Dataset Information

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.

SUBMITTER: Li X

PROVIDER: S-EPMC3746327 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Li Xingnan X Hawkins Gregory A GA Ampleford Elizabeth J EJ Moore Wendy C WC Li Huashi H Hastie Annette T AT Howard Timothy D TD Boushey Homer A HA Busse William W WW Calhoun William J WJ Castro Mario M Erzurum Serpil C SC Israel Elliot E Lemanske Robert F RF Szefler Stanley J SJ Wasserman Stephen I SI Wenzel Sally E SE Peters Stephen P SP Meyers Deborah A DA Bleecker Eugene R ER

The Journal of allergy and clinical immunology 20130328 2

<h4>Background</h4>Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.<h4>Objective</h4>We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.<h4>Methods</h4>Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were ...[more]

PMID: 23541324

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Project description:BackgroundSystemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE.MethodsA two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed.ResultsIn the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies.ConclusionsThe present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.

Dataset Information

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

Background

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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