Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma ...in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma ...phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits.
We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes.
We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen.
Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10−7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10−6) and PIK3R6 with eosinophil count (P = 4.10 × 10−5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge.
We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.
Given the high rate of off-protocol use of open-label OCSs combined with the small number of children managed per-protocol and the potential for selection bias of children with more severe episodes ...being managed with open-label OCSs by providers outside the trial, the OCELOT Data Safety and Monitoring Board recommended premature termination of the trial because of a lack of feasibility in April 2013. ...the primary outcome was not able to be evaluated. Compared with children treated per-protocol, children who received open-label OCS treatment were more likely to have at least 1 positive aeroallergen skin prick test response, higher IgE levels, higher blood eosinophil counts, higher asthma-related hospitalization rates in the year before enrollment, and/or self-reported black race at baseline (Table I). The major barrier was frequent use of open-label OCSs despite careful informed consent with parental education to encourage communication with research staff during illness, written action plans, letters about trial medications to the primary care physician for parents to bring to the emergency department, and real-time support from triage nurses and experienced research personnel. Children would be stratified by clearly defined clinical phenotypes that predict future wheezing LRTIs and response to these therapies.9 Finally, it might be helpful to conduct this study in a clinical setting to confirm that protocol-defined criteria for OCS intervention are met.Appendix Baseline characteristic Early terminators (n = 88)∗ Per-protocol (n = 61)∗ Age (mo), mean ± SD 41.1 ± 16.2 40.3 ± 16.8 Male sex, no. (%) 60 (68.2) 41 (67.2) Family reported race, no. (%) White 59 (67) 44 (72.1) Black/African American 19 (21.6) 8 (13.1) Other 4 (4.6) 1 (1.6) >1 Race reported 6 (6.8) 8 (13.1) Family reported ethnicity, no. (%) Hispanic/Latino 27 (30.7) 16 (26.2) Family-reported highest education level No high school diploma 4 (4.5) 1 (1.7) GED or high school diploma 13 (14.8) 5 (8.8) Post–high school education 71 (80.7) 51 (89.5) Family-reported income, no. (%) <$25,000 19 (21.6) 16 (27.6) $25,000-$49,999 19 (21.6) 14 (24.1) $50,000-$99,999 22 (25) 17 (29.3) ≥$100,000 20 (22.7) 11 (19.0) No. of asthma-related hospitalizations in past year, mean ± SD 0.25 ± 0.44 0.16 ± 0.37 No. of OCS courses in past year, mean ± SD 1.17 ± 0.96 1.36 ± 1.11 ICS use in past year, no. (%) 22 (25) 26 (42.6) >1 Positive aeroallergen sensitivity, no. (%) 46 (54.1), n = 85 22 (36.7), n = 60 Serum IgE (kU/L), median (quartile range) 115.8 (19.7-307.6), n = 81 77.6 (14.5-190.5), n = 56 Blood eosinophil count (%), median (quartile range) 3.8 (2-6.15), n = 84 3 (1.4-5), n = 58 Table I Baseline characteristics at enrollment Site ID Grant support Coordinator and investigator acknowledgement Site address Boston 112 HL098102 Lisa Bartnikas, MD Alisha Bouzaher, MS Christopher Burke, Matthew Cavanaugh, Julia Chen, PA-C Elizabeth Cunningham, Amparito Cunningham, James Friedlander, MD Enal Hindi, MD David Kantor MD, Perdita Permaul, MD Devako Rao, MD Melinda Rossi, MPH Doris Schierembergg, MS Kynda Schneider, MD Jennifer Troung, Dale Umetsu, MD Joseph Zhou, MD Children's Hospital Boston, 333 Longwood Ave, Suite 403, Boston, MA 02115 Phone: 857-218-5529 Chicago 122 HL098096 Jill Chmielewski, Anna Fishbein, Iliana Flexas, Ramsay Fuleihan, Rajesh Kumar, James Lane, Melanie Makhija, Louis Martos, Brandon Parker, Benjamin Prince, Nashmia Qamar, Mary Riordan, Rachel Robinson, Waheeda Samady, Christine Szychlinski, Daniel Tsang Ann & Robert H. Lurie Children's Hospital Division of Allergy & Immunology, 225 East Chicago Ave #60, Chicago, IL 60611 Phone: 312-227-6455 125 HL098096 Christopher Codispoti, Juan Fu, Grace Li, Diana Munoz-Mendoza, Benjamin Thompson Rush University Medical Center, 1725 W Harrison St, Ste 117, Chicago, IL 60612 Phone: 312-942-8701 Fax: 312-563-2201 Denver 132 HL098075 UL1 TR001082 Melanie Gleason, Sakari Graves, Jonathan Malka, Melanie Phillips, Gayle Spears, D. Sundstrom, Michael White National Jewish Health, Rm A303, 1400 Jackson St, Denver, CO 80206-2761 Phone: 303-398-1721 133 HL098075 Christina Batson, BS Lea Davies, MD Franceska Kelly, BS, CCRC Esmeralda Morales, MD Abby Redway, RRT, BOE Mary Spicher, BSN, MSN University of New Mexico Health Sciences Center, MSC 10-5590, 1 University of New Mexico, Albuquerque, NM 87131-0001 Phone: 505-272-9889 Madison 141 HL098090 Lauren Kaminski, BS Megan R. Knutson, MS, RCEP Kelly Miller, BS, CCRC Jennifer Promer, BS Sheila Turcsanyi, BS, CCRC Tanya Watson, RN, BSN University of Wisconsin-Madison, K4/968 CSC, MC 9988, 600 Highland Ave, Madison, WI 53792 Phone: 608-263-3360 Pittsburgh 152 HL098177 ULITR000439 Shean Aujla, MD John Broyles, CRNP Hey Chong, MD Patricia Dubin, MD Jonathan Finder, MD Todd D. Green, MD Lori Holt, CRNP Adam Kufen, RN Geoffrey Kurland, MD Rose Lanzo, RRT David Nash, MD Julianne Parente, Catherine Smith, RN Jonathan Spahr, MD Daniel J. Weiner, MD Department of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Dr, 4401 Penn Ave, AOB 3rd Fl, Ste 3300, Pittsburgh, PA 15224 Phone: 412-692-5872 153 HL098177 Daniel Craven, MD Danielle Goetz, Meeghan Hart MD Leigh A. Kerns, MD Laurie Logan, RN Ross Myers, MD Laura Veri, RA Rainbow Babies and Children's Hospital, 11100 Euclid Ave, Ste 3001, MS 6006, Cleveland, OH 44106 Phone: 216-844-7927 154 HL098177 Erica Butler, MBS, CCRC Jennifer Maiolo, PA-C Sara Misplay, MBA, CCRC David Skoner, MD Glennys Smith ASRI/AGH Department of Allergy, Asthma and Immunology, 490 E North Ave, Suite 207, Pittsburgh, PA 15212 Phone: 412-359-3328 St Louis 162 HL098098 UL1 TR000448 Wanda Caldwell, MBA, RRT, BHS Courtney Dula, MS Alysa Ellis, MD Caroline Horner, MD Lila Kertz, PNP Tina Norris, CRT Katherine Rivera-Spoljaric, MD Oscar Rodriguez, MD Robert Strunk, MD Washington University School of Medicine, Campus Box 8116, 660 S Euclid Ave, St Louis, MO 63110 Phone: 314-286-1173 San Francisco 172 HL098107 Jessica Bowman, Vicky Bowyer, Judy Gonzales-Vargas, Sara Hawkey, Susannah McCormick, Michelle McKean, Dan Shapiro, Katherine Tom University of California–San Francisco, 3333 California St, Suite 245, San Francisco, CA 94118 Phone: 415-476-2860 173 HL098107 Jason Decker, RN Keonna Harrison, Dayna Long, MD Jyothi Marbin, MD Robert Mok, LVN Cindy Nelson-Purdy, NP, MPH Dennis Ren, Hollie Stessel, CPhT Benioff Children's Hospital–Oakland, 5220 Claremont Ave, Oakland, CA 94618 Phone: 510-428-3885 x7492 Tucson 181 HL098112 Valerie Bloss, BS Mark Brown, MD Katherine Chee, BS Cori Daines, MD Clara S. Ehrman, BS, BSHS Dima Ezmigna, MBBS Jamie Goodwin, PhD Roni Grad, MD Anunya Hiranratta, MD Silvia Lopez, RN Andrea Paco, Janette Priefert, Natalie S. Provencio, BS Elizabeth Ryan, BS, RRT Monica Varela, LPN Monica Vasquez, MPH, MEd Rosemary Weese, RN, RRT Jesus Wences, BS Arizona Respiratory Center, University of Arizona, 1501 N Campbell Ave, Rm 2344, PO Box 245030, Tucson, AZ 85724-5030 Phone: 520-626-4200 WS/Charlottesville 192 HL098103 Deb Green, Denise Thompson-Batt, Kristin Wavell, Donna Wolf University of Virginia Health System, Pediatric Respiratory Medicine, PO Box 810386, 409 Lane Rd, Building MR4, Charlottesville, VA 22908-0386 194 HL098103 UL1 TR000454 Timothy Beaty, Alice C. Bruce, BS Karen DeMuth, Jennifer Dodds, Shaneka Douglas, Dawn M. Simon, Denise Whitlock, Shanae Brown, RRT Emory University Department of Pediatrics, 2015 Uppergate Dr, Rm 326, Atlanta, GA 30322 Phone: 404-727-5176 DCC HL098115 Susan Boehmer, MA Matthew Bowman, Loretta Doty, MSW Linda Ferrari, BS Beth Gern, Dave Mauger, PhD Aimee Merchlinski, James Schmidt, Daniel Tekely, Lindsay Texter, Angela Updegrave, Ronald Zimmerman, Jr, MPA Pennsylvania State University College of Medicine, Department of Public Health Sciences, 90 Hope Dr, Hershey, PA 17033 Phone: 717-531-3663 Table E1 AsthmaNet OCELOT grant support/acknowledgement roster
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