OJRD  Vol.3 No.4 , November 2013
Multivariate Asthma Phenotypes in Adults: The Quebec City Case-Control Asthma Cohort
ABSTRACT

Background and Objectives: Asthma is a heterogeneous disease where patient severity can be classified according to various models based on numerous variables. Large collections of well-phenotyped subjects are needed to find distinct clusters of patients for personalized medicine and future genetic studies. The objective of this study is to describe the collection of the Quebec City Case-Control Asthma Cohort and to identify homogeneous subgroups of asthma patients based on clinical characteristics. Methods: This cohort is part of an ongoing project initiated in 2007 to elucidate the genetic basis of asthma. All subjects are randomly recruited at the same site following advertisements. Subjects are unrelated French Canadian white adults 18 years of age or older. Each participant underwent a spirometry, methacholine challenge, and allergy skin-prick tests. Blood was collected for DNA, cell counts and total serum IgE measurements. So far, 982 subjects have been recruited and classified as cases (n = 566) or controls (n = 416). We performed factor and cluster analyses on collected phenotypes from this set to identify subgroups of phenotypically similar asthmatic patients. Results: Factor analysis with 13 variables led to the selection of five factors: lung function, numbers of allergens, blood eosinophil percentage, smoking status and age. K-means cluster analysis on the reduced dataset produced four significantly different groups with the following characteristics: smoking history, low atopy and low lung function, high atopy, and young non-smoking with average atopy. Conclusions: The Quebec City Case-Control Asthma Cohort is a new resource for local and collaborative clinical and genetic research on asthma. This new collection reveals distinct multivariate phenotypes of adult asthma that are likely to be important for future genetic studies and targeted therapies.


Cite this paper
É. Lavoie-Charland, J. Bérubé, M. Laviolette, L. Boulet and Y. Bossé, "Multivariate Asthma Phenotypes in Adults: The Quebec City Case-Control Asthma Cohort," Open Journal of Respiratory Diseases, Vol. 3 No. 4, 2013, pp. 133-142. doi: 10.4236/ojrd.2013.34021.
References
[1]   M. F. Moffatt, I. G. Gut, F. Demenais, et al., “A Large- Scale, Consortium-Based Genomewide Association Study of Asthma,” New England Journal of Medicine, Vol. 363, No. 13, 2010, pp. 1211-1221. http://dx.doi.org/10.1056/NEJMoa0906312

[2]   D. G. Torgerson, E. J. Ampleford, G. Y. Chiu, et al., “Meta-Analysis of Genome-Wide Association Studies of Asthma in Ethnically Diverse North American Populations,” Nature Genetics, Vol. 43, No. 9, 2011, pp. 887- 892. http://dx.doi.org/10.1038/ng.888

[3]   S. E. Wenzel, “Asthma: Defining of the Persistent Adult Phenotypes,” Lancet, Vol. 368, No. 9537, 2006, pp. 804-813. http://dx.doi.org/10.1016/S0140-6736(06)69290-8

[4]   J. Kiley, R. Smith and P. Noel, “Asthma Phenotypes,” Current Opinion in Pulmonary Medicine, Vol. 13, No. 1, 2007, pp. 19-23.

[5]   T. B. Kim, A. S. Jang, H. S. Kwon, et al., “Identification of Asthma Clusters in Two Independent Korean Adult Asthma Cohorts,” The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, Vol. 41, No. 6, 2013, pp. 1308-1314.

[6]   P. Haldar, I. D. Pavord, D. E. Shaw, et al., “Cluster Analysis and Clinical Asthma Phenotypes,” American Journal of Respiratory and Critical Care Medicine, Vol. 178, No. 3, 2008, pp. 218-224. http://dx.doi.org/10.1164/rccm.200711-1754OC

[7]   P. Shirtcliffe, M. Weatherall, J. Travers and R. Beasley, “The Multiple Dimensions of Airways Disease: Targeting Treatment to Clinical Phenotypes,” Current Opinion in Pulmonary Medicine, Vol. 17, No. 2, 2011, pp. 72-78. http://dx.doi.org/10.1097/MCP.0b013e328341f181

[8]   V. Siroux, X. Basagana, A. Boudier, et al., “Identifying Adult Asthma Phenotypes Using a Clustering Approach,” The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, Vol. 38, No. 2, 2011, pp. 310-317. http://dx.doi.org/10.1183/09031936.00120810

[9]   M. Amelink, S. B. de Nijs, J. C. de Groot, et al., “Three Phenotypes of Adult-Onset Asthma,” Allergy, Vol. 68, No. 5, 2013, pp. 674-680. http://dx.doi.org/10.1111/all.12136

[10]   A. M. Fitzpatrick, W. G. Teague, D. A. Meyers, et al., “Heterogeneity of Severe Asthma in Childhood: Confirmation by Cluster Analysis of Children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program,” The Journal of Allergy and Clinical Immunology, Vol. 127, No. 2, 2011, pp. 382-389.

[11]   J. Just, R. Gouvis-Echraghi, S. Rouve, et al., “Two Novel, Severe Asthma Phenotypes Identified during Childhood Using a Clustering Approach,” The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, Vol. 40, No. 1, 2012, pp. 55-60. http://dx.doi.org/10.1183/09031936.00123411

[12]   M. Weatherall, J. Travers, P. M. Shirtcliffe, et al., “Distinct Clinical Phenotypes of Airways Disease Defined by Cluster Analysis,” The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, Vol. 34, No. 4, 2009, pp. 812-818.

[13]   Society AT, “Standardization of Spirometry, 1994 Update. American Thoracic Society,” American Journal of Respiratory and Critical Care Medicine, Vol. 152, No. 3, 1995, pp. 1107-1136. http://dx.doi.org/10.1164/ajrccm.152.3.7663792

[14]   R. Crapo, R. Casaburi, A. Coates, et al., “Guidelines for Methacholine and Exercise Challenge Testing—1999: This Official Statement of the American Thoracic Society Was Adopted by the ATS Board of Directors, July 1999,” American Journal of Respiratory and Critical Care Medicine, Vol. 161, No. 1, 2000, pp. 309-329.

[15]   R. Knudson, M. Lebowitz, C. Holberg and B. Burrows, “Changes in the Normal Maximal Expiratory Flow-Volume Curve with Growth and Aging,” American Review of Respiratory Disease, Vol. 127, No. 6, 1983, pp. 725-734.

[16]   E. Juniper, P. Frith, C. Dunnet, D. Cockcroft and F. Hargreave, “Reproducibility and Comparison of Response to Inhaled Histamine and Methacholine,” Thorax, Vol. 33, No. 6, 1978, pp. 705-710. http://dx.doi.org/10.1136/thx.33.6.705

[17]   M. D. Lougheed, C. Lemiere, S. D. Dell, et al., “Canadian Thoracic Society Asthma Management Continuum— 2010 Consensus Summary for Children Six Years of Age and over, and Adults,” Canadian Respiratory Journal, Vol. 17, No. 1, 2010, pp. 15-24.

[18]   Immunology EAoAaC, “Skin Tests Used in Type I Allergy Testing Position Paper. Sub-Committee on Skin Tests of the European Academy of Allergology and Clinical Immunology,” Allergy, Vol. 44, Suppl. 10, 1989, pp. 1-59.

[19]   B. S. Everitt, S. Landau, M. Leese and D. Stahl, “Hierarchical Clustering,” Cluster Analysis, John Wiley & Sons, Ltd., pp. 71-110.

[20]   W. C. Moore, D. A. Meyers, S. E. Wenzel, et al., “Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program,” American Journal of Respiratory and Critical Care Medicine, Vol. 181, No. 4, 2010, pp. 315-323. http://dx.doi.org/10.1164/rccm.200906-0896OC

[21]   T. S. Lapperre, J. B. Snoeck-Stroband, M. M. Gosman, et al., “Dissociation of Lung Function and Airway Inflammation in Chronic Obstructive Pulmonary Disease,” American Journal of Respiratory and Critical Care Medicine, Vol. 170, No. 5, 2004, pp. 499-504. http://dx.doi.org/10.1164/rccm.200401-112OC

[22]   E. R. Rosi, M. C. Grazzini, M. Duranti, R. Scano and G. Scano, “Sputum Analysis, Bronchial Hyperresponsiveness, and Airway Function in Asthma: Results of a Factor Anlaysis,” Journal of Allergy and Clinical Immunology, Vol. 103, No. 2, 1999, pp. 232-237. http://dx.doi.org/10.1016/S0091-6749(99)70496-3

[23]   E. Noguchi, H. Sakamoto, T. Hirota, et al., “Genome- Wide Association Study Identifies HLA-DP as a Susceptibility Gene for Pediatric Asthma in Asian Populations,” PLOS Genetics, Vol. 7, No. 7, 2011, Article ID: e1002170. http://dx.doi.org/10.1371/journal.pgen.1002170

[24]   E. R. Sutherland, E. Goleva, T. S. King, et al., “Cluster Analysis of Obesity and Asthma Phenotypes,” PLoS One, Vol. 7, No. 5, 2012, Article ID: e36631. http://dx.doi.org/10.1371/journal.pone.0036631

[25]   Y. Bosse and T. J. Hudson, “Toward a Comprehensive Set of Asthma Susceptibility Genes,” Annual Review of Medicine, Vol. 58, 2007, pp. 171-184. http://dx.doi.org/10.1146/annurev.med.58.071105.111738

[26]   B. E. Himes, G. M. Hunninghake, J. W. Baurley, et al., “Genome-Wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene,” American Journal of Human Genetics, Vol. 84, No. 5, 2009, pp. 581-593. http://dx.doi.org/10.1016/j.ajhg.2009.04.006

[27]   D. F. Gudbjartsson, U. S. Bjornsdottir, E. Halapi, et al., “Sequence Variants Affecting Eosinophil Numbers Associate with Asthma and Myocardial Infarction,” Nature Genetics, Vol. 41, No. 3, 2009, pp. 342-347. http://dx.doi.org/10.1038/ng.323

[28]   C. Ober, Z. Tan, Y. Sun, et al., “Effect of Variation in CHI3L1 on Serum YKL-40 Level, Risk of Asthma, and Lung Function,” New England Journal of Medicine, Vol. 358, No. 16, 2008, pp. 1682-1691. http://dx.doi.org/10.1056/NEJMoa0708801

[29]   S. Weidinger, C. Gieger, E. Rodriguez, et al., “Genome- Wide Scan on Total Serum IgE Levels Identifies FCER1A as Novel Susceptibility Locus,” PLoS Genet, Vol. 4, No. 8, 2008, Article ID: e1000166. http://dx.doi.org/10.1371/journal.pgen.1000166

[30]   S. Choudhry, M. Taub, R. Mei, et al., “Genome-Wide Screen for Asthma in Puerto Ricans: Evidence for Association with 5q23 Region,” Human Genetics, Vol. 123, No. 5, 2008, pp. 455-468. http://dx.doi.org/10.1007/s00439-008-0495-7

[31]   A. T. DeWan, E. W. Triche, X. Xu, et al., “PDE11A Associations with Asthma: Results of a Genome-Wide Association Scan,” The Journal of Allergy and Clinical Immunology, Vol. 126, No. 4, 2010, pp. 871-873.

[32]   D. B. Hancock, I. Romieu, M. Shi, et al., “Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children,” PLoS Genet, Vol. 5, No. 8, 2009, Article ID: e1000623. http://dx.doi.org/10.1371/journal.pgen.1000623

[33]   J. Hui, A. Oka, A. James, et al., “A Genome-Wide Association Scan for Asthma in a General Australian Population,” Human Genetics, Vol. 123, No. 3, 2008, pp. 297- 306. http://dx.doi.org/10.1007/s00439-008-0477-9

[34]   S. H. Kim, B. Y. Cho, C. S. Park, et al., “Alpha-T-Catenin (CTNNA3) Gene Was Identified as a Risk Variant for Toluene Diisocyanate-Induced Asthma by Genome-Wide Association Analysis,” Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology, Vol. 39, No. 2, 2009, pp. 203-212. http://dx.doi.org/10.1111/j.1365-2222.2008.03117.x

[35]   R. A. Mathias, A. V. Grant, N. Rafaels, et al., “A Genome-Wide Association Study on African-Ancestry Populations for Asthma,” The Journal of Allergy and Clinical Immunology, Vol. 125, No. 2, 2010, pp. 336-346.

[36]   X. Li, T. D. Howard, S. L. Zheng, et al., “Genome-Wide Association Study of Asthma Identifies RAD50-IL13 and HLA-DR/DQ Regions,” The Journal of Allergy and Clinical Immunology, Vol. 125, No. 2, 2010, pp. 328-335.

[37]   M. F. Moffatt, M. Kabesch, L. Liang, et al., “Genetic Variants Regulating ORMDL3 Expression Contribute to the Risk of Childhood Asthma,” Nature, Vol. 448, No. 7152, 2007, pp. 470-473. http://dx.doi.org/10.1038/nature06014

[38]   P. M. Sleiman, J. Flory, M. Imielinski, et al., “Variants of DENND1B Associated with Asthma in Children,” New England Journal of Medicine, Vol. 362, No. 1, 2010, pp. 36-44. http://dx.doi.org/10.1056/NEJMoa0901867

[39]   T. Hirota, A. Takahashi, M. Kubo, et al., “Genome-Wide Association Study Identifies Three New Susceptibility Loci for Adult Asthma in the Japanese Population,” Nature Genetics, Vol. 43, No. 9, 2011, pp. 893-896. http://dx.doi.org/10.1038/ng.887

[40]   M. A. Ferreira, M. C. Matheson, D. L. Duffy, et al., “Identification of IL6R and Chromosome 11q13.5 as Risk Loci for Asthma,” Lancet, Vol. 378, No. 9795, 2011, pp. 1006-1014. http://dx.doi.org/10.1016/S0140-6736(11)60874-X

[41]   W. Y. Wang, B. J. Barratt, D. G. Clayton and J. A. Todd, “Genome-Wide Association Studies: Theoretical and Practical Concerns,” Nature Reviews, Vol. 6, No. 2, 2005, pp. 109-118. http://dx.doi.org/10.1038/nrg1522

[42]   D. G. Torgerson, D. Capurso, R. A. Mathias, et al., “Resequencing Candidate Genes Implicates Rare Variants in Asthma Susceptibility,” American Journal of Human Genetics, Vol. 90, No. 2, 2012, pp. 273-281. http://dx.doi.org/10.1016/j.ajhg.2012.01.008

[43]   M. A. Ferreira, A. F. McRae, S. E. Medland, et al., “Association between ORMDL3, IL1RL1 and a Deletion on Chromosome 17q21 with Asthma Risk in Australia,” European Journal of Human Genetics, Vol. 19, No. 4, 2011, pp. 458-464. http://dx.doi.org/10.1038/ejhg.2010.191

[44]   E. D. Green and M. S. Guyer, “National Human Genome Research I. Charting a Course for Genomic Medicine from Base Pairs to Bedside,” Nature, Vol. 470, No. 7333, 2011, pp. 204-213. http://dx.doi.org/10.1038/nature09764

[45]   M. A. Hamburg and F. S. Collins, “The Path to Personalized Medicine,” New England Journal of Medicine, Vol. 363, No. 4, 2010, pp. 301-304. http://dx.doi.org/10.1056/NEJMp1006304

 
 
Top