Genome-wide interaction study of dust mite allergen on lung function in children with asthma Erick Forno, MD, MPH, Joanne Sordillo, MD, MPH, John Brehm,

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Genome-wide interaction study of dust mite allergen on lung function in children with asthma Erick Forno, MD, MPH, Joanne Sordillo, MD, MPH, John Brehm, MD, MPH, Wei Chen, PhD, Takis Benos, PhD, Qi Yan, PhD, Lydiana Avila, MD, Manuel Soto-Quirós, MD, Michelle M. Cloutier, MD, Angel Colón-Semidey, MD, Maria Alvarez, MD, Edna Acosta-Pérez, PhD, Scott T. Weiss, MD, MS, Augusto A. Litonjua, MD, MPH, Glorisa Canino, PhD, Juan C. Celedón, MD, DrPH, FAAAAI Journal of Allergy and Clinical Immunology Volume 140, Issue 4, Pages 996-1003.e7 (October 2017) DOI: 10.1016/j.jaci.2016.12.967 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 140, 996-1003 Journal of Allergy and Clinical Immunology 2017 140, 996-1003.e7DOI: (10.1016/j.jaci.2016.12.967) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Manhattan plot of genome-wide interaction study interaction P values in PRGOAL for FEV1. Plot depicts the –log10(interaction P value) for FEV1 on the y-axis versus SNPs in each chromosome on the x-axis. Red line: genome-wide significance level (P < 5 × 10−8). Blue line: genome-wide suggestive level (P < 1 × 10−7). Journal of Allergy and Clinical Immunology 2017 140, 996-1003.e7DOI: (10.1016/j.jaci.2016.12.967) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Regional association plot for SNP rs117902240. Regional association plot generated using the LocusZoom tool from the Abecasis lab at the University of Michigan (http://locuszoom.sph.umich.edu/locuszoom/),34 with data imputed from the 1000 Genomes populations (phase I v3). Journal of Allergy and Clinical Immunology 2017 140, 996-1003.e7DOI: (10.1016/j.jaci.2016.12.967) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 FEV1 stratified by rs117902240 genotype and dust mite allergen level. FEV1 in PRGOAL stratified by dust mite allergen level (low in blue vs high in red) and rs117902240 genotype (AA = no minor alleles vs AC = 1 minor allele; there were no subjects homozygous for the minor allele [CC]). Model adjusted for age, sex, and height. Journal of Allergy and Clinical Immunology 2017 140, 996-1003.e7DOI: (10.1016/j.jaci.2016.12.967) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 CEBPβ in the IL-17 signaling pathway. IL-17 pathway (simplified). CEBPβ is one of the mediators of IL-17A and IL-17F signaling pathways, as well as nuclear factor kappa B signaling.37,38 CEBPβ is also involved in IL-4, IL-6, and other signaling pathways (not shown). ERK, Extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3 beta; NFκB, nuclear factor kappa B; TAK1, transforming growth factor beta 1-activated kinase 1; TRAF-6, Tumor necrosis factor receptor-associated factor 6. Journal of Allergy and Clinical Immunology 2017 140, 996-1003.e7DOI: (10.1016/j.jaci.2016.12.967) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Regional linkage disequilibrium (LD) plots of the 3 top SNPs for FEV1. LD plots generated at the SNP Annotation and Proxy Search (SNAP) Web site (https://www.broadinstitute.org/mpg/snap/ldplot.php) using data from the 1000 Genomes Pilot 1. Journal of Allergy and Clinical Immunology 2017 140, 996-1003.e7DOI: (10.1016/j.jaci.2016.12.967) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions