@article{fb4cba27947b43bf8039c44432b472d7,
title = "Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients",
abstract = "Background: Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. Objective: We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. Methods: Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses. Results: Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P <.05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10-4) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10-11). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10 -7) and the American Thoracic Society severe asthma classification (P =.005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function. Conclusion: Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.",
keywords = "IL12A, IL12RB1, IRF2, Lung function, STAT4, asthma",
author = "Xingnan Li and Hawkins, {Gregory A.} and Ampleford, {Elizabeth J.} and Moore, {Wendy C.} and Huashi Li and Hastie, {Annette T.} and Howard, {Timothy D.} and Boushey, {Homer A.} and Busse, {William W.} and Calhoun, {William J.} and Mario Castro and Erzurum, {Serpil C.} and Elliot Israel and Lemanske, {Robert F.} and Szefler, {Stanley J.} and Wasserman, {Stephen I.} and Wenzel, {Sally E.} and Peters, {Stephen P.} and Meyers, {Deborah A.} and Bleecker, {Eugene R.}",
note = "Funding Information: Severe Asthma Research Program (SARP) centers were supported by National Institutes of Health (NIH) grants HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, UL1RR024992, M01RR018390, M01RR07122, M01RR03186, HL87665, and HL091762 . Genetic studies for SARP and Collaborative Studies on the Genetics of Asthma (CSGA) were funded by NIH grant HL87665 and Go Grant RC2HL101487 . The clinical The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study was supported by Genentech and Novartis Pharmaceuticals Corporation , and the genetic studies were funded by NIH HL76285, HL87665 , and Go Grant RC2HL101487 . Funding Information: Disclosure of potential conflict of interest: X. Li, G. A. Hawkins, H. Li, and T. D. Howard have received grants from the National Institutes of Health (NIH) . W. C. Moore has received grants from the National Heart, Lung, and Blood Institute (NHLBI) and was a subinvestigator in clinical trials performed at Wake Forest University for Aerovance, Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, Ception, Forest, Genentech, GlaxoSmithKline, MedImmune, Novartis, Pfizer, Sanofi-Aventis, and Wyeth. A. T. Hastie has received a grant from the NHLBI . H. A. Boushey has received research support from the NIH/NHLBI ; has consultant arrangements with Merck, GlaxoSmithKline, Genentech, Kalbios, Pharmaxis, and Johnson & Johnson; has received research support from GlaxoSmithKline and Genentech ; has received payment for lectures from the Allergy, Asthma, and Immunology Foundation of Northern California and Breathe California ; and has received royalties from the McGraw Hill Companies . W. W. Busse has a board membership with Merck; has consultant arrangements with Amgen, Novartis, GlaxoSmithKline, MedImmune, and Genentech; has received grants from the NIH/National Institute of Allergy and Infectious Diseases and the NIH/NHLBI ; and has received royalties from Elsevier . W. J. Calhoun has consultant arrangements with Genentech and receives grants from the Federal Emergency Management Agency. M. Castro has received grants from the NIH , the American Lung Association, Asthmatx/Boston Scientific, Amgen, Ception/Cephalon/Teva, Genentech, MedImmune, Merck, Novartis, GlaxoSmithKline, Sanofi-Aventis, and Vectura ; has received travel support from the NIH; has consultant arrangements with Asthmatx/Boston Scientific, Genentech, IPS, Pulmagen, and Sanofi-Aventis; has received payment for lectures from Pfizer, Merck, GlaxoSmithKline, Genentech, and Asthmatx/Boston Scientific; and receives royalties from Elsevier. E. Israel has consultant arrangements with Abbott, Amgen, Cowen & Co, Infinity Pharmaceuticals, MedImmune (now AstraZeneca), Merck, newMentor, NKT Therapeutics, Ono Pharmaceuticals, Regeneron Pharmaceuticals, Schering-Plough, TEVA Specialty Pharmaceuticals, Gilead Sciences, Johnson & Johnson, and Agenzia Italiana del Farmico; has provided expert testimony for Campbell, Campbell, Edwards & Conroy, Diedrich & Donohue, Ficksman & Conley, Ryan Ryan Deluca LLP, and Sullway & Hollis; has received grants from Aerovance , Amgen, i3 Research (Biota), Genentech, MedImmune, and Novartis; has received payment for lectures from Merck, the Spanish Society of Allergy & Immunology, the Western Society of Allergy, Asthma & Immunology, and the World Allergy Congress; and has received royalties from UpToDate. R. F. Lemanske has received grants, travel support, and fees for participation in review activities from the NIH; has consultant arrangements with Merck, Sepracor, SA Voney and Associates LTD, GlaxoSmithKline, American Institute of Research, Genentech, Double Helix Development, and Boehringer Ingelheim; is employed by the University of Wisconsin School of Medicine and Public Health; has received grants from the NHLBI and Pharmaxis; has received payment for lectures from the Michigan Public Health Institute, Allegheny General Hospital, the American Academy of Pediatrics, West Allegheny Health Systems, California Chapter 4 of the American Academy of Pediatrics, the Colorado Allergy Society, the Pennsylvania Allergy and Asthma Association, Harvard Pilgrim Health, the California Society of Allergy, the New York City Allergy Society, the World Allergy Organization, the American College of Chest Physicians, and the APAPARi; has received payment for manuscript preparation from the American Academy of Allergy, Asthma & Immunology; and has received royalties from Elsevier and UpToDate. S. J. Szefler has received grants, travel support, payment for participation in review activities, and payment for writing or reviewing the manuscript from the NHLBI; has consultant arrangements with Merck, Genentech, Boehringer Ingelheim, and GlaxoSmithKline; has received grants from GlaxoSmithKline; has received payment for lectures from Merck; has received payment for manuscript preparation from Genentech; and has a submitted patent for a β-adrenergic receptor polymorphism for the CARE Network. S. I. Wasserman has received grants from the NIH and the American Lung Association, is President of the American Board of Allergy and Immunology, and has provided expert testimony for Scharf, Banks, Marmor in Chicago, Illinois. S. P. Peters has received grants from the NIH and the NHLBI; has consultant arrangements with AstraZeneca, Aerocrine, Airsonett, AB, GlaxoSmithKline, Merck, Targacept, and TEVA; has received payment for lectures from Integrity CE and Merck; and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest. ",
year = "2013",
month = aug,
doi = "10.1016/j.jaci.2013.01.051",
language = "English (US)",
volume = "132",
pages = "313--320.e15",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "2",
}