabin BS, Whiteside TL, Manuck SB. Immune system differences in men with hypo- or hypercholesterolemia. Clin Immunol Immunopathol. 1997;84(2):145–9.PubMed

48.

Moreno LA, Sarria A, Lazaro A, Lasierra MP, Larrad L, Bueno M. Lymphocyte T subset counts in children with hypercholesterolemia receiving dietary therapy. Ann Nutr Metab. 1998;42(5):261–5.PubMed

49.

Oda E. Longitudinal associations between lymphocyte count and LDL cholesterol in a health screening population. J Clin Transl Endocrinol. 2014;1(2):49–53.PubMedPubMedCentral

50.

Wu H, Perrard XD, Wang Q, Perrard JL, Polsani VR, Jones PH, et al. CD11c expression in adipose tissue and blood and its role in diet-induced obesity. Arterioscler Thromb Vasc Biol. 2010;30(2):186–92.PubMed

51.

Owens D, Collins P, Johnson A, Tomkin G. Cellular cholesterol metabolism in mitogen-stimulated lymphocytes--requirement for de novo synthesis. Biochim Biophys Acta. 1990;1051(2):138–43.PubMed

52.

Cuthbert JA, Lipsky PE. Provision of cholesterol to lymphocytes by high density and low density lipoproteins. Requirement for low density lipoprotein receptors. J Biol Chem. 1987;262(16):7808–18.PubMed

53.

Holven KB, Narverud I, Lindvig HW, Halvorsen B, Langslet G, Nenseter MS, et al. Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment. Atherosclerosis. 2014;233(2):561–7.PubMed

54.

Taghizadeh E, Taheri F, Gheibi Hayat SM, Montecucco F, Carbone F, Rostami D, et al. The atherogenic role of immune cells in familial hypercholesterolemia. IUBMB Life. 2020;72(4):782–9.PubMed

55.

Alborn WE, Cao G, Careskey HE, Qian YW, Subramaniam DR, Davies J, et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin Chem. 2007;53(10):1814–9.PubMed

56.

Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, et al. Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem. 2008;54(6):1038–45.PubMed

57.

Mohammadi A, Shabani M, Naseri F, Hosseni B, Soltanmohammadi E, Piran S, et al. Circulating PCSK9 affects serum LDL and cholesterol levels more than SREBP-2 expression. Adv Clin Exp Med. 2017;26(4):655–9.PubMed

58.

Li S, Guo YL, Xu RX, Zhang Y, Zhu CG, Sun J, et al. Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. Atherosclerosis. 2014;234(2):441–5.PubMed

59.

Makinen VP, Civelek M, Meng Q, Zhang B, Zhu J, Levian C, et al. Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet. 2014;10(7):e1004502.PubMedPubMedCentral

60.

Bjorkbacka H, Lavant EH, Fredrikson GN, Melander O, Berglund G, Carlson JA, et al. Weak associations between human leucocyte antigen genotype and acute myocardial infarction. J Intern Med. 2010;268(1):50–8.PubMed

61.

Davies RW, Wells GA, Stewart AF, Erdmann J, Shah SH, Ferguson JF, et al. A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex. Circ Cardiovasc Genet. 2012;5(2):217–25.PubMedPubMedCentral

62.

Elliott J, Bodinier B, Bond TA, Chadeau-Hyam M, Evangelou E, Moons KGM, et al. Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease. JAMA. 2020;323(7):636–45.PubMedPubMedCentral

63.

Mosley JD, Gupta DK, Tan J, Yao J, Wells QS, Shaffer CM, et al. Predictive accuracy of a polygenic risk score compared with a clinical risk score for incident coronary heart disease. JAMA. 2020;323(7):627–35.PubMedPubMedCentral

64.

Christiansen MK, Nissen L, Winther S, Moller PL, Frost L, Johansen JK, et al. Genetic risk of coronary artery disease, features of atherosclerosis, and coronary plaque burden. J Am Heart Assoc. 2020;9(3):e014795.PubMedPubMedCentral

65.

Eder L, Abji F, Rosen CF, Chandran V, Cook RJ, Gladman DD. The association of HLA-class I genes and the extent of atherosclerotic plaques in patients with psoriatic disease. J Rheumatol. 2016;43(10):1844–51.PubMed

66.

Eder L, Chandran V, Pellet F, Shanmugarajah S, Rosen CF, Bull SB, et al. Human leucocyte antigen risk alleles for psoriatic arthritis among patients with psoriasis. Ann Rheum Dis. 2012;71(1):50–5.PubMed

67.

Lopez-Mejias R, Carmona FD, Genre F, Remuzgo-Martinez S, Gonzalez-Juanatey C, Corrales A, et al. Identification of a 3'-Untranslated genetic variant of RARB associated with carotid intima-media thickness in rheumatoid arthritis: a genome-wide association study. Arthritis Rheumatol. 2019;71(3):351–60.PubMedPubMedCentral

68.

Mathur P, Ostadal B, Romeo F, Mehta JL. Gender-related differences in atherosclerosis. Cardiovasc Drugs Ther. 2015;29(4):319–27.PubMed

69.

Madonna R, Balistreri CR, de Rosa S, Muscoli S, Selvaggio S, Selvaggio G, et al. Impact of Sex Differences and Diabetes on Coronary Atherosclerosis and Ischemic Heart Disease. J Clin Med. 2019;8(1):98.

70.

Jobling MA, Tyler-Smith C. Human Y-chromosome variation in the genome-sequencing era. Nat Rev Genet. 2017;18(8):485–97.PubMed

71.

Eales JM, Maan AA, Xu X, Michoel T, Hallast P, Batini C, et al. Human Y chromosome exerts pleiotropic effects on susceptibility to atherosclerosis. Arterioscler Thromb Vasc Biol. 2019;39(11):2386–401.PubMedPubMedCentral

72.

Moros-Perez M, Fuster JJ. Clonal hematopoiesis driven by somatic mutations: a new player in atherosclerotic cardiovascular disease. Atherosclerosis. 2020;297:120–6.

73.

Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.PubMedPubMedCentral

74.

Kaasinen E, Kuismin O, Rajamaki K, Ristolainen H, Aavikko M, Kondelin J, et al. Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nat Commun. 2019;10(1):1252.PubMedPubMedCentral

75.

Bick AG, Pirruccello JP, Griffin GK, Gupta N, Gabriel S, Saleheen D, et al. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation. 2020;141(2):124–31.PubMed

76.

Chyu KY, Shah PK. In pursuit of an atherosclerosis vaccine. Circ Res. 2018;123(10):1121–3.PubMed

77.

Lutgens E, Atzler D, Doring Y, Duchene J, Steffens S, Weber C. Immunotherapy for cardiovascular disease. Eur Heart J. 2019;40(48):3937–46.PubMed

78.

Amirfakhryan H. Vaccination against atherosclerosis: an overview. Hell J Cardiol. 2019. https://doi.org/10.1016/j.hjc.2019.07.003.

79.

• Roy P, Ali AJ, Kobiyama K, Ghosheh Y, Ley K. Opportunities for an atherosclerosis vaccine: From mice to humans. Vaccine. 2020. https://doi.org/10.1016/j.vaccine.2019.12.039Detail summary of current knowledge on vaccine against atherosclerosis.

Titel: Immunogenetics of Atherosclerosis—Link between Lipids, Immunity, and Genes
verfasst von: Kuang-Yuh Chyu
Paul C. Dimayuga
Prediman K. Shah
Publikationsdatum: 01.10.2020
Verlag: Springer US
Erschienen in: Current Atherosclerosis Reports / Ausgabe 10/2020
Print ISSN: 1523-3804
Elektronische ISSN: 1534-6242
DOI: https://doi.org/10.1007/s11883-020-00874-4

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