Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients
Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. Genome-wide associ...
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| Published in | Journal of allergy and clinical immunology Vol. 132; no. 2; pp. 313 - 320.e15 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York, NY
Mosby, Inc
01.08.2013
Elsevier Elsevier Limited |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0091-6749 1097-6825 1097-6825 |
| DOI | 10.1016/j.jaci.2013.01.051 |
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| Abstract | Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.
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.
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.
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. |
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| AbstractList | Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.
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.
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.
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. Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.BACKGROUNDRecent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.OBJECTIVEWe sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.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.METHODSGenome-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.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.RESULTSSeven 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.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.CONCLUSIONGenes 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. Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. 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. 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. 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. 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, andZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A,IL12RB1,STAT4, andIRF2) 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 ppFEV1values in 4 populations (P = 3 x 10-11). Genetic scores of these 4 SNPs were associated with ppFEV1values (P = 2 x 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, andIL1RL1) 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. 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. |
| Author | Wasserman, Stephen I. Howard, Timothy D. Wenzel, Sally E. Li, Huashi Szefler, Stanley J. Hastie, Annette T. Castro, Mario Meyers, Deborah A. Hawkins, Gregory A. Lemanske, Robert F. Boushey, Homer A. Israel, Elliot Peters, Stephen P. Moore, Wendy C. Ampleford, Elizabeth J. Busse, William W. Erzurum, Serpil C. Bleecker, Eugene R. Calhoun, William J. Li, Xingnan |
| AuthorAffiliation | b the Department of Medicine, University of California at San Francisco a the Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem d the Department of Internal Medicine, University of Texas Medical Branch at Galveston e the Department of Medicine, Washington University School of Medicine, St Louis h the Clinical Science Center, University of Wisconsin School of Medicine and Public Health, Madison c the Department of Medicine, University of Wisconsin, Madison j the Department of Medicine, University of California at San Diego, La Jolla f the Lerner Research Institute, Cleveland g the Pulmonary and Critical Care Division, Brigham and Women’s Hospital and Harvard Medical School, Boston i the Department of Pediatrics, National Jewish Health, Denver k the Department of Medicine, University of Pittsburgh |
| AuthorAffiliation_xml | – name: g the Pulmonary and Critical Care Division, Brigham and Women’s Hospital and Harvard Medical School, Boston – name: h the Clinical Science Center, University of Wisconsin School of Medicine and Public Health, Madison – name: f the Lerner Research Institute, Cleveland – name: b the Department of Medicine, University of California at San Francisco – name: c the Department of Medicine, University of Wisconsin, Madison – name: e the Department of Medicine, Washington University School of Medicine, St Louis – name: d the Department of Internal Medicine, University of Texas Medical Branch at Galveston – name: k the Department of Medicine, University of Pittsburgh – name: j the Department of Medicine, University of California at San Diego, La Jolla – name: a the Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem – name: i the Department of Pediatrics, National Jewish Health, Denver |
| Author_xml | – sequence: 1 givenname: Xingnan surname: Li fullname: Li, Xingnan email: xinli@wakehealth.edu organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 2 givenname: Gregory A. surname: Hawkins fullname: Hawkins, Gregory A. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 3 givenname: Elizabeth J. surname: Ampleford fullname: Ampleford, Elizabeth J. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 4 givenname: Wendy C. surname: Moore fullname: Moore, Wendy C. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 5 givenname: Huashi surname: Li fullname: Li, Huashi organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 6 givenname: Annette T. surname: Hastie fullname: Hastie, Annette T. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 7 givenname: Timothy D. surname: Howard fullname: Howard, Timothy D. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 8 givenname: Homer A. surname: Boushey fullname: Boushey, Homer A. organization: Department of Medicine, University of California at San Francisco, San Francisco, Calif – sequence: 9 givenname: William W. surname: Busse fullname: Busse, William W. organization: Department of Medicine, University of Wisconsin, Madison, Wis – sequence: 10 givenname: William J. surname: Calhoun fullname: Calhoun, William J. organization: Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Tex – sequence: 11 givenname: Mario surname: Castro fullname: Castro, Mario organization: Department of Medicine, Washington University School of Medicine, St Louis, Mo – sequence: 12 givenname: Serpil C. surname: Erzurum fullname: Erzurum, Serpil C. organization: Lerner Research Institute, Cleveland, Ohio – sequence: 13 givenname: Elliot surname: Israel fullname: Israel, Elliot organization: Pulmonary and Critical Care Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass – sequence: 14 givenname: Robert F. surname: Lemanske fullname: Lemanske, Robert F. organization: Clinical Science Center, University of Wisconsin School of Medicine and Public Health, Madison, Wis – sequence: 15 givenname: Stanley J. surname: Szefler fullname: Szefler, Stanley J. organization: Department of Pediatrics, National Jewish Health, Denver, Colo – sequence: 16 givenname: Stephen I. surname: Wasserman fullname: Wasserman, Stephen I. organization: Department of Medicine, University of California at San Diego, La Jolla, Calif – sequence: 17 givenname: Sally E. surname: Wenzel fullname: Wenzel, Sally E. organization: Department of Medicine, University of Pittsburgh, Pittsburgh, Pa – sequence: 18 givenname: Stephen P. surname: Peters fullname: Peters, Stephen P. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 19 givenname: Deborah A. surname: Meyers fullname: Meyers, Deborah A. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC – sequence: 20 givenname: Eugene R. surname: Bleecker fullname: Bleecker, Eugene R. organization: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC |
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| Copyright | 2013 American Academy of Allergy, Asthma & Immunology 2014 INIST-CNRS Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. Copyright Elsevier Limited Aug 2013 2013 American Academy of Allergy, Asthma & Immunology 2013 |
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| Keywords | ACRN ATS TENOR GWAS TALC asthma SARP ppFVC BASALT FVC Lung function ppFEV1 NHLBI SNP CSGA IRF2 STAT4 LD FEV1 IL12A TH1 IL12RB1 Human Lung disease Immunopathology Respiratory disease Th1 lymphocyte Interferon regulatory factor 2 Asthma 1 Association Immunology Gene T Transcription factor STAT4 FEV T-Lymphocyte Bronchus disease Genetics Obstructive pulmonary disease Genome Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroids Forced vital capacity Linkage disequilibrium National Heart, Lung, and Blood Institute Asthma Clinical Research Network Percent predicted forced vital capacity Genome-wide association study Percent predicted FEV Collaborative Studies on the Genetics of Asthma ppFEV T(H)1 American Thoracic Society Severe Asthma Research Program The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens Best Adjustment Strategy for Asthma in Long Term Single nucleotide polymorphism |
| Language | English |
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| Snippet | Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
We sought to... Background Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.... Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.BACKGROUNDRecent... BACKGROUND: Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.... |
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| SubjectTerms | Asthma Asthma - genetics Asthma - metabolism Asthma - physiopathology Biological and medical sciences Female FEV1 Forced Expiratory Volume - genetics Fundamental and applied biological sciences. Psychology Fundamental immunology genes Genome-Wide Association Study Genomes Humans IL12A IL12RB1 inflammation Interferon Regulatory Factor-2 - genetics Interferon Regulatory Factor-2 - metabolism interleukin-12 Interleukin-12 - genetics Interleukin-12 - metabolism IRF2 loci Lung - metabolism Lung - physiopathology Lung function Male Medical sciences meta-analysis patients Polymorphism, Single Nucleotide Quality control Respiratory Function Tests Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis single nucleotide polymorphism STAT4 STAT4 Transcription Factor - genetics STAT4 Transcription Factor - metabolism Studies TH1 Th1 Cells - immunology Th1 Cells - metabolism variance Vital Capacity - genetics Whites |
| Title | Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients |
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