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Impact of inflammation, gene variants, and cigarette smoking on coronary artery disease risk

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Abstract

Background

The role of inflammation in coronary artery disease (CAD) pathogenesis is well recognized. Moreover, smoking inhalation increases the activity of inflammatory mediators through an increase in leukotriene synthesis essential in atherosclerosis pathogenesis.

Aim

The aim of this study is to investigate the effect of “selected” genetic variants within the leukotriene (LT) pathway and other variants on the development of CAD.

Methods

CAD was detected by cardiac catheterization. Logistic regression was performed to investigate the association of smoking and selected susceptibility variants in the LT pathway including ALOX5AP, LTA4H, LTC4S, PON1, and LTA as well as CYP1A1 on CAD risk while controlling for age, gender, BMI, family history, diabetes, hyperlipidemia, and hypertension.

Results

rs4769874 (ALOX5AP), rs854560 (PON1), and rs4646903 (CYP1A1 MspI polymorphism) are significantly associated with an increased risk of CAD with respective odds ratios of 1.53703, 1.67710, and 1.35520; the genetic variant rs9579646 (ALOX5AP) is significantly associated with a decreased risk of CAD (OR 0.76163). Moreover, a significant smoking-gene interaction is determined with CYP1A1 MspI polymorphism rs4646903 and is associated with a decreased risk of CAD in current smokers (OR 0.52137).

Conclusion

This study provides further evidence that genetic variation of the LT pathway, PON1, and CYP1A1 can modulate the atherogenic processes and eventually increase the risk of CAD in our study population. Moreover, it also shows the effect of smoking-gene interaction on CAD risk, where the CYP1A1 MspI polymorphism revealed a decreased risk in current smokers.

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References

  1. Cipollone F, Mezzetti A, Fazia ML, Cuccurullo C, Iezzi A, Ucchino S, et al. Association between 5-lipoxygenase expression and plaque instability in humans. Arterioscler Thromb Vasc Biol. 2005;25:1665–70.

    Article  CAS  PubMed  Google Scholar 

  2. Steinberg D. The LDL modification hypothesis of atherogenesis: an update. J Lipid Res. 2009;50(Suppl):S376–81.

    PubMed Central  PubMed  Google Scholar 

  3. Steinberg FM, Chait A. Antioxidant vitamin supplementation and lipid peroxidation in smokers. Am J Clin Nutr. 1998;68:319–27.

    CAS  PubMed  Google Scholar 

  4. Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect. 1985;64:111–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Webster RO, Hong SR, Johnston RB Jr, Henson PM. Biologial effects of the human complement fragments C5a and C5ades Arg on neutrophil function. Immunopharmacology. 1980;2:201–19.

    Article  CAS  PubMed  Google Scholar 

  6. Niki E. Do free radicals play causal role in atherosclerosis? Low density lipoprotein oxidation and vitamin E revisited. J Clin Biochem Nutr. 2011;48:3–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Guengerich FP. Cytochromes P-450. Comp Biochem Physiol, C: Comp Pharmacol Toxicol. 1988;89:1–4.

    Article  CAS  Google Scholar 

  8. Guengerich FP. Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res. 1988;48:2946–54.

    CAS  PubMed  Google Scholar 

  9. Wang XL, Greco M, Sim AS, Duarte N, Wang J, Wilcken DE. Effect of CYP1A1 MspI polymorphism on cigarette smoking related coronary artery disease and diabetes. Atherosclerosis. 2002;162:391–7.

    Article  CAS  PubMed  Google Scholar 

  10. Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007;357:1841–54.

    Article  CAS  PubMed  Google Scholar 

  11. Lotzer K, Funk CD, Habenicht AJ. The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. Biochim Biophys Acta. 2005;1736:30–7.

    PubMed  Google Scholar 

  12. Zhang SY, Xu ML, Zhang CE, Qu ZY, Zhang BB, Zheng ZY, et al. Association of ALOX5AP gene single nucleotide polymorphisms and cerebral infarction in the Han population of northern China. BMC Med Genet. 2012;13:61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Lohmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, et al. ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke. 2005;36:731–6.

    Article  CAS  PubMed  Google Scholar 

  14. Zee RY, Cheng S, Hegener HH, Erlich HA, Ridker PM. Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach. Stroke. 2006;37:2007–11.

    Article  CAS  PubMed  Google Scholar 

  15. Meschia JF, Brott TG, Brown RD Jr, Crook R, Worrall BB, Kissela B, et al. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol. 2005;58:351–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508–19.

    Article  CAS  PubMed  Google Scholar 

  17. Aharoni S, Aviram M, Fuhrman B. Paraoxonase 1 (PON1) reduces macrophage inflammatory responses. Atherosclerosis. 2013;228:353–61.

    Article  CAS  PubMed  Google Scholar 

  18. Ruiz J, Blanche H, James RW, Garin MC, Vaisse C, Charpentier G, et al. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet. 1995;346:869–72.

    Article  CAS  PubMed  Google Scholar 

  19. Schmidt H, Schmidt R, Niederkorn K, Gradert A, Schumacher M, Watzinger N, et al. Paraoxonase PON1 polymorphism leu-Met54 is associated with carotid atherosclerosis: results of the Austrian Stroke Prevention Study. Stroke. 1998;29:2043–8.

    Article  CAS  PubMed  Google Scholar 

  20. Robertson KS, Hawe E, Miller GJ, Talmud PJ, Humphries SE, Northwick Park Heart Study II. Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II. Biochim Biophys Acta. 2003;1639:203–12.

    Article  CAS  PubMed  Google Scholar 

  21. Youhanna S, Platt DE, Rebeiz A, Lauridsen M, Deeb ME, Nasrallah A, et al. Parental consanguinity and family history of coronary artery disease strongly predict early stenosis. Atherosclerosis. 2010;212:559–63.

    Article  CAS  PubMed  Google Scholar 

  22. Ghassibe-Sabbagh M, Platt DE, Youhanna S, Abchee AB, Stewart K, Badro DA, et al. Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk. Atherosclerosis. 2012;222:180–6.

    Article  CAS  PubMed  Google Scholar 

  23. Alwan A, Youhanna SC, Platt DE, El-Sibai M, Yerezian JS, Deeb ME, et al. ALOX5AP gene variants show differential association with coronary artery disease in different populations. J Community Genet. 2010;1:107–15.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Saade S, Cazier JB, Ghassibe-Sabbagh M, Youhanna S, Badro DA, Kamatani Y, et al. Large scale association analysis identifies three susceptibility loci for coronary artery disease. PLoS One. 2011;6:e29427.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5:e1000529.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Team RC. R: A language and environment for statistical computing. Vienna: Foundation for Statistical Computing; 2014.

    Google Scholar 

  27. Kaushal R, Pal P, Alwell K, Haverbusch M, Flaherty M, Moomaw C, et al. Association of ALOX5AP with ischemic stroke: a population-based case-control study. Hum Genet. 2007;121:601–7.

    Article  CAS  PubMed  Google Scholar 

  28. Domingues-Montanari S, Fernandez-Cadenas I, del Rio-Espinola A, Corbeto N, Krug T, Manso H, et al. Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study. Cerebrovasc Dis (Basel, Switzerland). 2010;29:528–37.

    Article  CAS  Google Scholar 

  29. Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Fonarow GC, et al. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res. 2004;45:993–1007.

    Article  CAS  PubMed  Google Scholar 

  30. Mackness B, Durrington PN, Mackness MI. The paraoxonase gene family and coronary heart disease. Curr Opin Lipidol. 2002;13:357–62.

    Article  CAS  PubMed  Google Scholar 

  31. Cao H, Girard-Globa A, Berthezene F, Moulin P. Paraoxonase protection of LDL against peroxidation is independent of its esterase activity towards paraoxon and is unaffected by the Q–> R genetic polymorphism. J Lipid Res. 1999;40:133–9.

    CAS  PubMed  Google Scholar 

  32. Shih DM, Xia YR, Wang XP, Miller E, Castellani LW, Subbanagounder G, et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem. 2000;275:17527–35.

    Article  CAS  PubMed  Google Scholar 

  33. Gupta N, Singh S, Maturu VN, Sharma YP, Gill KD. Paraoxonase 1 (PON1) polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis. PLoS One. 2011;6:e17805.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Iwanari M, Nakajima M, Kizu R, Hayakawa K, Yokoi T. Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences. Arch Toxicol. 2002;76:287–98.

    Article  CAS  PubMed  Google Scholar 

  35. Kerzee JK, Ramos KS. Activation of c-Ha-ras by benzo(a)pyrene in vascular smooth muscle cells involves redox stress and aryl hydrocarbon receptor. Mol Pharmacol. 2000;58:152–8.

    CAS  PubMed  Google Scholar 

  36. Kerzee JK, Ramos KS. Constitutive and inducible expression of Cyp1a1 and Cyp1b1 in vascular smooth muscle cells: role of the Ahr bHLH/PAS transcription factor. Circ Res. 2001;89:573–82.

    Article  CAS  PubMed  Google Scholar 

  37. McManus ME, Burgess WM, Veronese ME, Huggett A, Quattrochi LC, Tukey RH. Metabolism of 2-acetylaminofluorene and benzo(a)pyrene and activation of food-derived heterocyclic amine mutagens by human cytochromes P-450. Cancer Res. 1990;50:3367–76.

    CAS  PubMed  Google Scholar 

  38. McNamara P, FitzGerald GA. Smoking-induced vascular disease: a new twist on an old theme. Circ Res. 2001;89:563–5.

    CAS  PubMed  Google Scholar 

  39. Roberts-Thomson SJ, McManus ME, Tukey RH, Gonzalez FF, Holder GM. The catalytic activity of four expressed human cytochrome P450s towards benzo[a]pyrene and the isomers of its proximate carcinogen. Biochem Biophys Res Commun. 1993;192:1373–9.

    Article  CAS  PubMed  Google Scholar 

  40. Ingelman-Sundberg M. Genetic susceptibility to adverse effects of drugs and environmental toxicants. The role of the CYP family of enzymes. Mutat Res. 2001;482:11–9.

    Article  CAS  PubMed  Google Scholar 

  41. Silva AR, Pacheco P, Vieira-de-Abreu A, Maya-Monteiro CM, D’Alegria B, Magalhaes KG, et al. Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon. Biochim Biophys Acta. 2009;1791:1066–75.

    Article  CAS  PubMed  Google Scholar 

  42. Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B. Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway. Atherosclerosis. 2010;208:119–25.

    Article  CAS  PubMed  Google Scholar 

  43. Avis I, Hong SH, Martinez A, Moody T, Choi YH, Trepel J, et al. Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions. FASEB J. 2001;15:2007–9.

    CAS  PubMed  Google Scholar 

  44. Le P, Kawai M, Bornstein S, DeMambro VE, Horowitz MC, Rosen CJ. A high-fat diet induces bone loss in mice lacking the Alox5 gene. Endocrinology. 2012;153:6–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Kwak HJ, Park KM, Choi HE, Lim HJ, Park JH, Park HY. The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKC delta. Cell Signal. 2010;22:80–7.

    Article  CAS  PubMed  Google Scholar 

  46. Back M, Avignon A, Stanke-Labesque F, Boegner C, Attalin V, Leprieur E, et al. Leukotriene production is increased in abdominal obesity. PLoS One. 2014;9:e104593.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Stanke-Labesque F, Pepin JL, Gautier-Veyret E, Levy P, Back M. Leukotrienes as a molecular link between obstructive sleep apnoea and atherosclerosis. Cardiovasc Res. 2014;101:187–93.

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

This study has been approved by the Lebanese American University Institutional Review Board and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We would like to state that all the study participants gave their informed and written consent prior to their inclusion in the study.

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    Authors and Affiliations

    1. School of Medicine, Lebanese American University, P.O Box 36, Byblos, Lebanon

      Mahmoud Merhi, Essa Hariri, Nada Sabbah, Michella Ghassibe-Sabbagh, Joseph Naoum, Marc Haber, Elie Chammas, Roy Kanbar, Hamid el Bayeh, Youssef Chami & Pierre Zalloua

    2. School of Arts and Sciences, Brandeis University, Waltham, MA, USA

      Sally Demirdjian

    3. Division of Cardiology, Rafic Hariri University Hospital, Beirut, Lebanon

      Sonia Youhanna, Raed Othman & Samer Kibbani

    4. Department of Internal Medicine, American University of Beirut, Beirut, Lebanon

      Antoine Abchee

    5. Bioinformatics and Pattern Discovery, IBM T. J. Watson Research Centre, Yorktown Heights, NY, 10598, USA

      Daniel E. Platt

    6. Harvard School of Public Health, Boston, MA, 02215, USA

      Pierre Zalloua

    7. Department of Computer Science and Mathematics, School of Arts and Sciences, Lebanese American University, P.O Box 36, Byblos, Lebanon

      Georges Khazen

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    1. Mahmoud Merhi
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    Correspondence to Pierre Zalloua or Georges Khazen.

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    Responsible Editor: John Di Battista.

    M. Merhi, S. Demirdjian, E. Hariri and N. Sabbah contributed equaly.

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    Merhi, M., Demirdjian, S., Hariri, E. et al. Impact of inflammation, gene variants, and cigarette smoking on coronary artery disease risk. Inflamm. Res. 64, 415–422 (2015). https://doi.org/10.1007/s00011-015-0821-1

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    • DOI: https://doi.org/10.1007/s00011-015-0821-1

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