Cadherin-related family member 3 genetics and rhinovirus c respiratory Illnesses

Klaus Bønnelykke, Amaziah T. Coleman, Michael D. Evans, Jonathan Thorsen, Johannes Waage, Nadja H. Vissing, Christian J. Carlsson, Jakob Stokholm, Bo L. Chawes, Leon E. Jessen, Thea K. Fischer, Yury A. Bochkov, Carole Ober, Robert F. Lemanske, Daniel J. Jackson, James E. Gern, Hans Bisgaard

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Rationale: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. Objectives: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood. Methods: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC 2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses. Measurements and Main Results: The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05–1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC 2010 (IRR = 1.89 [1.14–3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02–1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13–2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92–1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages. Conclusions: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.

Original languageEnglish (US)
Pages (from-to)589-594
Number of pages6
JournalAmerican journal of respiratory and critical care medicine
Volume197
Issue number5
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Bibliographical note

Funding Information:
All private and public research funds supporting Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) are listed at www.copsac.com. The Lundbeck Foundation (grant R16-A1694), Danish Ministry of Health (grant 903516), Danish Council for Strategic Research (grant 0603-00280B), Danish Council for Independent Research (grants 10-082884 and 271-08-0815), the Capital Region Research Foundation, and NIH-NHLBI (grant R01 HL129735) have provided core support for COPSAC. No pharmaceutical company was involved in the study. The funding agencies did not have any role in design or conduct of the study, collection, management, or interpretation of the data, or preparation, review, or approval of the manuscript. The Childhood Origins of Asthma Birth Cohort Study is funded by NIH-NHLBI grant P01 HL070831.

Funding Information:
All private and public research funds supporting Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) are listed at www.copsac.com. The Lundbeck Foundation (grant R16-A1694), Danish Ministry of Health (grant 903516), Danish Council for Strategic Research (grant 0603-00280B), Danish Council for Independent Research (grants 10-082884 and 271-08-0815), the Capital Region Research Foundation, and NIH-NHLBI (grant R01 HL129735) have provided core support for COPSAC. No pharmaceutical company was involved in the study. The funding agencies did not have any role in design or conduct of the study, collection, management, or interpretation of the data, or preparation, review, or approval of the manuscript. The Childhood Origins of Asthma Birth Cohort Study is funded by NIH-NHLBI grant P01 HL070831. The authors thank the children and families of the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) cohorts for their support and commitment to their studies, and acknowledge and appreciate the unique efforts of the COPSAC and COAST research teams.

Publisher Copyright:
Copyright © 2018 by the American Thoracic Society

Keywords

  • Child
  • Genetics
  • Virus diseases
  • Viruses

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