Advertisement

Association between the surfactant protein D (SFTPD) gene and subclinical carotid artery atherosclerosis

  • Grith L. Sorensen
    Correspondence
    Corresponding author.
    Affiliations
    Department of Cancer and Inflammation, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
    Search for articles by this author
  • Else Marie Bladbjerg
    Affiliations
    Unit for Thrombosis Research, Department of Public Health, University of Southern, Denmark

    Department of Clinical Biochemistry, Hospital of Southwest Denmark, Esbjerg, Denmark
    Search for articles by this author
  • Rudi Steffensen
    Affiliations
    Regional Centre for Blood Transfusion and Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
    Search for articles by this author
  • Qihua Tan
    Affiliations
    Unit for Epidemiology, Department of Public Health, University of Southern Denmark, Odense, Denmark
    Search for articles by this author
  • Jens Madsen
    Affiliations
    Department of Child Health, Sir Henry Wellcome Laboratories, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom

    Institute for Life Sciences, University of Southampton, Southampton, United Kingdom

    National Institute for Health Research, Southampton Respiratory Biomedical Research Unit, Southampton Centre for Biomedical Research, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
    Search for articles by this author
  • Thomas Drivsholm
    Affiliations
    Research Centre for Prevention and Health, The Capital Region of Denmark, Rigshospitalet, Glostrup, Denmark

    The Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Uffe Holmskov
    Affiliations
    Department of Cancer and Inflammation, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
    Search for articles by this author

      Highlights

      • There is no association between plasma SP-D and subclinical atherosclerosis.
      • There is protective effect of rs3088308 frequent allele for presence of plaques.
      • There is protective effect of rs721917 frequent allele for intima-media-thickness.
      • Protective effects of the SFTPD structural polymorphisms are reversed by smoking.

      Abstract

      Objective

      Surfactant protein D (SP-D) is a defense collectin with inflammation-modulating properties. SP-D deficiency inhibits atherosclerosis in vivo, and the circulatory SP-D levels have been previously associated with cardiovascular disease mortality. We hypothesized that plasma SP-D (pSP-D) and SP-D gene (SFTPD) single nucleotide polymorphisms (SNPs) are risk factors for atherosclerosis.

      Methods

      We evaluated individuals who were all 60 years old and participated in The Glostrup Population Study. Subclinical atherosclerosis was diagnosed based on the ultrasonographic measurement of intima-media thickness (IMT) and protruding plaques in the right carotid artery. Associations between cardiovascular traits and the levels of pSP-D (n = 687) or two coding SFTPD SNPs rs3088308 and rs721917 (n = 396) were investigated using multiple linear regressions and logistic regressions.

      Results

      There was no significant association between pSP-D and the presence of plaques or IMT. The SFTPD SNP rs3088308 was nominally associated with the presence of plaques, and rs721917 was nominally associated with IMT. The directions of effects of associations were markedly dependent on current smoking status.

      Conclusions

      The results do not support that pSP-D levels influence the development of subclinical atherosclerosis. However, the SFTPD SNP data support previous observations from animal studies that SP-D plays a role in the etiology of atherosclerotic disease development. The nominal significant effects are likely to be mediated by structural variant SP-D modulation of effects of tobacco smoking and are independent of pSP-D levels. The data warrant confirmation in larger cohorts.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Libby P.
        • Lichtman A.H.
        • Hansson G.K.
        Immune effector mechanisms implicated in atherosclerosis: from mice to humans.
        Immunity. 2013; 38: 1092-1104
        • Humphries S.E.
        • Morgan L.
        Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches.
        Lancet Neurol. 2004; 3: 227-235
        • Madsen J.
        • Kliem A.
        • Tornoe I.
        • Skjodt K.
        • Koch C.
        • Holmskov U.
        Localization of lung surfactant protein d on mucosal surfaces in human tissues.
        J. Immunol. 2000; 164: 5866-5870
        • Sorensen G.L.
        • Madsen J.
        • Kejling K.
        • Tornoe I.
        • Nielsen O.
        • Townsend P.
        • Poulain F.
        • Nielsen C.H.
        • Reid K.B.
        • Hawgood S.
        • Falk E.
        • Holmskov U.
        Surfactant protein d is proatherogenic in mice.
        Am. J. Physiol. Heart Circ. Physiol. 2006; 290: H2286-2294
        • Lee M.Y.
        • Sorensen G.L.
        • Holmskov U.
        • Vanhoutte P.M.
        The presence and activity of sp-d in porcine coronary endothelial cells depend on akt/pi(3)k, erk and nitric oxide and decrease after multiple passaging.
        Mol. Immunol. 2009 Mar; 46: 1050-1057
        • Sorensen G.L.
        • Husby S.
        • Holmskov U.
        Surfactant protein A and surfactant protein D variation in pulmonary disease.
        Immunobiology. 2007; 212: 381-416
        • Lomas D.A.
        • Silverman E.K.
        • Edwards L.D.
        • Locantore N.W.
        • Miller B.E.
        • Horstman D.H.
        • Tal-Singer R.
        Serum surfactant protein d is steroid sensitive and associated with exacerbations of copd.
        Eur. Respir. J. 2009;
        • Johansson S.L.
        • Tan Q.
        • Holst R.
        • Christiansen L.
        • Hansen N.C.
        • Hojland A.T.
        • Wulf-Johansson H.
        • Schlosser A.
        • Titlestad I.L.
        • Vestbo J.
        • Holmskov U.
        • Kyvik K.O.
        • Sorensen G.L.
        Surfactant protein d is a candidate biomarker for subclinical tobacco smoke-induced lung damage.
        Am. J. Physiol. Lung Cell Mol. Physiol. 2014; 306: L887-895
        • Lock-Johansson S.
        • Vestbo J.
        • Sorensen G.
        Surfactant protein d, club cell protein 16, pulmonary and activation-regulated chemokine, c-reactive protein, and fibrinogen biomarker variation in chronic obstructive lung disease.
        Respir. Res. 2014; 15: 147
        • Fujita M.
        • Shannon J.M.
        • Ouchi H.
        • Voelker D.R.
        • Nakanishi Y.
        • Mason R.J.
        Serum surfactant protein d is increased in acute and chronic inflammation in mice.
        Cytokine. 2005; 31: 25-33
        • Wright J.R.
        Immunoregulatory functions of surfactant proteins.
        Nat. Rev. Immunol. 2005; 5: 58-68
        • Barrow A.D.
        • Palarasah Y.
        • Bugatti M.
        • Holehouse A.S.
        • Byers D.E.
        • Holtzman M.J.
        • Vermi W.
        • Skjodt K.
        • Crouch E.
        • Colonna M.
        Oscar is a receptor for surfactant protein d that activates tnf-alpha release from human ccr2+ inflammatory monocytes.
        J. Immunol. 2015; 194: 3317-3326
        • Nybo M.
        • Andersen K.
        • Sorensen G.L.
        • Lolk A.
        • Kragh-Sorensen P.
        • Holmskov U.
        Serum surfactant protein d is correlated to development of dementia and augmented mortality.
        Clin. Immunol. 2007; 123: 333-337
        • Wulf-Johansson H.
        • Thinggaard M.
        • Tan Q.
        • Johansson S.L.
        • Schlosser A.
        • Christensen K.
        • Holmskov U.
        • Sorensen G.L.
        Circulating surfactant protein d is associated to mortality in elderly women: a twin study.
        Immunobiology. 2013; 218: 712-717
        • Hill J.
        • Heslop C.
        • Man S.F.
        • Frohlich J.
        • Connett J.E.
        • Anthonisen N.R.
        • Wise R.A.
        • Tashkin D.P.
        • Sin D.D.
        Circulating surfactant protein-d and the risk of cardiovascular morbidity and mortality.
        Eur. Heart J. 2011; 32: 1918-1925
        • Snyder G.D.
        • Oberley-Deegan R.E.
        • Goss K.L.
        • Romig-Martin S.A.
        • Stoll L.L.
        • Snyder J.M.
        • Weintraub N.L.
        Surfactant protein d is expressed and modulates inflammatory responses in human coronary artery smooth muscle cells.
        Am. J. physiol. Heart Circ. physiol. 2008; 294: H2053-2059
        • Sorensen G.L.
        • Hoegh S.V.
        • Leth-Larsen R.
        • Thomsen T.H.
        • Floridon C.
        • Smith K.
        • Kejling K.
        • Tornoe I.
        • Crouch E.C.
        • Holmskov U.
        Multimeric and trimeric subunit sp-d are interconvertible structures with distinct ligand interaction.
        Mol. Immunol. 2009; 46: 3060-3069
        • Stidsen J.V.
        • Khorooshi R.
        • Rahbek M.K.
        • Kirketerp-Moller K.L.
        • Hansen P.B.
        • Bie P.
        • Kejling K.
        • Mandrup S.
        • Hawgood S.
        • Nielsen O.
        • Nielsen C.H.
        • Owens T.
        • Holmskov U.
        • Sorensen G.L.
        Surfactant protein d deficiency in mice is associated with hyperphagia, altered fat deposition, insulin resistance, and increased basal endotoxemia.
        PLoS One. 2012; 7: e35066
        • Ortega F.J.
        • Pueyo N.
        • Moreno-Navarrete J.M.
        • Sabater M.
        • Rodriguez-Hermosa J.I.
        • Ricart W.
        • Tinahones F.J.
        • Fernandez-Real J.M.
        The lung innate immune gene surfactant protein-d is expressed in adipose tissue and linked to obesity status.
        Int. J. Obes. (Lond). 2013; 37: 1532-1538
        • Layden B.T.
        • Durai V.
        • Newman M.V.
        • Marinelarena A.M.
        • Ahn C.W.
        • Feng G.
        • Lin S.
        • Zhang X.
        • Kaufman D.B.
        • Jafari N.
        • Sorensen G.L.
        • Lowe Jr., W.L.
        Regulation of pancreatic islet gene expression in mouse islets by pregnancy.
        J. Endocrinol. 2010; 207: 265-279
        • Aye T.
        • Toschi E.
        • Sharma A.
        • Sgroi D.
        • Bonner-Weir S.
        Identification of markers for newly formed beta-cells in the perinatal period: a time of recognized beta-cell immaturity.
        J. Histochem Cytochem. 2010; 58: 369-376
        • Sorensen G.L.
        • Hjelmborg J.B.
        • Kyvik K.O.
        • Fenger M.
        • Hoj A.
        • Bendixen C.
        • Sorensen T.I.
        • Holmskov U.
        Genetic and environmental influences of surfactant protein d serum levels.
        Am. J. Physiol. Lung Cell Mol. Physiol. 2006; 290: L1010-1017
        • Sorensen G.L.
        • Hjelmborg J.V.
        • Leth-Larsen R.
        • Schmidt V.
        • Fenger M.
        • Poulain F.
        • Hawgood S.
        • Sorensen T.I.
        • Kyvik K.O.
        • Holmskov U.
        Surfactant protein d of the innate immune defence is inversely associated with human obesity and sp-d deficiency infers increased body weight in mice.
        Scand. J. Immunol. 2006; 64: 633-638
        • Fernandez-Real J.M.
        • Valdes S.
        • Manco M.
        • Chico B.
        • Botas P.
        • Campo A.
        • Casamitjana R.
        • Delgado E.
        • Salvador J.
        • Fruhbeck G.
        • Mingrone G.
        • Ricart W.
        Surfactant protein d, a marker of lung innate immunity, is positively associated with insulin sensitivity.
        Diabetes Care. 2010; 33: 847-853
        • Leth-Larsen R.
        • Garred P.
        • Jensenius H.
        • Meschi J.
        • Hartshorn K.
        • Madsen J.
        • Tornoe I.
        • Madsen H.O.
        • Sorensen G.
        • Crouch E.
        • Holmskov U.
        A common polymorphism in the sftpd gene influences assembly, function, and concentration of surfactant protein d.
        J. Immunol. 2005; 174: 1532-1538
        • Pueyo N.
        • Ortega F.J.
        • Mercader J.M.
        • Moreno-Navarrete J.M.
        • Sabater M.
        • Bonas S.
        • Botas P.
        • Delgado E.
        • Ricart W.
        • Martinez-Larrad M.T.
        • Serrano-Rios M.
        • Torrents D.
        • Fernandez-Real J.M.
        Common genetic variants of surfactant protein-d (sp-d) are associated with type 2 diabetes.
        PLoS One. 2013; 8: e60468
        • Berg K.K.
        • Madsen H.O.
        • Garred P.
        • Wiseth R.
        • Gunnes S.
        • Videm V.
        The additive contribution from inflammatory genetic markers on the severity of cardiovascular disease.
        Scand. J. Immunol. 2009; 69: 36-42
        • Hollnagel H.
        The health structure of 40-year-old men and women in the glostrup area, denmark–an epidemiological survey. General design, sampling results and referrals for further medical care.
        Dan. Med. Bull. 1980; 27: 121-130
        • de Maat M.P.
        • Bladbjerg E.M.
        • Drivsholm T.
        • Borch-Johnsen K.
        • Moller L.
        • Jespersen J.
        Inflammation, thrombosis and atherosclerosis: results of the glostrup study.
        J. Thromb. Haemost. 2003; 1: 950-957
        • Leth-Larsen R.
        • Nordenbaek C.
        • Tornoe I.
        • Moeller V.
        • Schlosser A.
        • Koch C.
        • Teisner B.
        • Junker P.
        • Holmskov U.
        Surfactant protein d (sp-d) serum levels in patients with community-acquired pneumonia.
        Clin. Immunol. 2003; 108: 29-37
        • Zhao X.M.
        • Wu Y.P.
        • Wei R.
        • Cai H.X.
        • Tornoe I.
        • Han J.J.
        • Wang Y.
        • de Groot P.G.
        • Holmskov U.
        • Xia Z.L.
        • Sorensen G.L.
        Plasma surfactant protein d levels and the relation to body mass index in a chinese population.
        Scand. J. Immunol. 2007; 66: 71-76
        • Sorensen G.L.
        • Dahl M.
        • Tan Q.
        • Bendixen C.
        • Holmskov U.
        • Husby S.
        Surfactant protein-d-encoding gene variant polymorphisms are linked to respiratory outcome in premature infants.
        J. Pediatr. 2014; 165: 683-689
        • Kim D.K.
        • Cho M.H.
        • Hersh C.P.
        • Lomas D.A.
        • Miller B.E.
        • Kong X.
        • Bakke P.
        • Gulsvik A.
        • Agusti A.
        • Wouters E.
        • Celli B.
        • Coxson H.
        • Vestbo J.
        • MacNee W.
        • Yates J.C.
        • Rennard S.
        • Litonjua A.
        • Qiu W.
        • Beaty T.H.
        • Crapo J.D.
        • Riley J.H.
        • Tal-Singer R.
        • Silverman E.K.
        • Eclipse I.
        • Investigators C.O.
        Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease.
        Am. J. Respir. Crit. Care Med. 2012; 186: 1238-1247
        • Duvoix A.
        • Miranda E.
        • Perez J.
        • Sorensen G.L.
        • Holmskov U.
        • Trapnell B.C.
        • Madsen J.
        • Clark H.W.
        • Edwards L.D.
        • Miller B.E.
        • Tal-Singer R.M.
        • Lomas D.A.
        Evaluation of full-length, cleaved and nitrosylated serum surfactant protein d as biomarkers for copd.
        Copd. 2011; 8: 79-95
        • Foreman M.G.
        • Kong X.
        • Demeo D.L.
        • Pillai S.G.
        • Hersh C.P.
        • Bakke P.
        • Gulsvik A.
        • Lomas D.A.
        • Litonjua A.A.
        • Shapiro S.D.
        • Tal-Singer R.
        • Silverman E.K.
        Polymorphisms in surfactant protein d are associated with copd.
        Am. J. Respir. Cell Mol. Biol. 2010;
        • Ravani A.
        • Werba J.P.
        • Frigerio B.
        • Sansaro D.
        • Amato M.
        • Tremoli E.
        • Baldassarre D.
        Assessment and relevance of carotid intima-media thickness (c-imt) in primary and secondary cardiovascular prevention.
        Curr. Pharm. Des. 2015; 21: 1164-1171
        • Gardai S.J.
        • Xiao Y.Q.
        • Dickinson M.
        • Nick J.A.
        • Voelker D.R.
        • Greene K.E.
        • Henson P.M.
        By binding sirpalpha or calreticulin/cd91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation.
        Cell. 2003; 115: 13-23
        • Vandivier R.W.
        • Ogden C.A.
        • Fadok V.A.
        • Hoffmann P.R.
        • Brown K.K.
        • Botto M.
        • Walport M.J.
        • Fisher J.H.
        • Henson P.M.
        • Greene K.E.
        Role of surfactant proteins a, d, and c1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and cd91 as a common collectin receptor complex.
        J. Immunol. 2002; 169: 3978-3986
        • Botas C.
        • Poulain F.
        • Akiyama J.
        • Brown C.
        • Allen L.
        • Goerke J.
        • Clements J.
        • Carlson E.
        • Gillespie A.M.
        • Epstein C.
        • Hawgood S.
        Altered surfactant homeostasis and alveolar type ii cell morphology in mice lacking surfactant protein d.
        Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11869-11874
        • Clark H.
        • Palaniyar N.
        • Strong P.
        • Edmondson J.
        • Hawgood S.
        • Reid K.B.
        Surfactant protein d reduces alveolar macrophage apoptosis in vivo.
        J. Immunol. 2002; 169: 2892-2899
        • Seong S.Y.
        • Matzinger P.
        Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses.
        Nat. Rev. Immunol. 2004; 4: 469-478