The nuclear factor I/A (NFIA) gene is associated with the asthma plus rhinitis phenotype

Abstract

Background: A previous genome-wide linkage scan in 295 families of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) showed strong evidence of linkage of the 1p31 region to the combined asthma plus allergic rhinitis (AR) phenotype.

Objective: Our purpose was to conduct fine-scale mapping of the 1p31 linkage region to identify the genetic variants associated with asthma plus AR.

Methods: Association analyses with the asthma plus rhinitis phenotype were first conducted in the EGEA family sample using the family-based association method (FBAT) and logistic regression. The test of homogeneity of association between asthma plus AR versus asthma alone or AR alone was also applied. Replication of EGEA findings was sought in French-Canadian and United Kingdom family samples.

Results: We found a significant association between asthma plus rhinitis and a 1p31 genetic variant (P = 2 × 10(-5) for rs12122228, which reached the multiple testing-corrected threshold) in EGEA using FBAT. There was evidence of heterogeneity of association between asthma plus AR versus asthma alone or AR alone (P = .03). A Meta-analysis of FBAT results from EGEA and French-Canadian families improved evidence for both association and heterogeneity (P = 5 × 10(-6) and P = .008, respectively), whereas a meta-analysis of EGEA, French-Canadian, and United Kingdom samples based on logistic regression slightly increased the evidence for heterogeneity.

Conclusion: The single nucleotide polymorphism specifically associated to asthma plus rhinitis is located in the flanking 5' untranslated region of the nuclear factor I/A (NFIA) gene, a strong candidate gene for asthma and AR.

Keywords: Positional cloning; association study; asthma; family sample; family-based association study; logistic regression; rhinitis.