Asthma susceptibility variants are more strongly associated with clinically similar subgroups

Abstract

Objective: Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) reproducibly associated with asthma. This study evaluated whether GWAS-nominated SNPs are more strongly associated with asthma patients sharing the same clinical characteristics in order to refine the role of recently identified genes. Methods: Analyses were performed in unrelated French Canadian subjects (566 cases and 416 controls) with data collected on lung function, blood cell counts, atopy, disease history and medication. Previously defined asthma subgroups were used for analysis: 1) older patients with low atopy and low lung function, 2) high atopy, 3) young non-smoking women and 4) high smoking history. Allele frequencies of 68 GWAS-nominated SNPs were compared between controls and cases or controls and subgroups of cases defined by cluster analysis. Results: Twelve GWAS-nominated SNPs demonstrated evidence of replication (p value < 0.05) for association with asthma. In phenotypically similar asthma patients, rs10197862, located in IL1RL1/IL18R1, was the most strongly associated SNP with the high atopy subgroup (p = 0.0009). SNPs located at the IL33 and the STARD3/PGAP3 loci were also associated with the high atopy subgroup. Two SNPs, rs1544791 (PDE4D) and rs3806932 (TSLP), were more strongly associated with the high smoking history subgroup than with asthma or any other subgroups. All 10 SNPs that replicated for asthma per se and within subgroups had lower p values in subgroups. Moreover, 12 SNPs were only replicated in a subgroup. Conclusion: This study shows that the majority of GWAS-nominated SNPs are more strongly associated with homogeneous subgroups of asthma than broadly defined asthma.

Keywords:

• Asthma genetics
• cluster analysis
• phenotypes
• GWAS
• SNPs

Acknowledgements

We thank the research subjects for their participation in the Quebec City Case-Control Asthma Cohort. The authors would like to recognize the contribution of devoted research nurses and staff that collected this cohort including Johane Lepage, Joanne Milot, Hélène Villeneuve, Francine Deschesnes, Marie-Ève Boulay, and Hélène Turcotte. We are also grateful to the dedicated research staff at the Respiratory Health Network Tissue Bank including Christine Racine, Sabrina Biardel, Marie-Christine Allard, and Geneviève Guèvremont for storing biological materials and constantly updating the clinical database. Finally, we are thankful for the support and help of Nathalie Gaudreault, Laura Sbarra and Cyndi Henry for extracting the DNA and preparing the samples for genetic/genomic applications.

Declaration of interest

ELC, JCB and YB declare that they have no competing interests. LPB wishes to declare what can be perceived as “potential” conflicts of interests. Advisory Boards: GlaxoSmithKline, Novartis. Conferences (honoraria): AstraZeneca, GlaxoSmithKline, Merck, Novartis. Sponsorship for investigator-generated research: AstraZeneca, GlaxoSmithKline, Merck Frosst, Schering. Sponsorship for research funding for participating in multicenter studies: most of these studies are performed in the context of the Canadian Investigative Collaboration with the NCE AllerGen, Altair, Amgen, Asmacure, AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Ono Pharma, Pharmaxis, Schering, Wyeth. Support for the production of educational materials: AstraZeneca, GlaxoSmithKline, Merck Frosst, Boehringer-Ingelheim, Novartis. Governmental: Adviser for INNESS, the Quebec National Health Institute, Member of the Quebec Workmen Compensation Board Respiratory Committee. Organisational: Chair of the Canadian Thoracic Society Respiratory Guidelines Committee, Chair of the Global Initiative for Asthma (GINA) Guidelines Dissemination and Implementation Committee. Holder of the Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health. Member of the Knowledge Translation (KT Canada) supported by the CIHR, Member of the Executive Committee of InterAsma (Global Asthma Organisation), Representing Canadian Member on the GARD (Global Alliance for Respiratory Diseases), World Health Organization, Member of the French-speaking Space of Pneumology (L'Espace Francophone de Pneumologie - Société de pneumologie de langue française), Member of experts' numerous committees of the American College of Chest Physicians, European Respiratory Society, American Thoracic Society and Canadian Respiratory Society.

Funding

The collection of the Quebec City Case-Control Asthma Cohort was supported by grants from the Chaire de pneumologie de la Fondation JD Bégin de l'Université Laval, the Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec, and the Respiratory Health Network of the FRQS. This work was also supported by the Canadian Institutes of Health Research (MOP – 123369). YB was the recipient of a Junior 2 Research Scholar from the Fonds de recherche Québec Santé (FRQS) and now holds a Canada Research Chair in Genomics of Heart and Lung Diseases. JCB was a recipient of doctoral studentships from the Respiratory Health Network of the “Fonds de Recherche Québec-Santé” (FRQS) and the “Centre de Recherche Institut Universitaire de Cardiologie et de Pneumologie de Québec.” He is now recipient of a doctoral scholarship from the Canadian Respiratory Research Network (CRRN).