US EPA

2268241 

Journal Article 

Abstract 

Characterizing the genetic architecture of fractional exhaled nitric oxide (FeNO) levels in the Hutterites 

Thompson, E; Kuldanek, S; Du, G; Ober, C 

2010 

Yes 

American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 

181 

A3730 

English 

10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A3730 

WOS:000208771003087 

is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans

Rationale: Elevated levels of FeNO are a measure of airway inflammation. The purpose of this study was to characterize the genetic architecture of this phenotype, in a population that is well characterized with respect to asthma and allergic phenotypes. This constitutes the first population-based study of the genetic basis of FeNO.

Methods: We measured FeNO, total serum IgE and lung function, and performed skin prick allergen tests (SPT) and studies of bronchial hyperresponsiveness (BHR) to methacholine in 846 Hutterites, a founder population of European descent. Participants in our studies ranged in age from 6 to 85 years, and are related to each other in a single 13-generation, 3635-person pedigree. We estimated the heritability of FeNO using variance component analysis, and then performed a genome-wide association study (GWAS) using Affymetrix GeneChip® Mapping Arrays. We used a test of association that takes into account the relatedness between all pairs of Hutterites; thresholds for genome-wide and suggestive significance were determined by a permutation test.

Results: Levels of FeNO were significantly correlated with total serum IgE levels (P= 5.8 x 10^-8), BHR (P =0.024) and asthma (P =0.017), but not with percent predicted FEV1 (P >0.1). FeNO was significantly heritable, H^2 =0.43 (s.e.= 0.07), indicating that 43% of the variance in FeNO in the Hutterites is due to genetic differences between individuals. Moreover, there is a significant contribution from the X chromosome in males only, indicating a sex-specific genetic architecture. Four SNPs met criteria for suggestive significance. The strongest association signal was with a SNP on chromosome 11 (P=3.56 x 10^-6), 67 kb downstream of the gene, which encodes a transcription factor ETS1 involved in inflammatory pathways and Th cell differentiation.

Conclusions: This study of FeNO in a population-based sample revealed significant genetic architecture, with sex-specific contributions, and implicates ETS1 as a modulator of FeNO, a marker of airway inflammation. Additional studies of variation in this gene and its role in allergic sensitization and asthma in the Hutterites are underway. 

American Thoracic Society 2010 International Conference 

New Orleans, LA 

May 14-19, 2010