1932

Abstract

Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with COPD-related phenotypes, such as quantitative emphysema measures, have been found. Identifying the functional variants and key genes within these association regions remains a major challenge. However, newly identified COPD susceptibility genes are already providing novel insights into COPD pathogenesis. Network-based approaches that leverage these genetic discoveries have the potential to assist in decoding the complex genetic architecture of COPD.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-021317-121224
2020-02-10
2024-12-02
Loading full text...

Full text loading...

/deliver/fulltext/physiol/82/1/annurev-physiol-021317-121224.html?itemId=/content/journals/10.1146/annurev-physiol-021317-121224&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Nelson MR, Tipney H, Painter JL, Shen J, Nicoletti P et al. 2015. The support of human genetic evidence for approved drug indications. Nat. Genet. 47:856–60
    [Google Scholar]
  2. 2. 
    Silverman EK, Mosley JD, Palmer LJ, Barth M, Senter JM et al. 2002. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum. Mol. Genet. 11:623–32
    [Google Scholar]
  3. 3. 
    Hersh CP, Demeo DL, Lange C, Litonjua AA, Reilly JJ et al. 2005. Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am. J. Respir. Cell Mol. Biol. 33:71–78
    [Google Scholar]
  4. 4. 
    Hersh CP, DeMeo D, Silverman EK 2005. COPD. Respiratory Genetics EK Silverman, SD Shapiro, DA Lomas, ST Weiss 253–96 London: Hodder Arnold
    [Google Scholar]
  5. 5. 
    Silverman EK, Chapman HA, Drazen JM, Weiss ST, Rosner B et al. 1998. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease: risk to relatives for airflow obstruction and chronic bronchitis. Am. J. Respir. Crit. Care Med. 157:1770–78
    [Google Scholar]
  6. 6. 
    McCloskey SC, Patel BD, Hinchliffe SJ, Reid ED, Wareham NJ, Lomas DA 2001. Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction. Am. J. Respir. Crit. Care Med. 164:1419–24
    [Google Scholar]
  7. 7. 
    Ingebrigtsen T, Thomsen SF, Vestbo J, van der Sluis S, Kyvik KO et al. 2010. Genetic influences on chronic obstructive pulmonary disease—a twin study. Respir. Med. 104:1890–95
    [Google Scholar]
  8. 8. 
    Zhou JJ, Cho MH, Castaldi PJ, Hersh CP, Silverman EK, Laird NM 2013. Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers. Am. J. Respir. Crit. Care Med. 188:941–47
    [Google Scholar]
  9. 9. 
    Silverman EK, Sandhaus RA. 2009. Alpha1-antitrypsin deficiency. N. Engl. J. Med. 360:2749–57
    [Google Scholar]
  10. 10. 
    DeMeo DL, Sandhaus RA, Barker AF, Brantly ML, Eden E et al. 2007. Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency. Thorax 62:806–13
    [Google Scholar]
  11. 11. 
    Mostafavi B, Diaz S, Piitulainen E, Stoel BC, Wollmer P, Tanash HA 2018. Lung function and CT lung densitometry in 37- to 39-year-old individuals with alpha-1-antitrypsin deficiency. Int. J. Chron. Obstruct. Pulmon. Dis. 13:3689–98
    [Google Scholar]
  12. 12. 
    Chapman KR, Burdon JG, Piitulainen E, Sandhaus RA, Seersholm N et al. 2015. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 386:360–68
    [Google Scholar]
  13. 13. 
    Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK 2004. Chronic obstructive pulmonary disease in α1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 59:843–49
    [Google Scholar]
  14. 14. 
    Silverman EK. 2016. Risk of lung disease in PI MZ heterozygotes. Current status and future research directions. Ann. Am. Thorac. Soc. 13:Suppl. 4S341–45
    [Google Scholar]
  15. 15. 
    Sorheim IC, Bakke P, Gulsvik A, Pillai SG, Johannessen A et al. 2010. α;1-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts. Chest 138:1125–32
    [Google Scholar]
  16. 16. 
    Molloy K, Hersh CP, Morris VB, Carroll TP, O'Connor CA et al. 2014. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am. J. Respir. Crit. Care Med. 189:419–27
    [Google Scholar]
  17. 17. 
    Foreman MG, Wilson C, DeMeo DL, Hersh CP, Beaty TH et al. 2017. Alpha-1 antitrypsin PiMZ genotype is associated with chronic obstructive pulmonary disease in two racial groups. Ann. Am. Thorac. Soc. 14:1280–87
    [Google Scholar]
  18. 18. 
    Li X, Ortega VE, Ampleford EJ, Graham Barr R, Christenson SA et al. 2018. Genome-wide association study of lung function and clinical implication in heavy smokers. BMC Med. Genet. 19:134
    [Google Scholar]
  19. 19. 
    Pillai SG, Ge D, Zhu G, Kong X, Shianna KV et al. 2009. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLOS Genet 5:e1000421
    [Google Scholar]
  20. 20. 
    Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW et al. 2009. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLOS Genet 5:e1000429
    [Google Scholar]
  21. 21. 
    Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR et al. 2010. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42:45–52
    [Google Scholar]
  22. 22. 
    Repapi E, Sayers I, Wain LV, Burton PR, Johnson T et al. 2010. Genome-wide association study identifies five loci associated with lung function. Nat. Genet. 42:36–44
    [Google Scholar]
  23. 23. 
    Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP et al. 2010. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat. Genet. 42:200–2
    [Google Scholar]
  24. 24. 
    Cho MH, McDonald ML, Zhou X, Mattheisen M, Castaldi PJ et al. 2014. Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir. Med. 2:214–25
    [Google Scholar]
  25. 25. 
    Silverman EK, Vestbo J, Agusti A, Anderson W, Bakke PS et al. 2011. Opportunities and challenges in the genetics of COPD 2010: an International COPD Genetics Conference report. COPD 8:121–35
    [Google Scholar]
  26. 26. 
    Hobbs BD, de Jong K, Lamontagne M, Bosse Y, Shrine N et al. 2017. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat. Genet. 49:426–32
    [Google Scholar]
  27. 27. 
    Sakornsakolpat P, Prokopenko D, Lamontagne M, Reeve NF, Guyatt AL et al. 2019. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nat. Genet. 51:494–505
    [Google Scholar]
  28. 28. 
    Van Durme YM, Eijgelsheim M, Joos GF, Hofman A, Uitterlinden AG et al. 2010. Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study. Eur. Respir. J. 36:89–95
    [Google Scholar]
  29. 29. 
    Zhou X, Baron RM, Hardin M, Cho MH, Zielinski J et al. 2012. Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Hum. Mol. Genet. 21:1325–35
    [Google Scholar]
  30. 30. 
    Wain LV, Shrine N, Miller S, Jackson VE, Ntalla I et al. 2015. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir. Med. 3:769–81
    [Google Scholar]
  31. 31. 
    Young RP, Hopkins RJ, Hay BA, Whittington CF, Epton MJ, Gamble GD 2011. FAM13A locus in COPD is independently associated with lung cancer—evidence of a molecular genetic link between COPD and lung cancer. Appl. Clin. Genet. 4:1–10
    [Google Scholar]
  32. 32. 
    Xie J, Wu H, Xu Y, Wu X, Liu X et al. 2015. Gene susceptibility identification in a longitudinal study confirms new loci in the development of chronic obstructive pulmonary disease and influences lung function decline. Respir. Res. 16:49
    [Google Scholar]
  33. 33. 
    Ziółkowska-Suchanek I, Mosor M, Gabryel P, Grabicki M, Zurawek M et al. 2015. Susceptibility loci in lung cancer and COPD: association of IREB2 and FAM13A with pulmonary diseases. Sci. Rep. 5:13502
    [Google Scholar]
  34. 34. 
    Siedlinski M, Tingley D, Lipman PJ, Cho MH, Litonjua AA et al. 2013. Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility. Hum. Genet. 132:431–41
    [Google Scholar]
  35. 35. 
    Busch R, Hobbs BD, Zhou J, Castaldi PJ, McGeachie MJ et al. 2017. Genetic association and risk scores in a COPD meta-analysis of 16,707 subjects. Am. J. Respir. Cell Mol. Biol. 57:35–46
    [Google Scholar]
  36. 36. 
    Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B et al. 2017. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets. Nat. Genet. 49:416–25
    [Google Scholar]
  37. 37. 
    Burkart KM, Sofer T, London SJ, Manichaikul A, Hartwig FP et al. 2018. A genome-wide association study in Hispanics/Latinos identifies novel signals for lung function. The Hispanic Community Health Study/Study of Latinos. Am. J. Respir. Crit. Care Med. 198:208–19
    [Google Scholar]
  38. 38. 
    Wyss AB, Sofer T, Lee MK, Terzikhan N, Nguyen JN et al. 2018. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. Nat. Commun. 9:2976
    [Google Scholar]
  39. 39. 
    Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD et al. 2019. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nat. Genet. 51:481–93
    [Google Scholar]
  40. 40. 
    Lange P, Celli B, Agusti A, Jensen GB, Divo M et al. 2015. Lung-function trajectories leading to chronic obstructive pulmonary disease. N. Engl. J. Med. 373:111–22
    [Google Scholar]
  41. 41. 
    Tang W, Kowgier M, Loth DW, Artigas MS, Joubert BR et al. 2014. Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. PLOS ONE 9:e100776
    [Google Scholar]
  42. 42. 
    John C, Artigas MS, Hui J, Nielsen SF, Rafaels N et al. 2017. Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline. Thorax 72:400–8
    [Google Scholar]
  43. 43. 
    Ross JC, Castaldi PJ, Cho MH, Chen J, Chang Y et al. 2017. A Bayesian nonparametric model for disease subtyping: application to emphysema phenotypes. IEEE Trans. Med. Imaging 36:343–54
    [Google Scholar]
  44. 44. 
    Ragland MF, Benway CJ, Lutz SM, Bowler RP, Hecker J et al. 2019. Genetic advances in COPD: insights from COPDGene. Am. J. Respir. Crit. Care Med. 200:67790
    [Google Scholar]
  45. 45. 
    Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH et al. 2014. Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study. Am. J. Respir. Crit. Care Med. 189:408–18
    [Google Scholar]
  46. 46. 
    Yonchuk JG, Silverman EK, Bowler RP, Agusti A, Lomas DA et al. 2015. Circulating soluble receptor for advanced glycation end products (sRAGE) as a biomarker of emphysema and the RAGE axis in the lung. Am. J. Respir. Crit. Care Med. 192:785–92
    [Google Scholar]
  47. 47. 
    Cho MH, Castaldi PJ, Hersh CP, Hobbs BD, Barr RG et al. 2015. A genome-wide association study of emphysema and airway quantitative imaging phenotypes. Am. J. Respir. Crit. Care Med. 192:559–69
    [Google Scholar]
  48. 48. 
    Boueiz A, Lutz SM, Cho MH, Hersh CP, Bowler RP et al. 2017. Genome-wide association study of the genetic determinants of emphysema distribution. Am. J. Respir. Crit. Care Med. 195:757–71
    [Google Scholar]
  49. 49. 
    Castaldi PJ, San Jose Estepar R, Mendoza CS, Hersh CP, Laird N et al. 2013. Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers. Am. J. Respir. Crit. Care Med. 188:1083–90
    [Google Scholar]
  50. 50. 
    Castaldi PJ, Dy J, Ross J, Chang Y, Washko GR et al. 2014. Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax 69:415–22
    [Google Scholar]
  51. 51. 
    Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP et al. 2009. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. PNAS 106:9362–67
    [Google Scholar]
  52. 52. 
    Freedman ML, Monteiro AN, Gayther SA, Coetzee GA, Risch A et al. 2011. Principles for the post-GWAS functional characterization of cancer risk loci. Nat. Genet. 43:513–18
    [Google Scholar]
  53. 53. 
    Juran BD, Lazaridis KN. 2011. Genomics in the post-GWAS era. Semin. Liver Dis. 31:215–22
    [Google Scholar]
  54. 54. 
    Cooper GM, Shendure J. 2011. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Nat. Rev. Genet. 12:628–40
    [Google Scholar]
  55. 55. 
    Gibson G. 2011. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13:135–45
    [Google Scholar]
  56. 56. 
    Sanyal A, Lajoie BR, Jain G, Dekker J 2012. The long-range interaction landscape of gene promoters. Nature 489:109–13
    [Google Scholar]
  57. 57. 
    Pomerantz MM, Ahmadiyeh N, Jia L, Herman P, Verzi MP et al. 2009. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41:882–24
    [Google Scholar]
  58. 58. 
    Baxter JS, Leavy OC, Dryden NH, Maguire S, Johnson N et al. 2018. Capture Hi-C identifies putative target genes at 33 breast cancer risk loci. Nat. Commun. 9:1028
    [Google Scholar]
  59. 59. 
    Schaid DJ, Chen W, Larson NB 2018. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat. Rev. Genet. 19:491–504
    [Google Scholar]
  60. 60. 
    Melnikov A, Murugan A, Zhang X, Tesileanu T, Wang L et al. 2012. Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nat. Biotechnol. 30:271–77
    [Google Scholar]
  61. 61. 
    Melnikov A, Zhang X, Rogov P, Wang L, Mikkelsen TS 2014. Massively parallel reporter assays in cultured mammalian cells. J. Vis. Exp. 90:e51719
    [Google Scholar]
  62. 62. 
    Castaldi PJ, Guo F, Qiao D, Du F, Naing ZZC et al. 2019. Identification of functional variants in the FAM13A chronic obstructive pulmonary disease genome-wide association study locus by massively parallel reporter assays. Am. J. Respir. Crit. Care Med. 199:52–61
    [Google Scholar]
  63. 63. 
    Stanley SE, Chen JJ, Podlevsky JD, Alder JK, Hansel NN et al. 2015. Telomerase mutations in smokers with severe emphysema. J. Clin. Investig. 125:563–70
    [Google Scholar]
  64. 64. 
    Radder JE, Zhang Y, Gregory AD, Yu S, Kelly NJ et al. 2017. Extreme trait whole-genome sequencing identifies PTPRO as a novel candidate gene in emphysema with severe airflow obstruction. Am. J. Respir. Crit. Care Med. 196:159–71
    [Google Scholar]
  65. 65. 
    Qiao D, Lange C, Beaty TH, Crapo JD, Barnes KC et al. 2016. Exome sequencing analysis in severe, early-onset chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 193:1353–63
    [Google Scholar]
  66. 66. 
    Lao T, Glass K, Qiu W, Polverino F, Gupta K et al. 2015. Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring. Genome Med 7:12
    [Google Scholar]
  67. 67. 
    Jiang Z, Lao T, Qiu W, Polverino F, Gupta K et al. 2016. A chronic obstructive pulmonary disease susceptibility gene, FAM13A, regulates protein stability of β-catenin. Am. J. Respir. Crit. Care Med. 194:185–97
    [Google Scholar]
  68. 68. 
    Cloonan SM, Glass K, Laucho-Contreras M, Bhashyam AR, Cervo M et al. 2016. Mitochondrial iron as a therapeutic target for IRP2-regulated cigarette smoke-induced bronchitis and emphysema. Nat. Med. 22:163–74
    [Google Scholar]
  69. 69. 
    Sambamurthy N, Leme AS, Oury TD, Shapiro SD 2015. The receptor for advanced glycation end products (RAGE) contributes to the progression of emphysema in mice. PLOS ONE 10:e0118979
    [Google Scholar]
  70. 70. 
    D'Armiento J, Dalal SS, Okada Y, Berg RA, Chada K 1992. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 71:955–61
    [Google Scholar]
  71. 71. 
    Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD 1997. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277:2002–4
    [Google Scholar]
  72. 72. 
    Wert SE, Yoshida M, LeVine AM, Ikegami M, Jones T et al. 2000. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. PNAS 97:5972–77
    [Google Scholar]
  73. 73. 
    Lomas DA, Silverman EK, Edwards LD, Locantore NW, Miller BE et al. 2009. Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur. Resp. J. 34:95–102
    [Google Scholar]
  74. 74. 
    Boyle EA, Li YI, Pritchard JK 2017. An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–86
    [Google Scholar]
  75. 75. 
    Morrow J, Zhou X, Lao T, Jiang Z, Demeo DL et al. 2017. Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci. Rep. 7:44232
    [Google Scholar]
  76. 76. 
    Barabasi AL. 2007. Network medicine—from obesity to the “diseasome.”. N. Engl. J. Med. 357:404–7
    [Google Scholar]
  77. 77. 
    Barabasi AL, Gulbahce N, Loscalzo J 2011. Network medicine: a network-based approach to human disease. Nat. Rev. Genet. 12:56–68
    [Google Scholar]
  78. 78. 
    Loscalzo J, Barabasi AL, Silverman EK 2017. Network Medicine: Complex Systems in Human Disease and Therapeutics Cambridge, MA: Harvard Univ. Press
    [Google Scholar]
  79. 79. 
    Vidal M, Cusick ME, Barabasi AL 2011. Interactome networks and human disease. Cell 144:986–98
    [Google Scholar]
  80. 80. 
    Jia P, Zheng S, Long J, Zheng W, Zhao Z 2011. dmGWAS: dense module searching for genome-wide association studies in protein-protein interaction networks. Bioinformatics 27:95–102
    [Google Scholar]
  81. 81. 
    McDonald ML, Mattheisen M, Cho M, Liu Y-Y, Harshfield B et al. 2014. Beyond GWAS in COPD: probing the landscape between gene-set associations, genome-wide associations and protein-protein interaction networks. Hum. Heredity 78:131–39
    [Google Scholar]
  82. 82. 
    Sharma A, Kitsak M, Cho MH, Ameli A, Zhou X et al. 2018. Integration of molecular interactome and targeted interaction analysis to identify a COPD disease network module. Sci. Rep. 8:14439
    [Google Scholar]
  83. 83. 
    Langfelder P, Horvath S. 2008. WGCNA: an R package for weighted correlation network analysis. BMC Bioinform 9:559
    [Google Scholar]
  84. 84. 
    Glass K, Huttenhower C, Quackenbush J, Yuan GC 2013. Passing messages between biological networks to refine predicted interactions. PLOS ONE 8:e64832
    [Google Scholar]
  85. 85. 
    Hardin M, Silverman EK. 2014. Chronic obstructive pulmonary disease genetics: a review of the past and a look into the future. J. COPD Found. 1:33–46
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-021317-121224
Loading
/content/journals/10.1146/annurev-physiol-021317-121224
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error