Mechanisms of allergy and clinical immunologyA genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes
Section snippets
Methods
We provide a brief description of the cohorts below, with details shown in the supplementary text in this article's Online Repository at www.jacionline.org. The Institutional Review Board of Brigham and Women's Hospital approved these studies. Subject recruitment and procedures for the cohorts have been previously described.7, 11, 12
Asthma association testing of eSNPs
The baseline characteristics of the CAMP and Costa Rican index cases included in this study are presented in Table I. Baseline characteristics were similar between the CAMP and Costa Rican cohorts, including measures of asthma severity and lung function.
Of the 6706 SNPs identified as CD4+ lymphocyte cis-acting expression-associated eSNPs, 143 were associated with asthma under an additive genetic model in the CAMP cohort in either the case-control or family-based association analyses (see Table
Discussion
Although GWASs of complex traits have offered insight into the genetic underpinnings of complex diseases, such as asthma, the discovered variants explain only a fraction of the genetic contribution to such diseases.4 In part this is likely due to the stringent multiple-comparison burden imposed when testing millions of (mostly functionless) variants. Strategies that guide prioritization of functional genetic markers for testing can address this issue. We and others have demonstrated that eSNPs
The Asthma BRIDGE Consortium
Asthma BRIDGE Data Coordinating Center
CAMP Genetics Ancillary Study
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Benjamin A. Raby, MD, MPH (PI); Scott T. Weiss, MD, MSc (PI); Vincent Carey, PhD; Weiliang Qiu, PhD; Roxanne Kelly, BSc; Jody Sylvia Senter, MS; John Ziniti, BSc; Diana Tubbs; Brooke Schumann; Damien Croteau-Chonka, PhD.
Childhood Asthma Research and Education (CARE) Network
Arizona Respiratory Center, University of Arizona (Coordinating Center), Tucson,
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2017, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :There are several, well-replicated genetic variants that have been previously associated with asthma, notably variants at 17q21.7,13–17 Although associated single-nucleotide polymorphisms (SNPs) in this region encompass at least a 380-Kb span,7 including 5 annotated genes,13,18 initial attention has centered primarily on ORMDL3 and GSDMB. Calcium homeostasis, sphingolipid metabolism, and lymphocyte function are affected by variants that influence expression of ORMDL3,19–22 whereas GSDMB is highly expressed in T lymphocytes and thus potentially affects the inflammatory response, particularly to viral infection.16,23
Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases
2016, Journal of Allergy and Clinical ImmunologyCitation Excerpt :CD4+ T cells are divided into distinct subsets according to their cytokine profile.2 They differentiate from naive T cells, and their cytokine expression profile depends on the types of antigen-presenting cells (APCs), the type of the initial innate immune response, the adjuvanticity of the molecules presented with the antigen, and the existence and dose of many small molecules and other cytokines in the microenvironment.7 CD4+ naive T cells can differentiate into TH1, TH2, TH9, TH17, TH22, and follicular effector T cells, as well as different subsets of regulatory T (Treg) cells.4,8,9
Supported by R01 HL086601, RC2 HL101543, R37 HL066289, and K08 HL096833. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women's Hospital under appropriate CAMP policies and human subject protections. This work is supported by grants R01 HL086601 and RC2 HL101543 from the National Heart, Lung, and Blood Institute/National Institutes of Health (NIH/NHLBI). The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, and P01 HL083069 and through the Colorado CTSA grant 1 UL1 RR025780 from the NIH and National Center for Research Resources. B.E.H. was supported by NIH K99 HL105663. S.S. receives additional support from K08 HL096833 from NIH/NHLBI. Additional support was provided by NIH P01ES011627 (PI: F. Gilliland). Supported in part by the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH.
Disclosure of potential conflict of interest: S. Sharma, R. Strunk, A. E. Berger, J. Fan, M. P. Boorgula, C. Ober, and V. J. Carey have received research support from the National Institutes of Health. S. J. Szefler has received research support from and has received travel support from the National Heart, Lung, and Blood Institute; has received consultancy fees from Merck, Genentech, Boehringer Ingelheim, and GlaxoSmithKline; has received research support from GlaxoSmithKline; has received lecture fees from Merck; has received payment for manuscript preparation from Genentech; and has a patent with the NHLBI CARE Network. M. Castro has received research support from the National Institutes of Health; has received support for travel from National Institutes of Health (for AsthmaNet); has consultancy arrangements with Asthmatx/Boston Scientific, Genentech, IPS, Pulmagen, and Sanofi Aventis; has received 1 or more grants from or has 1 or more grants pending with Asthmatx/Boston Scientific, Amgen, Ception/Cephalon/Teva, Genentech, MedImmune, Merck, Novartis, GlaxoSmithKline, Sanofi Aventis, Vectura, Next Bio, and KaloBios; has received 1 or more payments for lecturing from or is on the speakers' bureau for Merck, GlaxoSmithKline, Genentech, Asthmatx/Boston Scientific, and Boehringer Ingelheim; and has received royalties from Elsevier. G. B. Diette has received research support from the Baurenschmidt Foundation. B. M. Vonakis has received research support from the NIH; has received consultancy fees from Sanofi-US; is employed by Johns Hopkins University; has received research support from the NHLBI, Sanofi-US, Novaremed, Los Alamos National Laboratory, and Luna Innovations; has received lecture fees from the NIH; and has received travel support from the AAI. L. Avila has received research support from the Costa Rica Genetics of Asthma Study (R37 HL066289). R. F. Lemanske, Jr, has received research support from, has received consultancy fees from, and has received participation fees from the NIH; is a board member for the American Academy of Allergy, Asthma & Immunology (AAAAI); has received consultancy fees from Merck, Sepracor, SA Boney and Associates, GlaxoSmithKline, the American Institute of Research, Genentech, and Double Helix Development; and Boerhinger Ingelheim; is employed by the University of Wisconsin School of Medicine and Public Health; has received research support from the National Heart, Lung, and Blood Institute and Pharmaxis; has received lecture fees from the Michigan Public Health Institute, Allegheny General Hospital, the American Academy of Pediatrics, West Allegheny Health Systems, California Chapter 4, the AAP, the Colorado Allergy Society, the Pennsylvania Allergy and Asthma Association, Harvard Pilgrim Health, the California Society of Allergy, the NYC Allergy Society, the World Allergy Organization, the American College of Chest Physicians, APAPARI, and the Western Society of Allergy, Asthma, and Immunology; has received payment for manuscript preparation from the AAAAI; and has received royalties from Elsevier and UpToDate. J. Solway has received research support from NIH grant U54 TR000016 and NIH grant K12 HL090003; is a board member for PulmOne Advanced Medical Devices; has received consultancy fees from Hollister, Cytokinetics, and the Novartis Institute for Biomedical Research; has received research support from the NIH (grants P50 HL107171, R01 HL097805, P01 HL090554, T32 HL07605, U10 HL098096, R01 HL107361, U19 AI095230, K12 HL119995, and R01 HL113395) and AstraZeneca; has a patent with and has received royalties from Boston Scientific; is a Principal Investigator on the Chicago Metropolitan AsthmaNet Consortium site funded by the NHLBI and is participating in an AsthmaNet clinical trial by using 2 medications donated by Sunovion Pharmaceuticals. S. R. White has provided expert testimony for Shook, Hardy & Bacon, LLC; has received research support from the National Institute of Allergy and Infectious Diseases, the NHLBI, and the University of Chicago CTSA; and has received lecture fees from Pfizer. D. Nicolae has received research support from the NIH/NHLBI. K. Barnes has received research support from the NIH; is a board member for Genentech; has received consultancy fees from Sanofi-Aventis, Sirius Genomics, and Merck; is employed by the JHU; has received research support from the NIH and the NHLBI; and has received royalties from UpToDate. F. Martinez has received research support from the NIH and has received travel support from Abbott and Merck. J. C. Celedón has received consultancy fees from Genentech; has received research support from the NIH; and has received royalties from UpToDate. S. T. Weiss has received consultancy fees from Novartis. B. A. Raby has received research support from the NIH, has received consultancy fees from Merck, and has received royalties from UpToDate.
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These authors contributed equally to this work.