Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy

Susanne Bornelöv equal contributor,
Annika Sääf equal contributor,
Erik Melén,
Anna Bergström,
Behrooz Torabi Moghadam,
Ville Pulkkinen,
Nathalie Acevedo,
Christina Orsmark Pietras,
Markus Ege,
Charlotte Braun-Fahrländer,
Josef Riedler,
Gert Doekes,
Michael Kabesch,
[ ... ],
Jan Komorowski ¶
, [ view all ]

Published: Nov 19, 2013
DOI: 10.1371/journal.pone.0080080

Abstract

Both genetic and environmental factors are important for the development of allergic diseases. However, a detailed understanding of how such factors act together is lacking. To elucidate the interplay between genetic and environmental factors in allergic diseases, we used a novel bioinformatics approach that combines feature selection and machine learning. In two materials, PARSIFAL (a European cross-sectional study of 3113 children) and BAMSE (a Swedish birth-cohort including 2033 children), genetic variants as well as environmental and lifestyle factors were evaluated for their contribution to allergic phenotypes. Monte Carlo feature selection and rule based models were used to identify and rank rules describing how combinations of genetic and environmental factors affect the risk of allergic diseases. Novel interactions between genes were suggested and replicated, such as between ORMDL3 and RORA, where certain genotype combinations gave odds ratios for current asthma of 2.1 (95% CI 1.2-3.6) and 3.2 (95% CI 2.0-5.0) in the BAMSE and PARSIFAL children, respectively. Several combinations of environmental factors appeared to be important for the development of allergic disease in children. For example, use of baby formula and antibiotics early in life was associated with an odds ratio of 7.4 (95% CI 4.5-12.0) of developing asthma. Furthermore, genetic variants together with environmental factors seemed to play a role for allergic diseases, such as the use of antibiotics early in life and COL29A1 variants for asthma, and farm living and NPSR1 variants for allergic eczema. Overall, combinations of environmental and life style factors appeared more frequently in the models than combinations solely involving genes. In conclusion, a new bioinformatics approach is described for analyzing complex data, including extensive genetic and environmental information. Interactions identified with this approach could provide useful hints for further in-depth studies of etiological mechanisms and may also strengthen the basis for risk assessment and prevention.

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Citation: Bornelöv S, Sääf A, Melén E, Bergström A, Torabi Moghadam B, et al. (2013) Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy. PLoS ONE 8(11): e80080. doi:10.1371/journal.pone.0080080
Editor: Raya Khanin, Memorial Sloan Kettering Cancer Center, United States of America
Received: May 14, 2013; Accepted: October 9, 2013; Published: November 19, 2013
Copyright: © 2013 Bornelöv et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was supported by the Swedish Research Council, the Stockholm County Council, the Centre for Allergy Research, Karolinska Institutet, the Swedish Heart Lung Foundation, Swedish Foundation for Strategic Research, and the European Union. Jan Komorowski was partially supported by the Polish Ministry of Science and Higher Education, grant number N301 239536. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
¶ Jointly directed the work.