Pharmacogenomics of Pulmonary and Respiratory Diseases

  • Luciana B. Crotti
  • Fernanda Kehdy
  • Eduardo Tarazona-Santos
  • Luis A. Espinoza


The identification of variations or mutations in genes encoding proteins that are involved in drug processing or metabolism can provide key information relevant to differential responses to therapeutic agents in specific genetic populations groups. It is well accepted that genetic variability (functional polymorphisms) may explain the failure of therapies and/or serious adverse side effects during and after treatment. Therefore, there is enormous interest in identifying these variants and determining their clinical relevance. In this regard, the main focus of pharmacogenomics is the study of inherited variations in genes that modulate drug response and their influence in predicting patient response to a specific treatment. For this purpose, pharmacogenomics integrates genomic information and technologies driving drug discovery and developing large-scale genomic studies to identify genetic variations. These findings may provide benefits in designing therapies more targeted to specific diseases, maximizing therapeutic effects, decreasing adverse reactions, and developing better methods to determine effective drug dosages. In addition to the anticipated benefit of personalized medicine, the identification of genetic markers may also influence the lifestyle, environment, and diet of those individuals with high susceptibility to develop a particular disease(s) and to prevent or delay the development of diseases. This chapter will focus on mutations and the variety of polymorphisms that may be associated with therapy resistance for people with different types of lung diseases such as chronic obstructive pulmonary disease (COPD), tuberculosis (TB), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), and interstitial lung damage (ILD). In fact, insights from recent evidences strongly support the notion that pharmacogenomics will be essential in improving innovative genomic-based therapies based on the genomic profiles of patients.


Chronic Obstructive Pulmonary Disease Pulmonary Arterial Hypertension Idiopathic Pulmonary Fibrosis Chronic Obstructive Pulmonary Disease Exacerbation Hereditary Hemorrhagic Telangiectasia 


  1. (2010a) Global tuberculosis control: key findings from the December 2009 WHO report. Wkly Epidemiol Rec 85:69–80Google Scholar
  2. 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA (2010b) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073PubMedGoogle Scholar
  3. Aldred MA, Machado RD, James V, Morrell NW, Trembath RC (2007) Characterization of the BMPR2 5′-untranslated region and a novel mutation in pulmonary hypertension. Am J Respir Crit Care Med 176:819–824PubMedGoogle Scholar
  4. Armstrong M, Fairbrother K, Idle JR, Daly AK (1994) The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics 4:73–81PubMedGoogle Scholar
  5. Ates O, Dalyan L, Musellim B, Hatemi G, Turker H, Ongen G, Hamuryudan V, Topal-Sarikaya A (2009) NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis. Int J Immunogenet 36:15–19PubMedGoogle Scholar
  6. Bachmann R, Laurell CB (1963) Electrophoretic and immunologic classification of M-components in serum. Scand J Clin Lab Invest 15(Suppl 69):11–24PubMedGoogle Scholar
  7. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M et al (2010) Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 137:376–387PubMedGoogle Scholar
  8. Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356:2751–2752PubMedGoogle Scholar
  9. Bakker JA, Bierau J, Drent M (2007) Therapeutic regimens in interstitial lung disease guided by genetic screening: fact or fiction? Eur Respir J 30:821–822PubMedGoogle Scholar
  10. Balmes JR, Earnest G, Katz PP, Yelin EH, Eisner MD, Chen H, Trupin L, Lurmann F, Blanc PD (2009) Exposure to traffic: lung function and health status in adults with asthma. J Allergy Clin Immunol 123:626–631PubMedCentralPubMedGoogle Scholar
  11. Barlo NP, van Moorsel CH, Korthagen NM, Heron M, Rijkers GT, Ruven HJ, van den Bosch JM, Grutters JC (2011) Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1beta in idiopathic pulmonary fibrosis. Clin Exp Immunol 166:346–351PubMedCentralPubMedGoogle Scholar
  12. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D (2011) Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 343:d4588PubMedCentralPubMedGoogle Scholar
  13. Bellamy R, Beyers N, McAdam KP, Ruwende C, Gie R, Samaai P, Bester D, Meyer M, Corrah T, Collin M et al (2000) Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. Proc Natl Acad Sci U S A 97:8005–8009PubMedCentralPubMedGoogle Scholar
  14. Benza RL, Gomberg-Maitland M, Miller DP, Frost A, Frantz RP, Foreman AJ, Badesch DB, McGoon MD (2012) The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 141:354–362PubMedGoogle Scholar
  15. Booth RA, Ansari MT, Tricco AC, Loit E, Weeks L, Doucette S, Skidmore B, Hoch JS, Tsouros S, Sears M et al (2010) Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs. Evid Rep Technol Assess (Full Rep) 196:1–282Google Scholar
  16. Burmester JK, Sedova M, Shapero MH, Mansfield E (2010) DMET microarray technology for pharmacogenomics- based personalized medicine. Methods Mol Biol 632:99–124PubMedGoogle Scholar
  17. Cai L, Deng SL, Liang L, Pan H, Zhou J, Wang MY, Yue J, Wan CL, He G, He L (2013) Identification of genetic associations of SP110/MYBBP1A/RELA with pulmonary tuberculosis in the Chinese Han population. Hum Genet 132(3):265–273PubMedGoogle Scholar
  18. Celedon JC, Lange C, Raby BA, Litonjua AA, Palmer LJ, DeMeo DL, Reilly JJ, Kwiatkowski DJ, Chapman HA, Laird N et al (2004) The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet 13:1649–1656PubMedGoogle Scholar
  19. Chappell S, Daly L, Morgan K, Baranes TG, Roca J, Rabinovich R, Millar A, Donnelly SC, Keatings V, MacNee W et al (2006) The SERPINE2 gene and chronic obstructive pulmonary disease. Am J Hum Genet 79:184–186, author reply 186–187PubMedCentralPubMedGoogle Scholar
  20. Chaumais MC, Garnier A, Chalard F, Peuchmaur M, Dauger S, Jacqz-Agrain E, Deschenes G (2009) Fatal pulmonary fibrosis after rituximab administration. Pediatr Nephrol 24:1753–1755PubMedGoogle Scholar
  21. Chaussabel D, Semnani RT, McDowell MA, Sacks D, Sher A, Nutman TB (2003) Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 102:672–681PubMedGoogle Scholar
  22. Chen L, Qin S, Xie J, Tang J, Yang L, Shen W, Zhao X, Du J, He G, Feng G et al (2008) Genetic polymorphism analysis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China. Pharmacogenomics 9:691–702PubMedGoogle Scholar
  23. Chen M, Liu XJ, Yan SD, Peng Y, Chai H, Li Q, Wei JF, Xu YN, Huang DJ (2012) Association between cytochrome P450 2C19 polymorphism and clinical outcomes in Chinese patients with coronary artery disease. Atherosclerosis 220:168–171PubMedGoogle Scholar
  24. Chensue SW, Lukacs NW, Yang TY, Shang X, Frait KA, Kunkel SL, Kung T, Wiekowski MT, Hedrick JA, Cook DN et al (2001) Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J Exp Med 193:573–584PubMedCentralPubMedGoogle Scholar
  25. Cho MH, Washko GR, Hoffmann TJ, Criner GJ, Hoffman EA, Martinez FJ, Laird N, Reilly JJ, Silverman EK (2010) Cluster analysis in severe emphysema subjects using phenotype and genotype data: an exploratory investigation. Respir Res 11:30PubMedCentralPubMedGoogle Scholar
  26. Cogan JD, Vnencak-Jones CL, Phillips JA 3rd, Lane KB, Wheeler LA, Robbins IM, Garrison G, Hedges LK, Loyd JE (2005) Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 7:169–174PubMedGoogle Scholar
  27. Collard HR, Loyd JE, King TE Jr, Lancaster LH (2007) Current diagnosis and management of idiopathic pulmonary fibrosis: a survey of academic physicians. Respir Med 101:2011–2016PubMedCentralPubMedGoogle Scholar
  28. Crystal RG, Gadek JE, Ferrans VJ, Fulmer JD, Line BR, Hunninghake GW (1981) Interstitial lung disease: current concepts of pathogenesis, staging and therapy. Am J Med 70:542–568PubMedGoogle Scholar
  29. Dahl M, Bowler RP, Juul K, Crapo JD, Levy S, Nordestgaard BG (2008) Superoxide dismutase 3 polymorphism associated with reduced lung function in two large populations. Am J Respir Crit Care Med 178:906–912PubMedCentralPubMedGoogle Scholar
  30. Dandara C, Lombard Z, Du Plooy I, McLellan T, Norris SA, Ramsay M (2011) Genetic variants in CYP (-1A2, -2C9, -2C19, -3A4 and -3A5), VKORC1 and ABCB1 genes in a black South African population: a window into diversity. Pharmacogenomics 12:1663–1670PubMedGoogle Scholar
  31. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, Ke X, Monsuur AJ, Whittaker P, Delgado M et al (2006) A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38:1166–1172PubMedCentralPubMedGoogle Scholar
  32. DeMeo DL, Mariani TJ, Lange C, Srisuma S, Litonjua AA, Celedon JC, Lake SL, Reilly JJ, Chapman HA, Mecham BH et al (2006) The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am J Hum Genet 78:253–264PubMedCentralPubMedGoogle Scholar
  33. DeMeo DL, Hersh CP, Hoffman EA, Litonjua AA, Lazarus R, Sparrow D, Benditt JO, Criner G, Make B, Martinez FJ et al (2007) Genetic determinants of emphysema distribution in the national emphysema treatment trial. Am J Respir Crit Care Med 176:42–48PubMedCentralPubMedGoogle Scholar
  34. Drazen JM, Silverman EK, Lee TH (2000) Heterogeneity of therapeutic responses in asthma. Br Med Bull 56:1054–1070PubMedGoogle Scholar
  35. Drent M, Wijnen P, Bast A (2012) Interstitial lung damage due to cocaine abuse: pathogenesis, pharmacogenomics and therapy. Curr Med Chem 19:5607–5611PubMedGoogle Scholar
  36. Feng Y, Shen J, Streaker ED, Lockwood M, Zhu Z, Low PS, Dimitrov DS (2011) A folate receptor beta-specific human monoclonal antibody recognizes activated macrophage of rheumatoid patients and mediates antibody-dependent cell-mediated cytotoxicity. Arthritis Res Ther 13:R59PubMedCentralPubMedGoogle Scholar
  37. Flockhart DA (2007) Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine,
  38. Folz RJ, Guan J, Seldin MF, Oury TD, Enghild JJ, Crapo JD (1997) Mouse extracellular superoxide dismutase: primary structure, tissue-specific gene expression, chromosomal localization, and lung in situ hybridization. Am J Respir Cell Mol Biol 17:393–403PubMedGoogle Scholar
  39. Fuselli S, Gilman RH, Chanock SJ, Bonatto SL, De Stefano G, Evans CA, Labuda D, Luiselli D, Salzano FM, Soto G et al (2007) Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity. Pharmacogenomics J 7:144–152PubMedCentralPubMedGoogle Scholar
  40. Gisbert JP, Gomollon F, Cara C, Luna M, Gonzalez-Lama Y, Pajares JM, Mate J, Guijarro LG (2007) Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Dig Dis Sci 52:1262–1269PubMedGoogle Scholar
  41. Hagaman JT, Kinder BW, Eckman MH (2010) Thiopurine S- methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis. Lung 188:125–132PubMedGoogle Scholar
  42. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V et al (2003) Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 40:865–871PubMedCentralPubMedGoogle Scholar
  43. He JQ, Ruan J, Connett JE, Anthonisen NR, Pare PD, Sandford AJ (2002) Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers. Am J Respir Crit Care Med 166:323–328PubMedGoogle Scholar
  44. He Y, Hoskins JM, McLeod HL (2011) Copy number variants in pharmacogenetic genes. Trends Mol Med 17:244–251PubMedCentralPubMedGoogle Scholar
  45. Hersh CP (2010) Pharmacogenetics of chronic obstructive pulmonary disease: challenges and opportunities. Pharmacogenomics 11:237–247PubMedCentralPubMedGoogle Scholar
  46. Hersh CP, Demeo DL, Lange C, Litonjua AA, Reilly JJ, Kwiatkowski D, Laird N, Sylvia JS, Sparrow D, Speizer FE et al (2005) Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am J Respir Cell Mol Biol 33:71–78PubMedCentralPubMedGoogle Scholar
  47. Hersh CP, Demeo DL, Lazarus R, Celedon JC, Raby BA, Benditt JO, Criner G, Make B, Martinez FJ, Scanlon PD et al (2006) Genetic association analysis of functional impairment in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173:977–984PubMedCentralPubMedGoogle Scholar
  48. Hogg JC (2004) Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364:709–721PubMedGoogle Scholar
  49. Hogg JC, Timens W (2009) The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 4:435–459PubMedGoogle Scholar
  50. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO et al (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350:2645–2653PubMedGoogle Scholar
  51. Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, Cuervo N, Moore KJ, Hodge SE, Knowles JA et al (2002) BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 20:518–523PubMedGoogle Scholar
  52. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F et al (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173:1023–1030PubMedGoogle Scholar
  53. Hutyrova B, Pantelidis P, Drabek J, Zurkova M, Kolek V, Lenhart K, Welsh KI, Du Bois RM, Petrek M (2002) Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 165:148–151PubMedGoogle Scholar
  54. Ishii T, Matsuse T, Teramoto S, Matsui H, Miyao M, Hosoi T, Takahashi H, Fukuchi Y, Ouchi Y (1999) Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease. Thorax 54:693–696PubMedCentralPubMedGoogle Scholar
  55. Ito M, Hanaoka M, Droma Y, Hatayama O, Sato E, Katsuyama Y, Fujimoto K, Ota M (2008) The association of transforming growth factor beta 1 gene polymorphisms with the emphysema phenotype of COPD in Japanese. Intern Med 47:1387–1394PubMedGoogle Scholar
  56. Jacquemin B, Kauffmann F, Pin I, Le Moual N, Bousquet J, Gormand F, Just J, Nadif R, Pison C, Vervloet D et al (2012) Air pollution and asthma control in the Epidemiological study on the Genetics and Environment of Asthma. J Epidemiol Community Health 66:796–802PubMedGoogle Scholar
  57. Jang IJ, Shin SG, Lee KH, Yim DS, Lee MS, Koo HH, Kim HK, Sohn DR (1996) Erythrocyte thiopurine methyltransferase activity in a Korean population. Br J Clin Pharmacol 42:638–641PubMedGoogle Scholar
  58. Jin J, Sun L, Jiao W, Zhao S, Li H, Guan X, Jiao A, Jiang Z, Shen A (2009) SLC11A1 (Formerly NRAMP1) gene polymorphisms associated with pediatric tuberculosis in China. Clin Infect Dis 48:733–738PubMedGoogle Scholar
  59. Juul K, Tybjaerg-Hansen A, Marklund S, Lange P, Nordestgaard BG (2006) Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173:858–864PubMedGoogle Scholar
  60. Kennedy JL, Heymann PW, Platts-Mills TA (2012) The role of allergy in severe asthma. Clin Exp Allergy 42:659–669PubMedCentralPubMedGoogle Scholar
  61. Kim WJ, Hersh CP, DeMeo DL, Reilly JJ, Silverman EK (2009a) Genetic association analysis of COPD candidate genes with bronchodilator responsiveness. Respir Med 103:552–557PubMedCentralPubMedGoogle Scholar
  62. Kim WJ, Sheen SS, Kim TH, Huh JW, Lee JH, Kim EK, Lee SM, Lee S, Lim SY, Shin TR et al (2009b) Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD. Respirology 14:260–263PubMedGoogle Scholar
  63. Kirchheiner J, Fuhr U, Brockmoller J (2005) Pharmacogenetics-based therapeutic recommendations–ready for clinical practice? Nat Rev Drug Discov 4:639–647PubMedGoogle Scholar
  64. Kokkotou E, Torres D, Moss AC, O’Brien M, Grigoriadis DE, Karalis K, Pothoulakis C (2006) Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses. J Immunol 177:3355–3361PubMedGoogle Scholar
  65. Korthagen NM, van Moorsel CH, Kazemier KM, Ruven HJ, Grutters JC (2012) IL1RN genetic variations and risk of IPF: a meta-analysis and mRNA expression study. Immunogenetics 64:371–377PubMedCentralPubMedGoogle Scholar
  66. Krynetski EY, Schuetz JD, Galpin AJ, Pui CH, Relling MV, Evans WE (1995) A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci U S A 92:949–953PubMedCentralPubMedGoogle Scholar
  67. Kuznetsov IB, McDuffie M, Moslehi R (2009) A web server for inferring the human N-acetyltransferase-2 (NAT2) enzymatic phenotype from NAT2 genotype. Bioinformatics 25:1185–1186PubMedCentralPubMedGoogle Scholar
  68. Lam MP, Cheung BM (2012) The pharmacogenetics of the response to warfarin in Chinese. Br J Clin Pharmacol 73:340–347PubMedCentralPubMedGoogle Scholar
  69. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84PubMedGoogle Scholar
  70. Larsson C, Eriksson S (1977) Liver function in asymptomatic adult individuals with severe alpha1-antitrypsin deficiency (Pi Z). Scand J Gastroenterol 12:543–546PubMedGoogle Scholar
  71. Launay D, Remy-Jardin M, Michon-Pasturel U, Mastora I, Hachulla E, Lambert M, Delannoy V, Queyrel V, Duhamel A, Matran R et al (2006) High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 33:1789–1801PubMedGoogle Scholar
  72. Lee SW, Chung LS, Huang HH, Chuang TY, Liou YH, Wu LS (2010) NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis 14:622–626PubMedGoogle Scholar
  73. Lei X, Zhu H, Zha L, Wang Y (2012) SP110 gene polymorphisms and tuberculosis susceptibility: a systematic review and meta-analysis based on 10 624 subjects. Infect Genet Evol 12:1473–1480PubMedGoogle Scholar
  74. Libby DM, Gibofsky A, Fotino M, Waters SJ, Smith JP (1983) Immunogenetic and clinical findings in idiopathic pulmonary fibrosis. Association with the B-cell alloantigen HLA-DR2. Am Rev Respir Dis 127:618–622PubMedGoogle Scholar
  75. Loenders B, Van Mechelen E, Nicolai S, Buyssens N, Van Osselaer N, Jorens PG, Willems J, Herman AG, Slegers H (1998) Localization of extracellular superoxide dismutase in rat lung: neutrophils and macrophages as carriers of the enzyme. Free Radic Biol Med 24:1097–1106PubMedGoogle Scholar
  76. Loyd JE, Primm RK, Newman JH (1984) Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis 129:194–197PubMedGoogle Scholar
  77. Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips JA 3rd, Newman JH (1995) Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 152:93–97PubMedGoogle Scholar
  78. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA 3rd, Newman J, Williams D, Galie N et al (2001) BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68:92–102PubMedCentralPubMedGoogle Scholar
  79. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W et al (2006) Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121–132PubMedGoogle Scholar
  80. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA 3rd, Soubrier F, Trembath RC et al (2009) Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54:S32–S42PubMedCentralPubMedGoogle Scholar
  81. Mak JC, Chan-Yeung MM, Ho SP, Chan KS, Choo K, Yee KS, Chau CH, Cheung AH, Ip MS (2009) Elevated plasma TGF-beta1 levels in patients with chronic obstructive pulmonary disease. Respir Med 103:1083–1089PubMedGoogle Scholar
  82. Manolio TA, Green ED (2011) Genomics reaches the clinic: from basic discoveries to clinical impact. Cell 147:14–16PubMedGoogle Scholar
  83. Martinelli M, Scapoli L, Carbonara P, Valentini I, Girardi A, Farinella F, Mattei G, Pacilli AM, Fasano L, Nava S et al (2013) Idiopathic pulmonary fibrosis and polymorphisms of the folate pathway genes. Clin Biochem 46(1–2):85–88PubMedGoogle Scholar
  84. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS et al (2009) ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 119:2250–2294PubMedGoogle Scholar
  85. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P et al (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304:1821–1830PubMedCentralPubMedGoogle Scholar
  86. Meilang Q, Zhang Y, Zhang J, Zhao Y, Tian C, Huang J, Fan H (2012) Polymorphisms in the SLC11A1 gene and tuberculosis risk: a meta-analysis update. Int J Tuberc Lung Dis 16:437–446PubMedGoogle Scholar
  87. Meng YY, Wilhelm M, Rull RP, English P, Ritz B (2007) Traffic and outdoor air pollution levels near residences and poorly controlled asthma in adults. Ann Allergy Asthma Immunol 98:455–463PubMedGoogle Scholar
  88. Metz G, Kraft M (2010) Effects of atypical infections with Mycoplasma and Chlamydia on asthma. Immunol Allergy Clin North Am 30:575–585, vii–viiiPubMedGoogle Scholar
  89. Mijatovic V, Iacobucci I, Sazzini M, Xumerle L, Mori A, Pignatti PF, Martinelli G, Malerba G (2012) Imputation reliability on DNA biallelic markers for drug metabolism studies. BMC Bioinformatics 13(Suppl 14):S7PubMedCentralPubMedGoogle Scholar
  90. Minematsu N, Nakamura H, Iwata M, Tateno H, Nakajima T, Takahashi S, Fujishima S, Yamaguchi K (2003) Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema. Thorax 58:623–628PubMedCentralPubMedGoogle Scholar
  91. Mishra G, Poojary SS, Raj P, Tiwari PK (2012) Genetic polymorphisms of CCL2, CCL5, CCR2 and CCR5 genes in Sahariya tribe of North Central India: an association study with pulmonary tuberculosis. Infect Genet Evol 12:1120–1127PubMedGoogle Scholar
  92. Mistry R, Cliff JM, Clayton CL, Beyers N, Mohamed YS, Wilson PA, Dockrell HM, Wallace DM, van Helden PD, Duncan K et al (2007) Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. J Infect Dis 195:357–365PubMedGoogle Scholar
  93. Mwenifumbo JC, Sellers EM, Tyndale RF (2007) Nicotine metabolism and CYP2A6 activity in a population of black African descent: impact of gender and light smoking. Drug Alcohol Depend 89:24–33PubMedGoogle Scholar
  94. Nasim MT, Ghouri A, Patel B, James V, Rudarakanchana N, Morrell NW, Trembath RC (2008) Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet 17:1683–1694PubMedGoogle Scholar
  95. Oh KT, Anis AH, Bae SC (2004) Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology (Oxford) 43:156–163Google Scholar
  96. Owen HR, Elser M, Cheung E, Gersbach M, Kraus WL, Hottiger MO (2007) MYBBP1a is a novel repressor of NF-kappaB. J Mol Biol 366:725–736PubMedGoogle Scholar
  97. Pan H, Yan BS, Rojas M, Shebzukhov YV, Zhou H, Kobzik L, Higgins DE, Daly MJ, Bloom BR, Kramnik I (2005) Ipr1 gene mediates innate immunity to tuberculosis. Nature 434:767–772PubMedCentralPubMedGoogle Scholar
  98. Perri D, Cole DE, Friedman O, Piliotis E, Mintz S, Adhikari NK (2007) Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase. Eur Respir J 30:1014–1017PubMedGoogle Scholar
  99. Philips JA, Ernst JD (2012) Tuberculosis pathogenesis and immunity. Annu Rev Pathol 7:353–384PubMedGoogle Scholar
  100. Pianezza ML, Sellers EM, Tyndale RF (1998) Nicotine metabolism defect reduces smoking. Nature 393:750PubMedGoogle Scholar
  101. Png E, Alisjahbana B, Sahiratmadja E, Marzuki S, Nelwan R, Adnan I, van de Vosse E, Hibberd M, van Crevel R, Ottenhoff TH et al (2012) Polymorphisms in SP110 are not associated with pulmonary tuberculosis in Indonesians. Infect Genet Evol 12:1319–1323PubMedGoogle Scholar
  102. Polosa R, Thomson NC (2013) Smoking and asthma: dangerous liaisons. Eur Respir J 41(3):716–728PubMedGoogle Scholar
  103. Qu C, Edwards EW, Tacke F, Angeli V, Llodra J, Sanchez-Schmitz G, Garin A, Haque NS, Peters W, van Rooijen N et al (2004) Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J Exp Med 200:1231–1241PubMedCentralPubMedGoogle Scholar
  104. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W et al (2006) Global variation in copy number in the human genome. Nature 444:444–454PubMedCentralPubMedGoogle Scholar
  105. Riha RL, Yang IA, Rabnott GC, Tunnicliffe AM, Fong KM, Zimmerman PV (2004) Cytokine gene polymorphisms in idiopathic pulmonary fibrosis. Intern Med J 34:126–129PubMedGoogle Scholar
  106. Sadof M, Kaslovsky R (2011) Adolescent asthma: a developmental approach. Curr Opin Pediatr 23:373–378PubMedGoogle Scholar
  107. Said SI, Hamidi SA (2011) Pharmacogenomics in pulmonary arterial hypertension: toward a mechanistic, target-based approach to therapy. Pulm Circ 1:383–388PubMedCentralPubMedGoogle Scholar
  108. Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF (2004) Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 14:615–626PubMedGoogle Scholar
  109. Shen CM, Zhu BF, Deng YJ, Ye SH, Yan JW, Yang G, Wang HD, Qin HX, Huang QZ, Zhang JJ (2010) Allele polymorphism and haplotype diversity of HLA-A, -B and -DRB1 loci in sequence-based typing for Chinese Uyghur ethnic group. PLoS One 5:e13458PubMedCentralPubMedGoogle Scholar
  110. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700PubMedGoogle Scholar
  111. Siedlinski M, van Diemen CC, Postma DS, Vonk JM, Boezen HM (2009) Superoxide dismutases, lung function and bronchial responsiveness in a general population. Eur Respir J 33:986–992PubMedGoogle Scholar
  112. Smith BP, Best DH, Elliott CG (2012) Genetics and pharmacogenomics in pulmonary arterial hypertension. Heart Fail Clin 8:319–330PubMedGoogle Scholar
  113. Snider GL (1985a) Distinguishing among asthma, chronic bronchitis, and emphysema. Chest 87:35S–39SPubMedGoogle Scholar
  114. Snider GL (1985b) Interstitial pulmonary fibrosis environmental or idiopathic? Hosp Pract (Off Ed) 20:94C-94H, 94M-94P, 94T-94U passimGoogle Scholar
  115. Sorheim IC, DeMeo DL, Washko G, Litonjua A, Sparrow D, Bowler R, Bakke P, Pillai SG, Coxson HO, Lomas DA et al (2010) Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD. COPD 7:262–268PubMedCentralPubMedGoogle Scholar
  116. Souza R, Humbert M, Sztrymf B, Jais X, Yaici A, Le Pavec J, Parent F, Herve P, Soubrier F, Sitbon O et al (2008) Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J 31:343–348PubMedGoogle Scholar
  117. Spire-Vayron de la Moureyre C, Debuysere H, Mastain B, Vinner E, Marez D, Lo Guidice JM, Chevalier D, Brique S, Motte K, Colombel JF et al (1998) Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol 125:879–887PubMedCentralPubMedGoogle Scholar
  118. Spire-Vayron de la Moureyre C, Debuysere H, Fazio F, Sergent E, Bernard C, Sabbagh N, Marez D, Lo Guidice JM, D’Halluin JC, Broly F (1999) Characterization of a variable number tandem repeat region in the thiopurine S-methyltransferase gene promoter. Pharmacogenetics 9:189–198PubMedGoogle Scholar
  119. Stingl JC, Parmar S, Huber-Wechselberger A, Kainz A, Renner W, Seeringer A, Brockmoller J, Langsenlehner U, Krippl P, Haschke-Becher E (2010) Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin 26:2535–2542PubMedGoogle Scholar
  120. Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P (2000) Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A 97:3479–3484PubMedCentralPubMedGoogle Scholar
  121. Taype CA, Castro JC, Accinelli RA, Herrera-Velit P, Shaw MA, Espinoza JR (2006) Association between SLC11A1 polymorphisms and susceptibility to different clinical forms of tuberculosis in the Peruvian population. Infect Genet Evol 6:361–367PubMedGoogle Scholar
  122. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 37:741–745PubMedCentralPubMedGoogle Scholar
  123. Thuong NT, Dunstan SJ, Chau TT, Thorsson V, Simmons CP, Quyen NT, Thwaites GE, Thi Ngoc Lan N, Hibberd M, Teo YY et al (2008) Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. PLoS Pathog 4:e1000229PubMedCentralPubMedGoogle Scholar
  124. Travis WD, Hunninghake G, King TE Jr, Lynch DA, Colby TV, Galvin JR, Brown KK, Chung MP, Cordier JF, du Bois RM et al (2008) Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med 177:1338–1347PubMedGoogle Scholar
  125. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Nolte IM, Boezen HM (2006) Decorin and TGF-beta1 polymorphisms and development of COPD in a general population. Respir Res 7:89PubMedCentralPubMedGoogle Scholar
  126. Varpela E, Tiilikainen A, Varpela M, Tukiainen P (1979) High prevalences of HLA-B15 and HLA-Dw6 in patients with cryptogenic fibrosing alveolitis. Tissue Antigens 14:68–71PubMedGoogle Scholar
  127. Volz A, Boyle JM, Cann HM, Cottingham RW, Orr HT, Ziegler A (1994) Report of the second international workshop on human chromosome 6. Genomics 21:464–472PubMedGoogle Scholar
  128. Voorter CE, Drent M, van den Berg-Loonen EM (2005) Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150101. Hum Immunol 66:826–835PubMedGoogle Scholar
  129. Wallin R, Wajih N, Hutson SM (2008) VKORC1: a warfarin-sensitive enzyme in vitamin K metabolism and biosynthesis of vitamin K-dependent blood coagulation factors. Vitam Horm 78:227–246PubMedGoogle Scholar
  130. Weinshilboum R (2003) Inheritance and drug response. N Engl J Med 348:529–537PubMedGoogle Scholar
  131. Whyte M, Hubbard R, Meliconi R, Whidborne M, Eaton V, Bingle C, Timms J, Duff G, Facchini A, Pacilli A et al (2000) Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms. Am J Respir Crit Care Med 162:755–758PubMedGoogle Scholar
  132. Wijnen PA, Drent M, Nelemans PJ, Kuijpers PM, Koek GH, Neef C, Haenen GR, Bekers O (2008) Role of cytochrome P450 polymorphisms in the development of pulmonary drug toxicity: a case–control study in the Netherlands. Drug Saf 31:1125–1134PubMedGoogle Scholar
  133. Wijnen PA, Bekers O, Drent M (2010) Relationship between drug-induced interstitial lung diseases and cytochrome P450 polymorphisms. Curr Opin Pulm Med 16:496–502PubMedGoogle Scholar
  134. Wijnen PA, Bekers O, Drent M (2011) Development of cocaine-induced interstitial lung damage in two CYP2C and VKORC1 variant allele carriers. Mol Diagn Ther 15:177–180PubMedGoogle Scholar
  135. Wilkinson GR (2005) Drug metabolism and variability among patients in drug response. N Engl J Med 352:2211–2221PubMedGoogle Scholar
  136. Xue J, Gochuico BR, Alawad AS, Feghali-Bostwick CA, Noth I, Nathan SD, Rosen GD, Rosas IO, Dacic S, Ocak I et al (2011) The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One 6:e14715PubMedCentralPubMedGoogle Scholar
  137. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV, Evans WE (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608–614PubMedGoogle Scholar
  138. Yoon HI, Silverman EK, Lee HW, Yoo CG, Lee CT, Chung HS, Kim YW, Han SK, Shim YS, Yim JJ (2006) Lack of association between COPD and transforming growth factor-beta1 (TGFB1) genetic polymorphisms in Koreans. Int J Tuberc Lung Dis 10:504–509PubMedGoogle Scholar
  139. Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills GD, Garrett JE, Eaton TE, Rees MI (2006) Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function. Thorax 61:394–399PubMedCentralPubMedGoogle Scholar
  140. Zhang J, Xu DJ, Xu KF, Wu B, Zheng MF, Chen JY, Huang JA (2012) HLA-A and HLA-B gene polymorphism and idiopathic pulmonary fibrosis in a Han Chinese population. Respir Med 106:1456–1462PubMedGoogle Scholar
  141. Zhou SF, Liu JP, Chowbay B (2009) Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 41:89–295PubMedGoogle Scholar

Copyright information

© Springer India 2013

Authors and Affiliations

  • Luciana B. Crotti
    • 1
  • Fernanda Kehdy
    • 2
  • Eduardo Tarazona-Santos
    • 2
  • Luis A. Espinoza
    • 3
  1. 1.Department of BiochemistryUniformed Services University of the Health SciencesBethesdaUSA
  2. 2.Departamento de Biologia GeralUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  3. 3.Department of Biochemistry and Molecular Biology & Cell BiologyGeorgetown UniversityWashingtonUSA

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