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Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

Genes & Immunity volume 8, pages 684–690 (2007)Cite this article

Abstract

Atherogenesis is a chronic inflammatory process. Critical in the inflammation process is monocyte chemoattractant protein-1 (MCP-1). To locate genomic regions that affect circulating MCP-1 levels, a genome-wide linkage scan was conducted in a sample of whites and blacks. Phenotype and genetic marker data were available for 2501 white and 513 black participants in the National Heart Lung Blood Institute Family Heart Study follow-up examination. Heritability for MCP-1 was 0.37 in whites and 0.47 in blacks after adjusting for the effects of sex, age, age–sex interaction, smoking status, lifetime smoking exposure (pack-years) and field center. Significant linkage was observed for MCP-1 in a combined black and white sample on chromosome 3 (logarithm of the odds ratio (LOD)=3.5 at 78 cM, P=0.0001) and suggestive linkage was observed in whites on chromosome 5 (LOD=1.8 at 128 cM, P=0.002). Located under the linkage peak on chromosome 3 is the chemokine receptor gene cluster, including CCR2, the receptor for MCP-1. This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the low-density lipoprotein receptor. Further characterization of these chromosomal regions is needed to identify the functional mutations associated with circulating levels of MCP-1.

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References

  1. Boring L, Gosling J, Cleary M, Charo IF . Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394: 894–897.

    Article  CAS  Google Scholar 

  2. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998; 2: 275–281.

    Article  CAS  Google Scholar 

  3. Nelken NA, Coughlin SR, Gordon D, Wilcox JN . Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest 1991; 88: 1121–1127.

    Article  CAS  Google Scholar 

  4. Cushing SD, Berliner JA, Valente AJ, Territo MC, Navab M, Parhami F et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA 1990; 87: 5134–5138.

    Article  CAS  Google Scholar 

  5. de Lemos JA, Morrow DA, Sabatine MS, Murphy SA, Gibson CM, Antman EM et al. Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 2003; 107: 690–695.

    Article  CAS  Google Scholar 

  6. Herder C, Baumert J, Thorand B, Martin S, Lowel H, Kolb H et al. Chemokines and incident coronary heart disease: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002. Arterioscler Thromb Vasc Biol 2006; 26: 2147–2152.

    Article  CAS  Google Scholar 

  7. Madej A, Okopien B, Kowalski J, Haberka M, Herman ZS . Plasma concentrations of adhesion molecules and chemokines in patients with essential hypertension. Pharmacol Rep 2005; 57: 878–881.

    CAS  PubMed  Google Scholar 

  8. McDermott DH, Yang Q, Kathiresan S, Cupples LA, Massaro JM, Keaney Jr JF et al. CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study. Circulation 2005; 112: 1113–1120.

    Article  CAS  Google Scholar 

  9. Hoogeveen RC, Morrison A, Boerwinkle E, Miles JS, Rhodes CE, Sharrett AR et al. Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: atherosclerosis risk in communities study. Atherosclerosis 2005; 183: 301–307.

    Article  CAS  Google Scholar 

  10. Tabara Y, Kohara K, Yamamoto Y, Igase M, Nakura J, Kondo I et al. Polymorphism of the monocyte chemoattractant protein (MCP-1) gene is associated with the plasma level of MCP-1 but not with carotid intima-media thickness. Hypertens Res 2003; 26: 677–683.

    Article  CAS  Google Scholar 

  11. Rothenbacher D, Muller-Scholze S, Herder C, Koenig W, Kolb H . Differential expression of chemokines, risk of stable coronary heart disease, and correlation with established cardiovascular risk markers. Arterioscler Thromb Vasc Biol 2006; 26: 194–199.

    Article  CAS  Google Scholar 

  12. Mosedale DE, Smith DJ, Aitken S, Schofield PM, Clarke SC, McNab D et al. Circulating levels of MCP-1 and eotaxin are not associated with presence of atherosclerosis or previous myocardial infarction. Atherosclerosis 2005; 183: 268–274.

    Article  CAS  Google Scholar 

  13. Iwai N, Kajimoto K, Kokubo Y, Okayama A, Miyazaki S, Nonogi H et al. Assessment of genetic effects of polymorphisms in the MCP-1 gene on serum MCP-1 levels and myocardial infarction in Japanese. Circ J 2006; 70: 805–809.

    Article  CAS  Google Scholar 

  14. Dupuis J, Larson MG, Vasan RS, Massaro JM, Wilson PW, Lipinska I et al. Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q. Atherosclerosis 2005; 182: 307–314.

    Article  CAS  Google Scholar 

  15. Han KH, Han KO, Green SR, Quehenberger O . Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia. Differential effects of plasma lipoproteins on monocyte function. J Lipid Res 1999; 40: 1053–1063.

    CAS  PubMed  Google Scholar 

  16. Humphries S, Coviello DA, Masturzo P, Balestreri R, Orecchini G, Bertolini S . Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy. Arterioscler Thromb 1991; 11: 509–516.

    Article  CAS  Google Scholar 

  17. Thompson GR, Soutar AK, Spengel FA, Jadhav A, Gavigan SJ, Myant NB . Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. Proc Natl Acad Sci USA 1981; 78: 2591–2595.

    Article  CAS  Google Scholar 

  18. Han KH, Chang MK, Boullier A, Green SR, Li A, Glass CK et al. Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma. J Clin Invest 2000; 106: 793–802.

    Article  CAS  Google Scholar 

  19. Valdes AM, Wolfe ML, O’Brien EJ, Spurr NK, Gefter W, Rut A et al. Val64Ile polymorphism in the C-C chemokine receptor 2 is associated with reduced coronary artery calcification. Arterioscler Thromb Vasc Biol 2002; 22: 1924–1928.

    Article  CAS  Google Scholar 

  20. Ortlepp JR, Vesper K, Mevissen V, Schmitz F, Janssens U, Franke A et al. Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age. J Mol Med 2003; 81: 363–367.

    Article  CAS  Google Scholar 

  21. Petrkova J, Cermakova Z, Drabek J, Lukl J, Petrek M . CC chemokine receptor (CCR)2 polymorphism in Czech patients with myocardial infarction. Immunol Lett 2003; 88: 53–55.

    Article  CAS  Google Scholar 

  22. Bjarnadottir K, Eiriksdottir G, Aspelund T, Gudnason V . Examination of genetic effects of polymorphisms in the MCP-1 and CCR2 genes on MI in the Icelandic population. Atherosclerosis 2006; 188: 341–346.

    Article  CAS  Google Scholar 

  23. Sanders SK, Crean SM, Boxer PA, Kellner D, LaRosa GJ, Hunt III SW . Functional differences between monocyte chemotactic protein-1 receptor A and monocyte chemotactic protein-1 receptor B expressed in a Jurkat T cell. J Immunol 2000; 165: 4877–4883.

    Article  CAS  Google Scholar 

  24. Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S et al. The DNA sequence and comparative analysis of human chromosome 5. Nature 2004; 431: 268–274.

    Article  CAS  Google Scholar 

  25. Higgins M, Province M, Heiss G, Eckfeldt J, Ellison RC, Folsom AR et al. NHLBI Family Heart Study: objectives and design. Am J Epidemiol 1996; 143: 1219–1228.

    Article  CAS  Google Scholar 

  26. Williams RR, Rao DC, Ellison RC, Arnett DK, Heiss G, Oberman A et al. NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network. Ann Epidemiol 2000; 10: 389–400.

    Article  CAS  Google Scholar 

  27. Almasy L, Blangero J . Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998; 62: 1198–1211.

    Article  CAS  Google Scholar 

  28. Amos CI . Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 1994; 54: 535–543.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Almasy L, Dyer TD, Blangero J . Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet Epidemiol 1997; 14: 953–958.

    Article  CAS  Google Scholar 

  30. Blangero J, Williams JT, Almasy L . Variance component methods for detecting complex trait loci. Adv Genet 2001; 42: 151–181.

    Article  CAS  Google Scholar 

  31. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  Google Scholar 

  32. Heath SC . Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am J Hum Genet 1997; 61: 748–760.

    Article  CAS  Google Scholar 

  33. Heath SC, Snow GL, Thompson EA, Tseng C, Wijsman EM . MCMC segregation and linkage analysis. Genet Epidemiol 1997; 14: 1011–1016.

    Article  CAS  Google Scholar 

  34. Miller MB . MER2SOL: Translating MERLIN or Loki IBD Data to SOLAR Format. Genet Epidemiol 2003; 25: 261–262.

    Google Scholar 

  35. Blangero J, Williams JT, Almasy L . Robust LOD scores for variance component-based linkage analysis. Genet Epidemiol 2000; 19 (Suppl 1): S8–S14.

    Article  Google Scholar 

  36. North BV, Curtis D, Sham PC . A note on the calculation of empirical P values from Monte Carlo procedures. Am J Hum Genet 2002; 71: 439–441.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful for resources from the University of Minnesota Supercomputing Institute, the NIH Training Grant in Cardiovascular Disease Genetic Epidemiology (no. 5 T32 HL007972) and the National Heart, Lung and Blood Institute cooperative agreement Grants U01 HL 67893, U01 HL67894, U01 HL67895, U01 HL67896, U01 HL67897, U01 HL67898, U01 HL67899, U01 HL67900, U01 HL67901 and U01 HL67902. Financial support was also partially provided by the National Heart, Lung and Blood Institute cooperative agreement Grants U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568 and U01 HL56569. This report is presented on behalf of the investigators of the NHLBI FHS. The investigators thank the study participants and staff for their valuable contributions.

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Authors and Affiliations

  1. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA

    S J Bielinski, J S Pankow & M B Miller

  2. Cardiovascular Genetics, University of Utah, Salt Lake City, UT, USA

    P N Hopkins

  3. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    J H Eckfeldt

  4. Human Genetics Center, School of Public Health, University of Texas, Houston, TX, USA

    J Hixson

  5. Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Y Liu

  6. Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    T Register

  7. Section of Preventative Medicine and Epidemiology, Boston University School of Medicine, MA, USA

    R H Myers

  8. Department of Epidemiology, University of Alabama, Birmingham, AL, USA

    D K Arnett

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  1. S J Bielinski
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  2. J S Pankow
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  3. M B Miller
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Correspondence to S J Bielinski.

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Bielinski, S., Pankow, J., Miller, M. et al. Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination. Genes Immun 8, 684–690 (2007). https://doi.org/10.1038/sj.gene.6364434

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  • DOI: https://doi.org/10.1038/sj.gene.6364434

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