Genetic risk factors for chronic obstructive pulmonary disease

European Respiratory Journal

Volumn 10, Issue 6, 1997, Pages 1380-1391

  Sandford, A J ^a   Weir, T D ^a   Pare P D ^a  

^a ST PAUL S HOSPITAL   (Canada)

Author keywords

Chronic obstructive pulmonary disease; Genetics; Risk factors

Indexed keywords

ALPHA 1 ANTICHYMOTRYPSIN; ALPHA 1 ANTITRYPSIN; ALPHA 2 MACROGLOBULIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; VITAMIN D BINDING PROTEIN;

ALPHA 1 ANTITRYPSIN DEFICIENCY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CIGARETTE SMOKING; CYSTIC FIBROSIS; GENETIC RISK; HOMOZYGOSITY; HUMAN; HUMAN CELL; HUMAN TISSUE; PRIORITY JOURNAL; PROTEINASE INHIBITION; REGULATOR GENE; REVIEW; RISK FACTOR;

DISEASE SUSCEPTIBILITY; GENES; HUMANS; LUNG DISEASES, OBSTRUCTIVE; ODDS RATIO; RISK; RISK FACTORS;

EID: 0030919876     PISSN: 09031936     EISSN: None     Source Type: Journal    
DOI: 10.1183/09031936.97.10061380     Document Type: Review

References (140)

1. Snider GL. Chronic obstructive pulmonary disease: risk factors, pathophysiology and pathogenesis. Ann Rev Med 1989; 40: 411-429.
2. Fletcher C, Peto R, Tinker C, Speizer FE. The natural history of chronic bronchitis: an eight year follow-up study of working men in London. Oxford, Oxford University Press, 1976.
3. Bascom R. Differential susceptibility to tobacco smoke: possible mechanisms. Pharmacogenetics 1991; 1: 102-106.
4. Tager IB, Rosner B, Tishler PV, Speizer FE, Kass EH. Household aggregation of pulmonary function and chronic bronchitis. Am Rev Respir Dis 1976; 114: 485-492.
5. Tager I, Tishler PV, Rosner B, Speizer FE, Litt M. Studies of the familial aggregation of chronic bronchitis and obstructive airways disease. Int J Epidemiol 1978; 7: 55-62.
6. Khoury MJ, Beaty TH, Newil CA, Bryant S, Cohen BH. Genetic-environmental interactions in chronic airways obstruction. Int J Epidemiol 1986; 15: 65-72.
7. Higgins M, Keller J. Familial occurrence of chronic respiratory disease and familial resemblance in ventilatory capacity. J Chron Dis 1975; 28: 239-251.
8. Speizer FE, Rosner B, Tager I. Familial aggregation of chronic respiratory disease: use of national health interview survey data for specific hypothesis testing. Int J Epidemiol 1976; 5: 167-172.
9. Kueppers F, Miller RD, Gordon H, Hepper NG, Offord K. Familial prevalence of chronic obstructive pulmonary disease in a matched pair study. Am J Med 1977; 63: 336-342.
10. Madison R, Zelman R, Mittman C. Inherited risk factors for chronic lung disease. Chest 1980; 77 (2 Suppl.): 255-257.
11. Larson RK, Barman ML, Kueppers F, Fudenberg HH. Genetic and environmental determinants of chronic obstructive pulmonary disease. Ann Intern Med 1970; 72: 627-632.
12. Cohen BH, Diamond EL, Graves CG, et al. A common familial component in lung cancer and chronic obstructive pulmonary disease. Lancet 1977; ii: 523-526.
13. Kauffmann F, Tager IB, Muñoz A, Speizer FE. Familial factors related to lung function in children aged 6-10 years. Am J Epidemiol 1989; 129: 1289-1299.
14. Devor FJ, Crawford MH. Family resemblance for normal pulmonary function. Ann Hum Biol 1984; 11: 439-448.
15. Redline S, Tishler PV, Rosner B, et al. Genotypic and phenotypic similarities in pulmonary function among family members of adult monozygotic and dizygotic twins. Am J Epidemiol 1989; 129: 827-836.
16. Silverman E, Chapman H, Drazen J, et al. Early-onset chronic obstructive pulmonary disease (COPD): preliminary evidence for genetic factors other than Pi type. Am J Respir Crit Care Med 1996; 153: A48.
17. Rybicki BA, Beaty TH, Cohen BH. Major genetic mechanisms in pulmonary function. J Clin Epidemiol 1990; 43: 667-675.
18. Astemborski JA, Beaty TH, Cohen BH. Variance components analysis of forced expiration in families. Am J Med Genet 1985; 21: 741-753.
19. Zamel N, Webster P, Lorimer E, Man S, Woolf C. Environment versus genetics in determining bronchial susceptibility to cigarette smoking. Chest 1981; 80: 57S.
20. Redline S, Tishler PV, Lewitter FI, Tager IB, Munoz A, Speizer FE. Assessment of genetic and nongenetic influences on pulmonary function: a twin study. Am Rev Respir Dis 1987; 135: 217-222.
21. Webster PM, Lorimer EG, Man SFP, Woolf CR, Zamel N. Pulmonary function in identical twins: comparison of nonsmokers and smokers. Am Rev Respir Dis 1979; 119: 223-228.
22. Hankins D, Drage C, Zamel N, Kronenberg R. Pulmonary function in identical twins raised apart. Am Rev Respir Dis 1982; 125: 119-121.
23. Hubert HB, Fabsitz RR, Feinleib M, Gwinn C. Genetic and environmental influences on pulmonary function in adult twins. Am Rev Respir Dis 1982; 125: 409-415.
24. Man SFP, Zamel N. Genetic influences on normal variability of maximum expiratory flow-volume curves. J Appl Physiol 1976; 41: 874-877.
25. Soubrier F, Lathrop GM. The genetic basis of hypertension. Curr Opin Nephrol Hypertens 1995; 4: 177-181.
26. Davies JL, Kawaguchi Y, Bennett ST, et al. A genomewide search for human type 1 diabetes susceptibility genes. Nature 1994; 371: 130-136.
27. Vollmer WM, Johnson LR, Buist AS. Relationship of response to a bronchodilator and decline in forced expiratory volume in one second in population studies. Am Rev Respir Dis 1985; 132: 1186-1193.
28. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994; 265: 2037-2048.
29. Knowler WC, Williams RC, Pettitt DJ, Steinberg AG. Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am J Hum Genet 1988; 43: 520-526.
30. 1-antitrypsin deficiency. Scand J Clin Invest 1963; 15: 132-140.
31. 1-antitrypsin deficient individuals. J Clin Invest 1986; 77: 1952-1961.
32. 1-antitrypsin. Hum Genet 1980; 53: 429-433.
33. 1-antitrypsin. Prog Med Genet 1970; 7: 96-111.
34. 1-antitrypsin phenotypes using isoelectric focusing on polyacrylamide gel slabs. Am J Clin Pathol 1974; 62: 732-739.
35. 1-anitrypsin deficiency and liver disease. J Inher Metab Dis 1991; 14: 512-525.
36. 1-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis 1978; 117: 421-428.
37. 1-antitrypsin deficiency. Lancet 1985; i: 152-154.
38. 1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 1988; 138: 327-336.
39. 1-antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z: a survey by the British Thoracic Association. Br J Dis Chest 1983; 77: 14-27.
40. 1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976; 294: 1316-1321.
41. 1-antitrypsin deficiency. J Pediatr 1978; 92: 1006-1010.
42. 1-antitrypsin heterozygotes (PiMZ) in patients with obstructive pulmonary disease. Am Rev Respir Dis 1976; 114: 1077-1084.
43. Bartmann K, Fooke-Achterrath M, Koch G, et al. Heterozygosity in the Pi system as a pathogenetic co-factor in chronic obstructive pulmonary disease (COPD). Eur J Respir Dis 1985; 66: 284-296.
44. 1-antitrypsin heterozygote controversy. Am Rev Respir Dis 1976; 113: 601-606.
45. 1-antitrypsin Pi types in COPD patients. Chest 1988; 94: 446-447.
46. 1-antitrypsin Pi types in 965 COPD patients. Chest 1986; 89: 370-373.
47. Mittman C, Lieberman J, Rumsfeld J. Prevalence of abnormal protease inhibitor phenotypes in patients with chronic obstructive lung disease. Am Rev Respir Dis 1974; 109: 295-296.
48. Barnett TB, Gottovi D, Johnson AM. Protease inhibitors in chronic obstructive pulmonary disease. Am Rev Respir Dis 1975; 111: 587-593.
49. 1-antitrypsin variants. Am Rev Respir Dis 1973; 108: 918-925.
50. 1-antitrypsin phenotype to the performance of pulmonary function tests and to the prevalence of respiratory illness in a working population. Thorax 1976; 31: 149-157.
51. Morse JO, Lebowitz MD, Knudson RJ, Burrows B. Relation of protease inhibitor phenotypes to obstructive lung diseases in a community. N Engl J Med 1977; 296: 1190-1194.
52. 1-antitrypsin phenotype groups in a community population. Am Rev Respir Dis 1978; 117: 179-181.
53. Chan-Yeung M, Ashley MJ, Corey P, Maledy H. Pi phenotypes and the prevalence of chest symptoms and lung function abnormalities in workers employed in dusty industries. Am Rev Respir Dis 1978; 117:239-245.
54. 1-antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. J Clin Invest 1979; 63: 299-309.
55. 1-antitrypsin deficiency: a case-control study. Am Rev Respir Dis 1979; 120: 759-766.
56. Bruce RM, Cohen BH, Diamond EL, et al. Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects. Am Rev Respir Dis 1984; 130: 386-390.
57. 1-antitrypsin. Am Rev Respir Dis 1975; 112: 71-75.
58. 1-antitrypsin heterozygotes (Pi type MZ). Am Rev Respir Dis 1974; 110: 708-715.
59. 1-antitrypsin deficiency. Thorax 1979; 34: 637-646.
60. 1-antitrypsin deficiency. J Clin Invest 1976; 58: 1069-1077.
61. Tárjan E, Magyar P, Váczi Z, Lantos Å, Vaszár L. Longitudinal lung function study in heterozygous PiMZ phenotype subjects. Ear Respir J 1994; 7: 2199-2204.
62. 1-antitrypsin Pittsburgh (358 met→arg), a fatal bleeding disorder. N Engl J Med 1983; 309: 694-698.
63. 1-antitrypsin gene in chronic lung disease. Br Med J 1987; 294: 1511-1514.
64. 1-antitrypsin gene region in patients with chronic obstructive pulmonary disease. Eur J Clin Invest 1990; 20: 1-7.
65. 1-antitrypsin gene are associated with chronic obstructive airways disease. Dis Markers 1990; 8: 151-157.
66. 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280 kb region on chromosome 14q32.1. Am J Hum Genet 1993; 52: 343-353.
67. Cruickshank AM, Hansell DT, Burns HJG, Shenkin A. Effect of nutritional status on acute phase protein response to elective surgery. Br J Surg 1989; 76: 165-168.
68. 1-antitrypsin gene commonly associated with chronic obstructive airways disease. Eur J Clin Invest 1992; 22: 134-137.
69. 1-antitrypsin gene associated with chronic respiratory disease occurs in a regulatory sequence. Hum Mol Genet 1993; 2: 253-257.
70. 1-antitrypsin in human mononuclear phagocytes and in human hepatoma cells. J Clin Invest 1989; 84: 139-144.
71. Ramji DP, Vitelli A, Tronche F, Cortese R, Ciliberto G. The two C/EBP isoforms, IL-6 DBP/NF-IL-6 and C/EBP δ NF-IL-6 βare induced by IL-6 to promote acute phase gene transcription via different mechanisms. Nucleic Acids Res 1993; 21: 289-294.
72. 1-antitrypsin gene polymorphism related to respiratory system disease. Klin Woschr 1987; 65: 538-541.
73. 1-antichymotrypsin. J Immunol 1991; 146: 2388-2393.
74. 1-antichymotrypsin. Am Rev Respir Dis 1984; 129: 473-176.
75. 1-antichymotrypsin deficiency. Acta Med Scand 1986; 220: 447-453.
76. 1-antichymotrypsin. Am Rev Respir Dis 1990; 141: 884-888.
77. 1-antitrypsin deficiency: prevalence and clinical spectrum in asthmatic children. Allergy 1990; 45: 197-203.
78. 1-antichymotrypsin gene associated with chronic lung disease. Lancet 1992; 339: 1538.
79. 1-antichymotrypsin allele associated with familial obstructive lung disease. Genomics 1993; 17: 740-743.
80. 1-antichymotrypsin gene and chronic lung disease. Lancet 1993; 342: 624.
81. Welch MJ, Tsui L-T, Boat TF, Beaudet AL. The Metabolic Basis of Inherited Disease. In: Scriver CL, Beaudel AL, Sly WS, Valle D, eds. New York, McGraw-Hill Inc., 1995; pp. 3799-3876.
82. Meindl RS. Hypothesis: a selective advantage for cystic fibrosis heterozygotes. Am J Phys Anthropol 1987; 74: 39-45.
83. Shier WT. Increased resistance to influenza as a possible source of heterozygote advantage in cystic fibrosis. Med Hypotheses 1979; 5: 661-667.
84. Quinton PM. Fluid and Electrolyte Abnormalities in Exocrine Glands in Cystic Fibrosis. In: Quinton PM, Martinez RJ, Hopfer U, eds. San Francisco, San Francisco Press, 1982; pp. 53-76.
85. Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ. Cystic fibrosis resistance to cholera toxin in the cystic fibrosis mouse model. Science 1994; 266: 107-109.
86. Anderson CM, Freeman M, Allan J, Hubbard L. Observations on: i) sweat sodium levels in relation to chronic respiratory disease in adults; and ii) the incidence of respiratory and other disease in parents and siblings of patients with fibrocystic disease of the pancreas. Med J Aust 1962; 1: 965-969.
87. Orzaleski MM, Kohner D, Cook CD, Shwachman H. Anamnesis: sweat electrolyte and pulmonary function studies in parents of patients with cystic fibrosis of the pancreas. Acta Paediatr 1963; 52: 267-276.
88. Batten J, Muir D, Simon G, Cedric C. The prevalence of respiratory disease in heterozygotes for the gene for fibrocystic disease of the pancreas. Lancet 1963; i: 1348-1350.
89. Hallett WY, Knudson AG, Massey FJ. Absence of detrimental effect of the carrier state for the cystic fibrosis gene. Am Rev Respir Dis 1965; 90: 714-724.
90. Davies PB. Autonomic and airway reactivity in obligate heterozygotes for cystic fibrosis. Am Rev Respir Dis 1984; 129: 911-914.
91. Davis PB, Vargo K. Pulmonary abnormalities in obligate heterozygotes for cystic fibrosis. Thorax 1987; 42: 120-125.
92. Kerem B-S, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073-1080.
93. Poller W, Faber J-P, Scholtz S, Olek K, Müller K-M. Sequence analysis of the cystic fibrosis gene in patients with disseminated bronchiectatic lung disease. Klin Wschr 1991; 69: 657-663.
94. Dumur V, Lafitte J-J, Gervais R, et al. Abnormal distribution of cystic fibrosis ΔF508 allele in adults with chronic bronchial hypersecretion. Lancet 1990; 335: 1340.
95. Gervais R, Lafitte J-J, Dumur V, et al. Sweat chloride and ΔF508 mutation in chronic bronchitis or bronchiectasis. Lancet 1993; 342: 997.
96. Akai S, Okayama H, Shimura S, Tanno Y, Sasaki H, Takisima T. ΔF508 mutation of cystic fibrosis gene is not found in chronic bronchitis with severe obstruction in Japan. Am Rev Respir Dis 1992; 146: 781-783.
97. Artlich A, Boysen A, Bunge S, Entzian P, Schlaak M, Schwinger E. Common CFTR mutations are not likely to predispose to chronic bronchitis in Northern Germany. Hum Genet 1995; 95: 226-228.
98. Entzian P, Müller E, Boysen A, Artlich A, Schwinger E, Schlaak M. Frequency of common cystic fibrosis gene mutations in chronic bronchitis patients. Scand J Lab Invest 1995; 55: 263-266.
99. Pignatti PF, Bombieri C, Mango C, Benetazzo M, Luisetti M. Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum Mol Genet 1995; 4: 635-636.
100. Pignatti PF, Bombieri C, Benetazzo M, et al. CFTR gene variant IVS8-5T in disseminated bronchiectasis. Am J Hum Genet 1996; 58: 889-892.
101. Gasparini P, Savoia A, Luisetti M, Peona V, Pignatti PF. The cystic fibrosis gene is not likely to be involved in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 1990; 2: 297-299.
102. Kew RR, Webster RO. Gc-globulin (vitamin D-binding protein) enhances the neutrophil chemotactic activity of C5a and C5a des Arg. J Clin Invest 1988; 82: 364-369.
103. Yamamoto N, Homma S. Vitamin D-binding protein (group-specific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes. Proc Natl Acad Sci USA 1991; 88: 8539-8543.
104. Home SL, Cockcroft DW, Dosman JA. Possible protective effect against chronic obstructive airways disease by the GC 2 allele. Hum Hered 1990; 40: 173-176.
105. Kauffmann F, Kleisbauer J-P, Cambon-de-Mouzon A, et al. Genetic markers in chronic airflow limitation: a genetic epidemiologic study. Am Rev Respir Dis 1983; 127: 263-269.
106. 2-macroglobulin by alveolar macrophages. Lung 1980; 158: 9-14.
107. 2-macroglobulin by cultured human fibroblasts. J Exp Med 1976; 143: 462-467.
108. 2-macroglobulin deficiency syndrome: light microscopic evidence of collagenolytic, elastolytic and myolytic tissue lesions. Path Res Prac 1980; 168: 17-35.
109. 2-macroglobulin in patients with chronic obstructive airways disease. Thorax 1981; 36: 512-516.
110. 1-antitrypsin deficiency. Clin Chim Acta 1983; 128: 241-248.
111. 1-antitrypsin deficiency. Scand J Clin Lab Invest 1967; 19: 205-208.
112. 2-macroglobulin deficiency. Scand J Haematol 1979; 23: 433-436.
113. 2-macroglobulin deficiency. Thrombosis Res 1981; 22: 491-495.
114. 2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site. Hum Genet 1992; 88: 313-319.
115. 2-macroglobulin deficiency. Hum Genet 1989; 83: 93-96.
116. Drakoulis N, Cascorbi I, Brockmöller J, Gross CR, Roots I. Polymorphisms in the human CYP1A1 gene as susceptibility factors for lung cancer: exon-7 mutation (4889 A to G), and a T to C mutation in the 3′-flanking region. Clin Invest 1994; 72: 240-248.
117. Cantlay AM, Lamb D, Gillooly M, et al. Association between the CYP1A1 gene polymorphism and susceptibility to emphysema and lung cancer. J Clin Pathol: Mol Pathol 1995; 48: M210-214.
118. Cohen BH, Ball WC, Brashears S, et al. Risk factors in chronic obstructive pulmonary disease (COPD). Am J Epidemiol 1977; 105: 223-232.
119. Beatty TH, Menkes HA, Cohen BH, Newill CA. Risk factors associated with longitudinal change in pulmonary function. Am Rev Respir Dis 1984; 129: 660-667.
120. Krzyzanowski M, Jedrychowski W, Wysocki M. Factors associated with the change in ventilatory function and the development of chronic obstructive pulmonary disease in a 13 year follow-up of the Cracow study. Am Rev Respir Dis 1986; 134: 1011-1019.
121. Higgins MW, Keller JB, Becker M, et al. An index of risk for obstructive airways disease. Am Rev Respir Dis 1982; 125: 144-151.
122. Vestbo J, Hein HO, Suadicani P, Sørensen H, Gyntelberg F. Genetic markers for chronic bronchitis and peak expiratory expiratory flow in the Copenhagen Male Study. Dan Med Bull 1993; 40: 378-380.
123. Cohen BH, Bias WB, Chase GA, et al. Is ABH non-secretor status a risk factor for obstructive lung disease? Am J Epidemiol 1980; 111: 285-291.
124. Haines AP, Imeson JD, Meade TW. ABH secretor status and pulmonary function. Am J Epidemiol 1982; 115: 367-370.
125. Abboud RT, Yu P, Chan-Yeung M, Tan F. Lack of relationship between ABH secretor status and lung function in pulp-mill workers. Am Rev Respir Dis 1982; 126: 1089-1091.
126. Horne SL, Cockcroft DW, Lovegrove A, Dosman JA. ABO, Lewis and secretor status and relative incidence of airflow obstruction. Dis Markers 1985; 3: 55-62.
127. Kauffmann F, Frette C, Pham Q-T, Nafissi S, Bertrand J-P, Oriol R. Associations of blood group-related antigens to FEV1, wheezing and asthma. Am J Respir Crit Care Med 1996; 153: 76-82.
128. Raza MW, Blackwell CC, Molyneaux P, et al. Association between secretor status and respiratory viral illness. Br Med J 1991; 303: 815-818.
129. Sugiyama Y, Kudoh S, Maeda H, Suzaki H, Takaku F. Analysis of HLA antigens in patients with diffuse panbronchiolitis. Am Rev Respir Dis 1990; 141: 1459-1462.
130. Björkander J, Bake B, Oxelius VA, Hanson LÅ. Impaired lung function in patients with IgA deficiency and low levels of IgG2 or IgG3. N Engl J Med 1985; 313: 720-724.
131. O'Keefe S, Gzel A, Drury R, Cullina M, Greally J, Finnegan P. Immunoglobulin G subclasses and spirometry in patients with chronic obstructive pulmonary disease. Eur Respir J 1991; 4: 932-938.
132. Oxelius VA, Laurell AB, Lindquist B, et al. IgG subclasses in selective IgA deficiency. N Engl J Med 1981; 304: 1476-1477.
133. Webb DR, Condemi JJ. Selective immunoglobulin A deficiency and chronic obstructive lung disease. Ann Intern Med 1974; 80: 618-621.
134. Folz RJ, Peno-Green L, Crapo JD. Identification of a homozygous mis-sense mutation (Arg to Gly) in the critical binding region of the human EC-SOD gene (SOD3) and its association with dramatically increased serum enzyme levels. Hum Mol Genet 1994; 3: 2251-2254.
135. Sandström J, Nilsson P, Karlsson K, Marklund SL. Tenfold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparinbinding domain. J Biol Chem 1994; 268: 19163-19166.
136. Peno-Green L, Crapo JD, Folz RJ. Characterization of human serum extracellular Superoxide dismutase variants in normal and lung disease individuals. Am J Respir Crit Care Med 1995; 151: A167.
137. Sallenave J-M, Shulmann J, Crossley J, Jordana M, Gauldie J. Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/Elafin) in human airway epithelial airway cells by cytokines and neutrophilic enzymes. Am J Respir Cell Mol Biol 1994; 11: 733-741.
138. Abe T, Kobayashi N, Yoshimura K, et al. Expression of the secretory leukoprotease inhibitor gene in epithelial cells. J Clin Invest 1991; 87: 2207-2215.
139. Lüdecke B, Poller W, Olek K, Bartholomé K. Sequence variant of the human cathepsin G gene. Hum Genet 1993; 91: 83-84.
140. Weiss ST, Segal MR, Sparrow D, Wager C. Relation of FEV1 and peripheral blood leukocyte count to total mortality: the normative aging study. Am J Epidemiol 1995; 142: 493-498.