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Quantitative genetic analysis of cellular adhesion molecules: The Fels Longitudinal Study

      Abstract

      Circulating concentrations of inflammatory markers predict cardiovascular disease (CVD) risk and are closely associated with obesity. However, little is known concerning genetic influences on serum levels of inflammatory markers. In this study, we estimated the heritability (h2) of soluble cellular adhesion molecule (sCAM) concentrations and examined the correlational architecture between different sCAMs. The study population included 234 men and 270 women aged 18–76 years, belonging to 121 families participating in the Fels Longitudinal Study. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sESEL-1) and P-selectin (sPSEL-1) were assayed using commercially available kits. A variance components-based maximum likelihood method was used to estimate the h2 of the different serum inflammatory markers while simultaneously adjusting for the effects of known CVD risk factors, such as age and smoking. Additionally, we used bivariate extensions of these methods to estimate genetic and random environmental correlations among sCAMs. Levels of sCAMs were significantly heritable: h2 = 0.24 ± 0.10 for sICAM-1, h2 = 0.22 ± 0.10 for sVCAM-1, h2 = 0.50 ± 0.11 for sESEL-1, and h2 = 0.46 ± 0.10 for sPSEL-1. In addition, a significant genetic correlation (ρG = 0.63) was found between sICAM-1 and sVCAM-1 indicating some degree of shared genetic control. In the Fels Longitudinal Study, the levels of four sCAMs are significantly influenced by genetic effects, and sICAM-1 shares a common genetic background with sVCAM-1.

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      References

        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Blankenberg S.
        • Barbaux S.
        • Tiret L.
        Adhesion molecules and atherosclerosis.
        Atherosclerosis. 2003; 170: 191-203
        • Patel K.D.
        • Cuvelier S.L.
        • Wiehler S.
        Selectins: critical mediators of leukocyte recruitment.
        Semin Immunol. 2002; 14: 73-81
        • Pigott R.
        • Dillon L.P.
        • Hemingway I.H.
        • Gearing A.J.
        Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells.
        Biochem Biophys Res Commun. 1992; 187: 584-589
        • Leeuwenberg J.F.
        • Smeets E.F.
        • Neefjes J.J.
        • et al.
        E-selectin and intercellular adhesion molecule-1 are released by activated human endothelial cells in vitro.
        Immunology. 1992; 77: 543-549
        • Nakai K.
        • Itoh C.
        • Kawazoe K.
        • et al.
        Concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) correlated with expression of VCAM-1 mRNA in the human atherosclerotic aorta.
        Coron Artery Dis. 1995; 6: 497-502
        • Ridker P.M.
        • Hennekens C.H.
        • Roitman-Johnson B.
        • Stampfer M.J.
        • Allen J.
        Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men.
        Lancet. 1998; 351: 88-92
        • De Lemos J.A.
        • Hennekens C.H.
        • Ridker P.M.
        Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk.
        J Am Coll Cardiol. 2000; 36: 423-426
        • Cesari M.
        • Penninx B.W.
        • Newman A.B.
        • et al.
        Inflammatory markers and onset of cardiovascular events: results from the Health ABC study.
        Circulation. 2003; 108: 2317-2322
        • Malik I.
        • Danesh J.
        • Whincup P.
        • et al.
        Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis.
        Lancet. 2001; 358: 971-976
        • Hwang S.J.
        • Ballantyne C.M.
        • Sharrett A.R.
        • et al.
        Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study.
        Circulation. 1997; 96: 4219-4225
        • Bourdillon M.C.
        • Poston R.N.
        • Covacho C.
        • et al.
        ICAM-1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE(−/−)/ICAM-1(−/−)) fed a fat or a chow diet.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2630-2635
        • Dansky H.M.
        • Barlow C.B.
        • Lominska C.
        • et al.
        Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1662-1667
        • Dong Z.M.
        • Brown A.A.
        • Wagner D.D.
        Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice.
        Circulation. 2000; 101: 2290-2295
        • Subramaniam M.
        • Saffaripour S.
        • Watson S.R.
        • et al.
        Reduced recruitment of inflammatory cells in a contact hypersensitivity response in P-selectin-deficient mice.
        J Exp Med. 1995; 181: 2277-2282
        • Wenzel K.
        • Stahn R.
        • Speer A.
        • et al.
        Functional characterization of atherosclerosis-associated Ser128Arg and Leu554Phe E-selectin mutations.
        Biol Chem. 1999; 380: 661-667
        • Ponthieux A.
        • Lambert D.
        • Herbeth B.
        • et al.
        Association between Gly241Arg ICAM-1 gene polymorphism and serum sICAM-1 concentration in the Stanislas cohort.
        Eur J Hum Genet. 2003; 11: 679-686
        • Bannan S.
        • Mansfield M.W.
        • Grant P.J.
        Soluble vascular cell adhesion molecule-1 and E-selectin levels in relation to vascular risk factors and to E-selectin genotype in the first degree relatives of NIDDM patients and in NIDDM patients.
        Diabetologia. 1998; 41: 460-466
        • Barbaux S.C.
        • Blankenberg S.
        • Rupprecht H.J.
        • et al.
        Association between P-selectin gene polymorphisms and soluble P-selectin levels and their relation to coronary artery disease.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1668-1673
        • Carter A.M.
        • Anagnostopoulou K.
        • Mansfield M.W.
        • Grant P.J.
        Soluble P-selectin levels, P-selectin polymorphisms and cardiovascular disease.
        J Thromb Haemost. 2003; 1: 1718-1723
        • Tregouet D.A.
        • Barbaux S.
        • Escolano S.
        • et al.
        Specific haplotypes of the P-selectin gene are associated with myocardial infarction.
        Hum Mol Genet. 2002; 11: 2015-2023
        • de Maat M.P.
        • Bladbjerg E.M.
        • Hjelmborg J.B.
        • et al.
        Genetic influence on inflammation variables in the elderly.
        Arterioscler Thromb Vasc Biol. 2004; 24: 2168-2173
        • Hixson J.E.
        • Blangero J.
        Genomic searches for genes that influence atherosclerosis and its risk factors.
        Ann NY Acad Sci. 2000; 902: 1-7
        • Kent Jr., J.W.
        • Comuzzie A.G.
        • Mahaney M.C.
        • et al.
        Intercellular adhesion molecule-1 concentration is genetically correlated with insulin resistance, obesity, and HDL concentration in Mexican Americans.
        Diabetes. 2004; 53: 2691-2695
        • Keaney Jr., J.F.
        • Massaro J.M.
        • Larson M.G.
        • et al.
        Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study.
        J Am Coll Cardiol. 2004; 44: 168-173
        • Neish A.S.
        • Read M.A.
        • Thanos D.
        • et al.
        Endothelial interferon regulatory factor 1 cooperates with NF-kappa B as a transcriptional activator of vascular cell adhesion molecule 1.
        Mol Cell Biol. 1995; 15: 2558-2569
        • Collins T.
        • Read M.A.
        • Neish A.S.
        • et al.
        Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers.
        FASEB J. 1995; 9: 899-909
        • Luc G.
        • Arveiler D.
        • Evans A.
        • et al.
        Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and incident coronary heart disease: the PRIME Study.
        Atherosclerosis. 2003; 170: 169-176
        • Blankenberg S.
        • Rupprecht H.J.
        • Bickel C.
        • et al.
        Circulating cell adhesion molecules and death in patients with coronary artery disease.
        Circulation. 2001; 104: 1336-1342
        • Roche A.F.
        Growth, maturation and body composition: the Fels Longitudinal Study 1929–1991.
        Cambridge University Press, Cambridge1992
        • Demerath E.
        • Towne B.
        • Blangero J.
        • Siervogel R.M.
        The relationship of soluble ICAM-1, VCAM-1, P-selectin and E-selectin to cardiovascular disease risk factors in healthy men and women.
        Ann Hum Biol. 2001; 28: 664-678
        • Lohman T.
        • Martorell R.
        • Roche A.F.
        Anthropometric standardization reference manual.
        Human Kinetics, Champaign, IL1988
        • Siri W.E.
        Body composition from fluid spaces and density: analysis of methods.
        in: Brozek J. Henschel A. Techniques for measuring body composition. National Academy of Sciences/National Research Council, Washington, DC1961: 223-224
        • Anon
        Manual of laboratory operations I: lipid and lipoprotein analysis.
        National Heart, Lung and Blood Institute, National Institutes of Health, US Government Printing Office, Lipid Research Clinics Program, Bethesda, MD1974
        • Friedewald W.T.
        • Levy R.I.
        • Frederickson D.S.
        Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Almasy L.
        • Blangero J.
        Multipoint quantitative-trait linkage analysis in general pedigrees.
        Am J Hum Genet. 1998; 62: 1198-1211
        • Lynch M.
        • Walsh B.
        Genetics and data analysis of quantitative traits.
        Sinauer, Sunderland, MA1998
        • Blangero J.
        • Konigsberg L.W.
        Multivariate segregation analysis using the mixed model.
        Genet Epidemiol. 1991; 8: 299-316
        • Herrmann S.M.
        • Ricard S.
        • Nicaud V.
        • et al.
        The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction.
        Hum Mol Genet. 1998; 7: 1277-1284
        • Jilma B.
        • Marsik C.
        • Kovar F.
        • et al.
        The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia.
        Blood. 2005; 105: 2380-2383
        • Miller M.A.
        • Kerry S.M.
        • Dong Y.
        • et al.
        Circulating soluble E-selectin levels and the Ser128Arg polymorphism in individuals from different ethnic groups.
        Nutr Metab Cardiovasc Dis. 2005; 15: 65-70
        • Yokoyama H.
        • Tahara H.
        • Emoto M.
        • et al.
        The K469E polymorphism of the intercellular adhesion molecule-1 gene is associated with plasma fibrinogen level in type 2 diabetes.
        Metabolism. 2005; 54: 381-386
        • Rohde L.E.
        • Hennekens C.H.
        • Ridker P.M.
        Cross-sectional study of soluble intercellular adhesion molecule-1 and cardiovascular risk factors in apparently healthy men.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1595-1599
        • Blann A.D.
        • Steele C.
        • McCollum C.N.
        The influence of smoking on soluble adhesion molecules and endothelial cell markers.
        Thromb Res. 1997; 85: 433-438
        • Verhaar M.C.
        • Beutler J.J.
        • Gaillard C.A.
        • et al.
        Progressive vascular damage in hypertension is associated with increased levels of circulating P-selectin.
        J Hypertens. 1998; 16: 45-50
        • Hackman A.
        • Abe Y.
        • Insull Jr., W.
        • et al.
        Levels of soluble cell adhesion molecules in patients with dyslipidemia.
        Circulation. 1996; 93: 1334-1338
        • van Haelst P.L.
        • van Doormaal J.J.
        • Asselbergs F.W.
        • et al.
        Correlates of endothelial function and their relationship with inflammation in patients with familial hypercholesterolaemia.
        Clin Sci (Lond). 2003; 104: 627-632
        • Bender J.R.
        • Sadeghi M.M.
        • Watson C.
        • Pfau S.
        • Pardi R.
        Heterogeneous activation thresholds to cytokines in genetically distinct endothelial cells: evidence for diverse transcriptional responses.
        Proc Natl Acad Sci USA. 1994; 91: 3994-3998
        • Iiyama K.
        • Hajra L.
        • Iiyama M.
        • et al.
        Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation.
        Circ Res. 1999; 85: 199-207
        • Dustin M.L.
        • Rothlein R.
        • Bhan A.K.
        • Dinarello C.A.
        • Springer T.A.
        Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1).
        J Immunol. 1986; 137: 245-254
        • Watson M.L.
        • Kingsmore S.F.
        • Johnston G.I.
        • et al.
        Genomic organization of the selectin family of leukocyte adhesion molecules on human and mouse chromosome 1.
        J Exp Med. 1990; 172: 263-272
        • Vestweber D.
        • Blanks J.E.
        Mechanisms that regulate the function of the selectins and their ligands.
        Physiol Rev. 1999; 79: 181-213
        • Pan J.
        • Xia L.
        • McEver R.P.
        Comparison of promoters for the murine and human P-selectin genes suggests species-specific and conserved mechanisms for transcriptional regulation in endothelial cells.
        J Biol Chem. 1998; 273: 10058-10067
        • McEver R.P.
        GMP-140: a receptor for neutrophils and monocytes on activated platelets and endothelium.
        J Cell Biochem. 1991; 45: 156-161
        • Gearing A.J.
        • Newman W.
        Circulating adhesion molecules in disease.
        Immunol Today. 1993; 14: 506-512