The CD14 C-260T single nucleotide polymorphism (SNP) modulates monocyte/macrophage activation in treated HIV-infected individuals

Journal of Translational Medicine

Sharon R Lewin¹  Adeeba Kamarulzaman⁴  Sasheela Ponampalavanar⁴  Muhamad Yazli Yuhana⁶  Tim Spelman²  Noor Kamila Abdullah³  Reshika Nadarajah³  Yong Yean Kong³  Reena Rajasuriar⁵ 

[1] Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne 3010, Australia;Centre for Population Health, Burnet Institute, Melbourne, 3004, Australia;Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, 50603, Malaysia;Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia;Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, 3004, Australia;Faculty of Medicine, University Teknologi MARA, Sungai Buloh, 47000, Selangor, Malaysia

关键词: Carotid intima media thickness;    Atherosclerosis;    C-reactive protein;    Monocyte activation;    Soluble CD163;    Soluble CD14;    CD12 C-260T;    Lipopolysaccharide;    HIV;   

Others  :  1137699
DOI  :  10.1186/s12967-015-0391-6

 received in 2014-10-13, accepted in 2015-01-13,  发布年份 2015

【 摘 要 】

Background

HIV-infected individuals have an increased risk of cardiovascular disease (CVD). T-allele carriers of the CD14 C-260T single-nucleotide polymorphism (SNP) have reported increased expression of the LPS-binding receptor, CD14 and inflammation in the general population. Our aim was to explore the relationship of this SNP with monocyte/macrophage activation and inflammation and its association with sub-clinical atherosclerosis in HIV-infected individuals.

Methods

Patients with no pre-existing CVD risk factors on suppressive antiretroviral therapy were recruited from University Malaya Medical Centre, Malaysia (n = 84). The CD14 C-260T and TLR4 SNPs, Asp299Gly and Thr399Ile were genotyped and soluble(s) CD14 and sCD163 and high-sensitivity C-reactive protein, hsCRP were measured in plasma. Subclinical atherosclerosis was assessed by measuring carotid intima media thickness (cIMT). The association between CD14 C-260T SNP carriage and cIMT was assessed in a multivariable quantile regression model where a p-value of <0.05 was considered significant.

Results

We found the CD14 C-260T T-allele in 56% of the cohort and evidence of subclinical atherosclerosis in 27%. TT genotype was associated with higher sCD163 (p = 0.009) but only marginally higher sCD14 (p = 0.209) and no difference in hsCRP (p = 0.296) compared to CC/CT. In multivariable analysis, only Framingham risk score was independently associated with higher cIMT while lower sCD163 was trending towards significance. No association was found in TT-genotype carriers and cIMT measurements.

Conclusion

The CD14 C-260T SNP was associated with increased monocyte activation but not systemic inflammation or cIMT in this HIV-infected cohort with low CVD risk profile.

【 授权许可】

   
2015 Rajasuriar et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW: Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 2013, 119:51-83.
• [2]Duprez DA, Kuller LH, Tracy R, Otvos J, Cooper DA, Hoy J, et al.: Lipoprotein particle subclasses, cardiovascular disease and HIV infection. Atherosclerosis 2009, 207:524-9.
• [3]Tincati C, Bellistri GM, Casana M, Merlini E, Comi L, Bai F, et al.: CD8+ hyperactivation and senescence correlate with early carotid intima-media thickness in HIV+ patients with no cardiovascular disease. J Acquir Immune Defic Syndr 2009, 51:642-4.
• [4]Triant VA, Meigs JB, Grinspoon SK: Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr 2009, 51:268-73.
• [5]Funderburg NT, Mayne E, Sieg SF, Asaad R, Jiang W, Kalinowska M, et al.: Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 2010, 115:161-7.
• [6]Steele AK, Lee EJ, Vestal B, Hecht D, Dong Z, Rapaport E, et al.: Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature. PLoS One 2014, 9:e97171.
• [7]Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al.: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006, 12:1365-71.
• [8]Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, et al.: Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 2009, 199:1177-85.
• [9]Rajasuriar R, Booth D, Solomon A, Chua K, Spelman T, Gouillou M, et al.: Biological Determinants of Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy: The Role of Interleukin 7 and Interleukin 7 Receptor α and Microbial Translocation. J Infect Dis 2010, 202:1254-64.
• [10]Kelesidis T, Kendall MA, Yang OO, Hodis HN, Currier JS: Biomarkers of microbial translocation and macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J Infect Dis 2012, 206:1558-67.
• [11]Dauphinee SM, Karsan A: Lipopolysaccharide signaling in endothelial cells. Lab Invest 2006, 86:9-22.
• [12]Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, et al.: Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol 1999, 34:1975-81.
• [13]Reiner AP, Lange EM, Jenny NS, Chaves PH, Ellis J, Li J, et al.: Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. Arterioscler Thromb Vasc Biol 2013, 33:158-64.
• [14]Triantafilou M, Triantafilou K: Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol 2002, 23:301-4.
• [15]Bas S, Gauthier BR, Spenato U, Stingelin S, Gabay C: CD14 is an acute-phase protein. J Immunol 2004, 172:4470-9.
• [16]Pugin J, Schurer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ, Tobias PS: Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A 1993, 90:2744-8.
• [17]Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD: A Polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999, 20:976-83.
• [18]Hubacek JA, Rothe G, Pit’ha J, Skodova Z, Stanek V, Poledne R, et al.: C(−260)–>T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation 1999, 99:3218-20.
• [19]Eng HL, Wang CH, Chen CH, Chou MH, Cheng CT, Lin TM: A CD14 promoter polymorphism is associated with CD14 expression and Chlamydia-stimulated TNF alpha production. Genes Immun 2004, 5:426-30.
• [20]LeVan TD, Bloom JW, Bailey TJ, Karp CL, Halonen M, Martinez FD, et al.: A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 2001, 167:5838-44.
• [21]Gu W, Dong H, Jiang DP, Zhou J, Du DY, Gao JM, et al.: Functional significance of CD14 promoter polymorphisms and their clinical relevance in a Chinese Han population. Crit Care Med 2008, 36:2274-80.
• [22]Koenig W, Khuseyinova N, Hoffmann MM, Marz W, Frohlich M, Hoffmeister A, et al.: CD14 C(−260)–>T polymorphism, plasma levels of the soluble endotoxin receptor CD14, their association with chronic infections and risk of stable coronary artery disease. J Am Coll Cardiol 2002, 40:34-42.
• [23]Rizzello V, Liuzzo G, Trabetti E, Di Giannuario G, Brugaletta S, Santamaria M, et al.: Role of the CD14 C(−260) T promoter polymorphism in determining the first clinical manifestation of coronary artery disease. J Cardiovasc Med (Hagerstown) 2010, 11:20-5.
• [24]Marsik C, Jilma B, Joukhadar C, Mannhalter C, Wagner O, Endler G: The Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms influence the late inflammatory response in human endotoxemia. Clin Chem 2005, 51:2178-80.
• [25]Montes AH, Asensi V, Alvarez V, Valle E, Ocana MG, Meana A, et al.: The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis. Clin Exp Immunol 2006, 143:404-13.
• [26]Unkelbach K, Gardemann A, Kostrzewa M, Philipp M, Tillmanns H, Haberbosch W: A new promoter polymorphism in the gene of lipopolysaccharide receptor CD14 is associated with expired myocardial infarction in patients with low atherosclerotic risk profile. Arterioscler Thromb Vasc Biol 1999, 19:932-8.
• [27]Arroyo-Espliguero R, El-Sharnouby K, Vazquez-Rey E, Kalidas K, Jeffery S, Kaski JC: CD14 C(−260) T promoter polymorphism and prevalence of acute coronary syndromes. Int J Cardiol 2005, 98:307-12.
• [28]Hermann M, Fischer D, Hoffmann MM, Gasser T, Quitzau K, Meinertz T, et al.: CRP and CD14 polymorphisms correlate with coronary plaque volume in patients with coronary artery disease–IVUS substudy of the ENCORE trials. Atherosclerosis 2012, 220:172-6.
• [29]Koch W, Kastrati A, Mehilli J, von Beckerath N, Schomig A: CD14 gene -159C/T polymorphism is not associated with coronary artery disease and myocardial infarction. Am Heart J 2002, 143:971-6.
• [30]Haberbosch W, Unkelbach K, Schuster D, Gardemann A, Tillmanns H, Holschermann H: CD14 promoter polymorphism (− 159C–> t) is not associated with myocardial infarction or coronary artery disease in patients with assumed high genetic risk. Thorac Cardiovasc Surg 2009, 57:386-90.
• [31]Elghannam H, Tavackoli S, Ferlic L, Gotto AM Jr, Ballantyne CM, Marian AJ: A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary atherosclerosis and its response to therapy. J Mol Med (Berl) 2000, 78:562-8.
• [32]Zhang HF, Zhong BL, Zhu WL, Xie SL, Qiu LX, Zhu LG, et al.: CD14 C-260T gene polymorphism and ischemic heart disease susceptibility: a HuGE review and meta-analysis. Genet Med 2009, 11:403-8.
• [33]Pu H, Yin J, Wu Y, Zhang D, Wang Y, Zhou R, et al.: The association between CD14 gene C-260T polymorphism and coronary heart disease risk: a meta-analysis. Mol Biol Rep 2013, 40:4001-8.
• [34]Longenecker CT, Jiang Y, Orringer CE, Gilkeson RC, Debanne S, Funderburg NT, et al.: Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection. AIDS 2014, 28:969-77.
• [35]Baker JV, Hullsiek KH, Singh A, Wilson E, Henry K, Lichtenstein K, et al.: Immunologic predictors of coronary artery calcium progression in a contemporary HIV cohort. AIDS 2014, 28:831-40.
• [36]Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al.: Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008, 21:93-111. quiz 189–190
• [37]Solomon A, Cameron PU, Bailey M, Dunne AL, Crowe SM, Hoy JF, et al.: Immunological and virological failure after antiretroviral therapy is associated with enhanced peripheral and thymic pathogenicity. J Infect Dis 2003, 187:1915-23.
• [38]Amar J, Ruidavets JB, Bal dit Sollier C, Bongard V, Boccalon H, Chamontin B, et al.: CD14 C(−260) T gene polymorphism, circulating soluble CD14 levels and arteriosclerosis. J Hypertens 2004, 22:1523-8.
• [39]Armah KA, McGinnis K, Baker J, Gibert C, Butt AA, Bryant KJ, et al.: HIV status, burden of comorbid disease, and biomarkers of inflammation, altered coagulation, and monocyte activation. Clin Infectious Dis Off Publ Infectious Dis Soc Am 2012, 55:126-36.
• [40]Martin GE, Gouillou M, Hearps A, Angelovich TA ACC, Lynch F, Cheng WJ, et al.: Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women. Plos One 2013, 8(1):e55279.
• [41]Weaver LK, Pioli PA, Wardwell K, Vogel SN, Guyre PM: Up-regulation of human monocyte CD163 upon activation of cell-surface Toll-like receptors. J Leukoc Biol 2007, 81:663-71.
• [42]Hintz KA, Rassias AJ, Wardwell K, Moss ML, Morganelli PM, Pioli PA, et al.: Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163. J Leukoc Biol 2002, 72:711-7.
• [43]Moestrup SK, Moller HJ: CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 2004, 36:347-54.
• [44]Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, et al.: Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis 2011, 204:154-63.
• [45]Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, et al.: Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis 2013, 208:1737-46.
• [46]Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al.: Arterial inflammation in patients with HIV. JAMA 2012, 308:379-86.
• [47]Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al.: Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infectious Dis 2011, 204:1227-36.
• [48]Funderburg NT, Zidar DA, Shive C, Lioi A, Mudd J, Musselwhite LW, et al.: Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome. Blood 2012, 120:4599-608.
• [49]Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, et al.: Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection. J Infect Dis 2011, 203:780-90.
• [50]Wilson EM, Singh A, Hullsiek KH, Gibson D, Henry WK, Lichtenstein K, Onen NF, Kojic E, Patel P, Brooks JT, et al.: Monocyte activation phenotypes are associated with biomarkers of inflammation and coagulation in chronic HIV infection. J Infect Dis 2014, 210:1396-406.
• [51]Heesen M, Blomeke B, Schluter B, Heussen N, Rossaint R, Kunz D: Lack of association between the −260 C–> T promoter polymorphism of the endotoxin receptor CD14 gene and the CD14 density of unstimulated human monocytes and soluble CD14 plasma levels. Intensive Care Med 2001, 27:1770-5.
• [52]Bernardo E, Angiolillo DJ, Ramirez C, Cavallari U, Trabetti E, Sabate M, et al.: Influence of the CD14 C260T promoter polymorphism on C-reactive protein levels in patients with coronary artery disease. Am J Cardiol 2006, 98:1182-4.
• [53]Morange PE, Saut N, Alessi MC, Frere C, Hawe E, Yudkin JS, et al.: Interaction between the C-260T polymorphism of the CD14 gene and the plasma IL-6 concentration on the risk of myocardial infarction: the HIFMECH study. Atherosclerosis 2005, 179:317-23.
• [54]Westhorpe S, Maisa A, Spelman T, Hoy J, Dewar EK S, Hearps A, et al.: Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals. Immunol Cell Biol 2014, 92(2):133-8.
• [55]Knudsen A, Moller HJ, Katzenstein TL, Gerstoft J, Obel N, Kronborg G, et al.: Soluble CD163 does not predict first-time myocardial infarction in patients infected with human immunodeficiency virus: a nested case–control study. BMC Infect Dis 2013, 13:230. BioMed Central Full Text
• [56]Hogger P, Sorg C: Soluble CD163 inhibits phorbol ester-induced lymphocyte proliferation. Biochem Biophys Res Commun 2001, 288:841-3.
• [57]Frings W, Dreier J, Sorg C: Only the soluble form of the scavenger receptor CD163 acts inhibitory on phorbol ester-activated T-lymphocytes, whereas membrane-bound protein has no effect. FEBS Lett 2002, 526:93-6.
• [58]Morange PE, Tiret L, Saut N, Luc G, Arveiler D, Ferrieres J, et al.: TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and the risk of coronary heart disease: The PRIME Study. Eur J Hum Genet 2004, 12:1041-9.
• [59]Wang Z, Hu J, Fan R, Zhou J, Zhong J: Association between CD14 gene C-260T polymorphism and inflammatory bowel disease: a meta-analysis. PLoS One 2012, 7:e45144.
• [60]Jarvelainen HA, Orpana A, Perola M, Savolainen VT, Karhunen PJ, Lindros KO: Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease. Hepatology 2001, 33:1148-53.
• [61]Wang F, Tahara T, Arisawa T, Shibata T, Nakamura M, Fujita H, et al.: Genetic polymorphisms of CD14 and Toll-like receptor-2 (TLR2) in patients with ulcerative colitis. J Gastroenterol Hepatol 2007, 22:925-9.
• [62]Zambelli-Weiner A, Ehrlich E, Stockton ML, Grant AV, Zhang S, Levett PN, et al.: Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J Allergy Clin Immunol 2005, 115:1203-9.