Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Abstract

Background: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes.

Objective: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.

Methods: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110).

Results: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.

Conclusion: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.

Keywords: Airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study.

Figure I. Study design

SNPs, single nucleotide polymorphisms; LD, linkage disequilibrium; eQTLs, expression quantitative trait loci; LCLs, lymphoblastoid cell lines.

Figure II. QQ and Manhattan plots of 2,253,077 SNPs of 14 GWA studies (N = 8,858)

QQ plot of 2,253,077 SNPs of 14 GWA studies. The black dots represent observed P values and the red line represents the expected P values under the null distribution. Manhattan plot showing the association P values of FeNO of the 14 studies. The –log₁₀ of the P value for each of 2,253,077 SNPs (y-axis) is plotted against the genomic position (x-axis).

Figure III. Association plots of the 17q11.2-q12 and 17q12-q21 regions

For both the 17q11.2-q12 and 17q12-q21 regions, SNPs are plotted with their P values (as –log₁₀ values; left y-axis) as a function of genomic position (x-axis). Estimated recombination rates (right y-axis) taken from HapMap are plotted to reflect the local LD structure around the top associated SNP (purple circle) and their correlated proxies (according to a blue to red scale from r² = 0 to 1). Triangles represent nonsynonymous SNPs.

Figure IV. Forest plots of the associations between FeNO and the 3 SNPs associated with FeNO at P < 5 × 10⁻⁸

Forest plots of the associations between FeNO and the SNPs in LYRM9 (a), NOS2 (b) and near ZPBP2-GSDMB (c) at P < 5×10⁻⁸. In each plot, the triangle indicates the effect size and the confidence interval in the 14 studies. The P values in the plots are without genomic control correction.