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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:132

Article

Li, Xingnan¹  Hawkins, Gregory A.¹  Ampleford, Elizabeth J.¹  Moore, Wendy C.¹  Li, Huashi¹  Hastie, Annette T.¹  Howard, Timothy D.¹  Boushey, Homer A.²  Busse, William W.³  Calhoun, William J.⁴  Castro, Mario⁵  Erzurum, Serpil C.⁶  Israel, Elliot^7,8  Lemanske, Robert F., Jr.⁹  Szefler, Stanley J.¹⁰  Wasserman, Stephen I.¹¹  Wenzel, Sally E.¹²  Peters, Stephen P.¹  Meyers, Deborah A.¹  Bleecker, Eugene R.¹ 

[1] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA

[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[3] Univ Wisconsin, Dept Med, Madison, WI 53706 USA

[4] Univ Texas Med Branch Galveston, Dept Internal Med, Galveston, TX USA

[5] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[6] Lerner Res Inst, Cleveland, OH USA

[7] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Boston, MA USA

[9] Univ Wisconsin, Sch Med & Publ Hlth, Ctr Clin Sci, Madison, WI 53706 USA

[10] Natl Jewish Hlth, Dept Pediat, Denver, CO USA

[11] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[12] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA

关键词: Lung function;    FEV1;    asthma;    T(H)1;    IL12A;    IL12RB1;    STAT4;    IRF2;   

DOI  :  10.1016/j.jaci.2013.01.051

来源: Elsevier

【 摘 要 】

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 [ppFEV(1)], 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 ppFEV(1) (P < 10(-4)) belong to the T(H)1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 T(H)1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV(1) values in 4 populations (P = 3 x 10(-11)). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 x 10(-7)) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. T(H)2 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. T(H)1 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.

【 授权许可】

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