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Semin Respir Crit Care Med 2003; 24(2): 161-168
DOI: 10.1055/s-2003-39015
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Genetics of Acute Respiratory Distress Syndrome: Challenges, Approaches, Surfactant Proteins as Candidate Genes

Joanna Floros1,2 , Jelena Pavlovic1
  • 1Cellular and Molecular Physiology, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania
  • 2Pediatrics, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania
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Publication History

Publication Date:
07 May 2003 (online)

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ABSTRACT

There are challenges "inherent" in studying the genetics of a complex disease, such as acute respiratory distress syndrome (ARDS). It is necessary to define each ARDS subgroup using considerably narrower definitions that better reflect the particular subgroup. ARDS consists of several phenotypic subgroups, and findings from one subgroup may not be applicable to another. By extension, different treatment therapies may be appropriate for each phenotypic subgroup. This article presents the findings of a small pilot case-control association study where the surfactant proteins were used as candidate genes in the study of ARDS. This article discusses the relevance of surfactant protein genes in ARDS as well as the significance of genetic variants associated with ARDS subgroups.

KEYWORDS

Surfactant protein B (SP-B) - SP-A - transmission disequilibrium test (TDT) - case-control study - genetic variants - multigenic

REFERENCES

  • 1 Ashbaugh D G, Bigelow D B, Petty T L, Levine B E. Acute respiratory distress in adults.  Lancet . 1967;  2 319-323
    PubMedGoogle Scholar
  • 2 Murray J F, Matthay M A, Luce J M, Flick M R. An expanded definition of the adult respiratory distress syndrome.  Am Rev Respir Dis . 1988;  138 720-723
    CrossrefPubMedGoogle Scholar
  • 3 Bernard G R, Artigas A, Brigham K L. et al . The American- European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med . 1994;  149(3 pt 1) 818-824
    CrossrefPubMedGoogle Scholar
  • 4 Ware L B, Matthay M A. The acute respiratory distress syndrome.  N Engl J Med . 2000;  342 1334-1349
    CrossrefPubMedGoogle Scholar
  • 5 Pelosi P, Gattinoni L. Acute respiratory distress syndrome of pulmonary and extra-pulmonary origin: fancy or reality?.  Intensive Care Med . 2001;  27 457-460
    CrossrefPubMedGoogle Scholar
  • 6 Gattinoni L, Pelosi P, Suter P M. et al . Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?.  Am J Respir Crit Care Med . 1998;  158 3-11
    CrossrefPubMedGoogle Scholar
  • 7 Goodman L R, Fumagalli R, Tagliabue P. et al . Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations.  Radiology . 1999;  213 545-552
    PubMedGoogle Scholar
  • 8 Brower R G, Ware L B, Berthiaume Y, Matthay M A. Treatment of ARDS.  Chest . 2001;  120 1347-1367
    CrossrefPubMedGoogle Scholar
  • 9 Sporik R, Platts-Mills T A. Allergen exposure and the development of asthma.  Thorax . 2001;  56(suppl 2) ii58-63
    PubMedGoogle Scholar
  • 10 Svanes C, Jarvis D, Chinn S, Burney P. Childhood environment and adult atopy: results from the European Community Respiratory Health Survey.  J Allergy Clin Immunol . 1999;  103(3 pt 1) 415-420
    PubMedGoogle Scholar
  • 11 Bonini S, Rasi G, Torre A. et al . The heterogeneity of allergic phenotypes: genetic and environmental interactions.  Ann Allergy Asthma Immunol . 2001;  87(6 suppl 3) S48-S51
    PubMedGoogle Scholar
  • 12 Fahy J V. Remodeling of the airway epithelium in asthma.  Am J Respir Crit Care Med . 2001;  164(10 pt 2) S46-S51
    PubMedGoogle Scholar
  • 13 Howard T D, Koppelman G H, Xu J. et al . Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma.  Am J Hum Genet . 2002;  70 230-236
    CrossrefPubMedGoogle Scholar
  • 14 Hakonarson H, Wjst M. Current concepts on the genetics of asthma.  Curr Opin Pediatr . 2001;  13 267-277
    CrossrefPubMedGoogle Scholar
  • 15 Floros J, Fan R. Surfactant protein A and B genetic variants and respiratory distress syndrome: allele interactions.  Biol Neonate . 2001(suppl 1);  80 S22-S25
    CrossrefPubMedGoogle Scholar
  • 16 Floros J, Fan R, DiAngelo S. et al . Surfactant protein (SP) B associations and interactions with SP-A in white and black subjects with respiratory distress syndrome.  Pediatr Int . 2001;  43 567-576
    CrossrefPubMedGoogle Scholar
  • 17 Saltini C, Amicosante M, Franchi A. et al . Immunogenetic basis of environmental lung disease: lessons from the berylliosis model.  Eur Respir J . 1998;  12 1463-1475
    CrossrefPubMedGoogle Scholar
  • 18 Cookson W. The alliance of genes and environment in asthma and allergy.  Nature . 1999;  402(suppl 4) 733-742
    CrossrefPubMedGoogle Scholar
  • 19 Walter R, Gottlieb D J, O'Connor G T. Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.  Environ Health Perspect . 2000;  108(suppl 4) 733-742
    PubMedGoogle Scholar
  • 20 Lympany P A, du Bois M R. Diffuse lung disease: product of genetic susceptibility and environmental encounters.  Thorax . 1997;  52 92-94
    PubMedGoogle Scholar
  • 21 Phillips P C. The language of gene interaction.  Genetics . 1998;  149 1167-1171
    PubMedGoogle Scholar
  • 22 Fijneman R J, de Vries S S, Jansen R C, Demant P. Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse.  Nat Genet . 1996;  14 465-467
    PubMedGoogle Scholar
  • 23 van Wezel T, Stassen A P, Moen C J. et al . Gene interaction and single gene effects in colon tumour susceptibility in mice.  Nat Genet . 1996;  14 468-470
    PubMedGoogle Scholar
  • 24 Ghosh S, Collins F S. The geneticist's approach to complex disease.  Annu Rev Med . 1996;  47 333-353
    CrossrefPubMedGoogle Scholar
  • 25 Risch N J. Searching for genetic determinants in the new millennium.  Nature . 2000;  405 847-856
    CrossrefPubMedGoogle Scholar
  • 26 Guo S W, Lange K. Genetic mapping of complex traits: promises, problems, and prospects.  Theor Popul Biol . 2000;  57 1-11
    PubMedGoogle Scholar
  • 27 Martinez F D. Complexities of the genetics of asthma.  Am J Respir Crit Care Med . 1997;  156(4 pt 2) S117-S122
    PubMedGoogle Scholar
  • 28 Schork N J. Genetics of complex disease: approaches, problems, and solutions.  Am J Respir Crit Care Med . 1997;  156(4 pt 2) S103-S109
    PubMedGoogle Scholar
  • 29 Spielman R S, McGinnis R E, Ewens W J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).  Am J Hum Genet . 1993;  52 506-516
    PubMedGoogle Scholar
  • 30 Schulze T G, McMahon F J. Genetic association mapping at the crossroads: which test and why?.  Overview and practical guidelines. Am J Med Genet . 2002;  114 1-11
    PubMedGoogle Scholar
  • 31 Sham P C, Curtis D. An extended transmission/disequilibrium test (TDT) for multi-allele marker loci.  Ann Hum Genet . 1995;  59 323-336
    PubMedGoogle Scholar
  • 32 Fan R, Floros J, Xiong M. Transmission disequilibrium test of two unlinked disease loci: application to respiratory distress syndrome.  Advances and Application in Statistics . 2002;  1 277-308
    PubMedGoogle Scholar
  • 33 Spielman R S, Ewens W J. The TDT and other family-based tests for linkage disequilibrium and association.  Am J Hum Genet . 1996;  59 983-989
    PubMedGoogle Scholar
  • 34 Risch N, Merikangas K. The future of genetic studies of complex human diseases.  Science . 1996;  273 1516-1517
    CrossrefPubMedGoogle Scholar
  • 35 Fan R, Floros J, Xiong M. Models and tests of linkage and association studies of QTL for multi-allele marker loci.  Human Heredity . 2002;  53 130-145
    CrossrefPubMedGoogle Scholar
  • 36 Nakos G, Kitsiouli E I, Tsangaris I, Lekka M E. Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS: alterations in leukocytes, proteins, PAF and surfactant components.  Intensive Care Med . 1998;  24 296-303
    CrossrefPubMedGoogle Scholar
  • 37 Iannuzzi M C, Maliarik M, Rybicki B. Genetic polymorphisms in lung disease: bandwagon or breakthrough?.  Respir Res . 2002;  3 15-22
    CrossrefPubMedGoogle Scholar
  • 38 Floros J, Phelps D S. Pulmonary surfactant. In: Yaksh TL, Lynch C III, Zapol WM, Maze M, Biebuck J, Saidman LJ, eds. Anesthesia: Biologic Foundations Philadelphia, PA: Lippincott-Raven 1997: 1259-1279
    Google Scholar
  • 39 Phelps D S. Surfactant regulation of host defense function in the lung: a question of balance.  Pediatr Pathol Mol Med . 2001;  20 269-292
    PubMedGoogle Scholar
  • 40 Gregory T J, Longmore W J, Moxley M A. et al . Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.  J Clin Invest . 1991;  88 1976-1981
    PubMedGoogle Scholar
  • 41 Gunther A, Siebert C, Schmidt R. et al . Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema.  Am J Respir Crit Care Med . 1996;  153 176-184
    PubMedGoogle Scholar
  • 42 Pison U, Seeger W, Buchhorn R. et al . Surfactant abnormalities in patients with respiratory failure after multiple trauma.  Am Rev Respir Dis . 1989;  140 1033-1039
    PubMedGoogle Scholar
  • 43 Greene K E, Wright J R, Steinberg K P. et al . Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS.  Am J Respir Crit Care Med . 1999;  160 1843-1850
    CrossrefPubMedGoogle Scholar
  • 44 Gunther A, Schmidt R, Feustel A. et al . Surfactant subtype conversion is related to loss of surfactant apoprotein B and surface activity in large surfactant aggregates: experimental and clinical studies.  Am J Respir Crit Care Med . 1999;  159 244-251
    PubMedGoogle Scholar
  • 45 Doyle I R, Bersten A D, Nicholas T E. Surfactant proteins-A and -B are elevated in plasma of patients with acute respiratory failure.  Am J Respir Crit Care Med . 1997;  156(4 pt 1) 1217-1229
    CrossrefPubMedGoogle Scholar
  • 46 Bersten A D, Hunt T, Nicholas T E, Doyle I R. Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure.  Am J Respir Crit Care Med . 2001;  164 648-652
    CrossrefPubMedGoogle Scholar
  • 47 Gunther A, Ruppert C, Schmidt R. et al . Surfactant alteration and replacement in acute respiratory distress syndrome.  Respir Res . 2001;  2 353-364
    CrossrefPubMedGoogle Scholar
  • 48 Pison U, Obertacke U, Seeger W, Hawgood S. Surfactant protein A (SP-A) is decreased in acute parenchymal lung injury associated with polytrauma.  Eur J Clin Invest . 1992;  22 712-718
    PubMedGoogle Scholar
  • 49 Greene K E, Ye S, Mason R J, Parsons P E. Serum surfactant protein-A levels predict development of ARDS in at-risk patients.  Chest . 1999;  116 S90-S91
    CrossrefPubMedGoogle Scholar
  • 50 Gregory T J, Steinberg K P, Spragg R. et al . Bovine surfactant therapy for patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1997;  155 1309-1315
    PubMedGoogle Scholar
  • 51 Walmrath D, Gunther A, Ghofrani H A. et al . Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis.  Am J Respir Crit Care Med . 1996;  154 57-62
    PubMedGoogle Scholar
  • 52 Anzueto A, Baughman R P, Guntupalli K K. et al . Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group.  N Engl J Med . 1996;  334 1417-1421
    CrossrefPubMedGoogle Scholar
  • 53 Lin Z, deMello D E, Wallot M, Floros J. An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4.  Mol Genet Metab . 1998;  64 25-35
    CrossrefPubMedGoogle Scholar
  • 54 Clark J C, Weaver T E, Iwamoto H S. et al . Decreased lung compliance and air trapping in heterozygous SP-B- deficient mice.  Am J Respir Cell Mol Biol . 1997;  16 46-52
    PubMedGoogle Scholar
  • 55 Clark J C, Wert S E, Bachurski C J. et al . Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.  Proc Natl Acad Sci USA . 1995;  92 7794-7798
    PubMedGoogle Scholar
  • 56 Ingenito E P, Mora R, Cullivan M. et al . Decreased surfactant protein-B expression and surfactant dysfunction in a murine model of acute lung injury.  Am J Respir Cell Mol Biol . 2001;  25 35-44
    PubMedGoogle Scholar
  • 57 Lewis J F, Veldhuizen R, Possmayer F. et al . Altered alveolar surfactant is an early marker of acute lung injury in septic adult sheep.  Am J Respir Crit Care Med . 1994;  150 123-130
    PubMedGoogle Scholar
  • 58 Hoover R R, Floros J. Organization of the human SP-A and SP-D loci at 10q22-q23: physical and radiation hybrid mapping reveal gene order and orientation.  Am J Respir Cell Mol Biol . 1998;  18 353-362
    PubMedGoogle Scholar
  • 59 Floros J, DiAngelo S, Koptides M. et al . Human SP-A locus: allele frequencies and linkage disequilibrium between the two surfactant protein A genes.  Am J Respir Cell Mol Biol . 1996;  15 489-498
    PubMedGoogle Scholar
  • 60 DiAngelo S, Lin Z, Wang G. et al . Novel, nonradioactive, simple and multiplex PCR-cRFLP methods for genotyping human SP-A and SP-D marker alleles.  Dis Markers . 1999;  15 269-281
    PubMedGoogle Scholar
  • 61 Floros J, Wang G. A point of view: quantitative and qualitative imbalance in disease pathogenesis; pulmonary surfactant protein A genetic variants as a model.  Comp Biochem Physiol A Mol Integr Physiol . 2001;  129 295-303
    PubMedGoogle Scholar
  • 62 Floros J, Hoover R R. Genetics of the hydrophilic surfactant proteins A and D.  Biochim Biophys Acta . 1998;  1408 312-322
    PubMedGoogle Scholar
  • 63 Karinch A M, Deiter G, Ballard P L, Floros J. Regulation of expression of human SP-A1 and SP-A2 genes in fetal lung explant culture.  Biochim Biophys Acta . 1998;  1398 192-202
    PubMedGoogle Scholar
  • 64 Hoover R R, Floros J. SP-A 3'-UTR is involved in the glucocorticoid inhibition of human SP-A gene expression.  Am J Physiol . 1999;  276(6 pt 1) L917-924
    PubMedGoogle Scholar
  • 65 Wang G, Phelps D S, Umstead T M, Floros J. Human SP-A protein variants derived from one or both genes stimulate TNF-alpha production in the THP-1 cell line.  Am J Physiol Lung Cell Mol Physiol . 2000;  278 L946-954
    PubMedGoogle Scholar
  • 66 Wang G, Umstead T M, Phelps D S. et al . The effect of ozone exposure on the ability of human surfactant protein a variants to stimulate cytokine production.  Environ Health Perspect . 2002;  110 79-84
    PubMedGoogle Scholar
  • 67 Zhu S, Ware L B, Geiser T. et al . Increased levels of nitrate and surfactant protein A nitration in the pulmonary edema fluid of patients with acute lung injury.  Am J Respir Crit Care Med . 2001;  163 166-172
    CrossrefPubMedGoogle Scholar
  • 68 Schochett P, Mora R, Mark L. et al . Calcium-dependent degradation of surfactant protein A by activated neutrophils due to serine proteases.  Exp Lung Res . 1999;  25 595-616
    PubMedGoogle Scholar
  • 69 Puligandla P S, Gill T, McCaig L A. et al . Alveolar environment influences the metabolic and biophysical properties of exogenous surfactants.  J Appl Physiol . 2000;  88 1061-1071
    PubMedGoogle Scholar
  • 70 Baker C S, Evans T W, Randle B J, Haslam P L. Damage to surfactant-specific protein in acute respiratory distress syndrome.  Lancet . 1999;  353 1232-1237
    CrossrefPubMedGoogle Scholar
  • 71 Lin Z, Pearson C, Chinchilli V. et al . Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS.  Clin Genet . 2000;  58 181-191
    CrossrefPubMedGoogle Scholar
  • 72 Korimilli A, Gonzales L W, Guttentag S H. Intracellular localization of processing events in human surfactant protein B biosynthesis.  J Biol Chem . 2000;  275 8672-8679
    CrossrefPubMedGoogle Scholar
  • 73 Hawgood S, Latham D, Borchelt J. et al . Cell-specific posttranslational processing of the surfactant-associated protein SP-B.  Am J Physiol . 1993;  264(3 pt 1) L290-299
    PubMedGoogle Scholar
  • 74 Weaver T E. Synthesis, processing and secretion of surfactant proteins B and C.  Biochim Biophys Acta . 1998;  1408 173-179
    PubMedGoogle Scholar
  • 75 Wikenheiser K A, Wert S E, Wispe J R. et al . Distinct effects of oxygen on surfactant protein B expression in bronchiolar and alveolar epithelium.  Am J Physiol . 1992;  262(1 pt 1) L32-39
    PubMedGoogle Scholar
  • 76 Wang G, Christensen N D, Wigdahl B, Guttentag S H, Floros J. Differences in N-linked glycosylation between human surfactant protein-B variants of the C or T allele at the single-nucleotide polymorphism at position 1580: implications for disease.  Biochem J . 2003;  369 179-184
    CrossrefPubMedGoogle Scholar
  • 77 Roberts S J, Petropavlovskaja M, Chung K N. et al . Role of individual N-linked glycosylation sites in the function and intracellular transport of the human alpha folate receptor.  Arch Biochem Biophys . 1998;  351 227-235
    CrossrefPubMedGoogle Scholar
  • 78 Helenius A. How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum.  Mol Biol Cell . 1994;  5 253-265
    PubMedGoogle Scholar
  • 79 McFarlane I, Georgopoulou N, Coughlan C M. et al . The role of the protein glycosylation state in the control of cellular transport of the amyloid beta precursor protein.  Neuroscience . 1999;  90 15-25
    CrossrefPubMedGoogle Scholar
  • 80 Chui D, Sellakumar G, Green R. et al . Genetic remodeling of protein glycosylation in vivo induces autoimmune disease.  Proc Natl Acad Sci USA . 2001;  98 1142-1147
    CrossrefPubMedGoogle Scholar
  • 81 Scanlin T F, Glick M C. Glycosylation and the cystic fibrosis transmembrane conductance regulator.  Respir Res . 2001;  2 276-279
    CrossrefPubMedGoogle Scholar
  • 82 Nihlen U, Montnemery P, Lindholm L H, Lofdahl C G. Increased serum levels of carbohydrate-deficient transferrin in patients with chronic obstructive pulmonary disease.  Scand J Clin Lab Invest . 2001;  61 341-347
    PubMedGoogle Scholar
  • 83 Van Rozendaal A B, van Golde M L, Haagsman H P. Localization and functions of SP-A and SP-D at mucosal surfaces.  Pediatr Pathol Mol Med . 2001;  20 319-339
    PubMedGoogle Scholar
  • 84 Hartshorn K L, Crouch E, White M R. et al . Pulmonary surfactant proteins A and D enhance neutrophil uptake of bacteria.  Am J Physiol . 1998;  274(6 pt 1) L958-969
    PubMedGoogle Scholar
  • 85 Schagat T L, Wofford J A, Wright J R. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils.  J Immunol . 2001;  166 2727-2733
    PubMedGoogle Scholar
  • 86 Bersten A D, Davidson K, Nicholas T E, Doyle I R. Respiratory mechanics and surfactant in the acute respiratory distress syndrome.  Clin Exp Pharmacol Physiol . 1998;  25 955-963
    PubMedGoogle Scholar
  • 87 Floros J, Lin Z. Genetic variability of surfactant protein-B and respiratory distress syndrome: clinical implication: Medscape Respiratory Care 1999. Available at: http://www.respiratory care.medscape.com/Meds . . . 3.n02/mrc-4664.flor/pnt- mrc4664.flor.html
    Google Scholar