Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients

Xingnan Li, Gregory A. Hawkins, Elizabeth J. Ampleford, Wendy C. Moore, Huashi Li, Annette T. Hastie, Timothy D. Howard, Homer A. Boushey, William W. Busse, William Calhoun, Mario Castro, Serpil C. Erzurum, Elliot Israel, Robert F. Lemanske, Stanley J. Szefler, Stephen I. Wasserman, Sally E. Wenzel, Stephen P. Peters, Deborah A. Meyers, Eugene R. Bleecker

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume132
Issue number2
DOIs
StatePublished - Aug 2013

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Genome-Wide Association Study
Lung
Asthma
Genes
Population
Single Nucleotide Polymorphism
Vital Capacity
Meta-Analysis
Airway Remodeling
Population Control
Interleukin-13
Virus Diseases
Interleukin-12
Bacterial Infections
Linear Models
Pneumonia
Cytokines
Research

Keywords

  • asthma
  • FEV
  • IL12A
  • IL12RB1
  • IRF2
  • Lung function
  • STAT4
  • T1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. / Li, Xingnan; Hawkins, Gregory A.; Ampleford, Elizabeth J.; Moore, Wendy C.; Li, Huashi; Hastie, Annette T.; Howard, Timothy D.; Boushey, Homer A.; Busse, William W.; Calhoun, William; Castro, Mario; Erzurum, Serpil C.; Israel, Elliot; Lemanske, Robert F.; Szefler, Stanley J.; Wasserman, Stephen I.; Wenzel, Sally E.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.

In: Journal of Allergy and Clinical Immunology, Vol. 132, No. 2, 08.2013.

Research output: Contribution to journalArticle

Li, X, Hawkins, GA, Ampleford, EJ, Moore, WC, Li, H, Hastie, AT, Howard, TD, Boushey, HA, Busse, WW, Calhoun, W, Castro, M, Erzurum, SC, Israel, E, Lemanske, RF, Szefler, SJ, Wasserman, SI, Wenzel, SE, Peters, SP, Meyers, DA & Bleecker, ER 2013, 'Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients', Journal of Allergy and Clinical Immunology, vol. 132, no. 2. https://doi.org/10.1016/j.jaci.2013.01.051
Li, Xingnan ; Hawkins, Gregory A. ; Ampleford, Elizabeth J. ; Moore, Wendy C. ; Li, Huashi ; Hastie, Annette T. ; Howard, Timothy D. ; Boushey, Homer A. ; Busse, William W. ; Calhoun, William ; Castro, Mario ; Erzurum, Serpil C. ; Israel, Elliot ; Lemanske, Robert F. ; Szefler, Stanley J. ; Wasserman, Stephen I. ; Wenzel, Sally E. ; Peters, Stephen P. ; Meyers, Deborah A. ; Bleecker, Eugene R. / Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. In: Journal of Allergy and Clinical Immunology. 2013 ; Vol. 132, No. 2.
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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.",
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AU - Li, Xingnan

AU - Hawkins, Gregory A.

AU - Ampleford, Elizabeth J.

AU - Moore, Wendy C.

AU - Li, Huashi

AU - Hastie, Annette T.

AU - Howard, Timothy D.

AU - Boushey, Homer A.

AU - Busse, William W.

AU - Calhoun, William

AU - Castro, Mario

AU - Erzurum, Serpil C.

AU - Israel, Elliot

AU - Lemanske, Robert F.

AU - Szefler, Stanley J.

AU - Wasserman, Stephen I.

AU - Wenzel, Sally E.

AU - Peters, Stephen P.

AU - Meyers, Deborah A.

AU - Bleecker, Eugene R.

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N2 - 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.

AB - 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.

KW - asthma

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KW - IRF2

KW - Lung function

KW - STAT4

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