Candidate gene association analysis on the interaction between SNPs and air pollutants on FeNO in adult patients from the Italian general population

<bold>Background:</bold> Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. <bold>Aim:</bold> The present candidate gene-environment interaction analysis is aimed at identifying SNPs that modify the association between different air pollutants (long- and short-term exposures to NO₂, O₃, PM_2.5 and PM₁₀) and fractional exhaled nitric oxide (FeNO) in adult subjects with asthma. <bold>Methods:</bold> We evaluated phenotypic and genetic data from 258 subjects with ever asthma (age range: 20-66 yrs; female 47.7%) who had been identified from the general population in Verona (Italy) as part of the Gene Environment Interactions in Respiratory Diseases (GEIRD; 2008-2010) survey. With a reparametrized linear regression model, the association of log-transformed FeNO was tested separately for each of the 166 tag-SNP (classified according to the additive genetic model) in 50 candidate genes, adjusting for sex, age and season. For each of the three pairs of genotypes, the difference in slope was tested and the lowest p-value was corrected using Simes’ multiple testing procedure to control the false discovery rate (FDR). <bold>Results:</bold> We recognized an interaction between SNP rs27548 (genotype AA: 99 subjects; AC: 128 subjects; CC: 31 subjects) in phosphodiesterase 4D (PDE4D) gene and long-term exposure to NO₂ (average concentration in 2013-2015) on FeNO (uncorrected p-value: 0.0003; FDR-corrected p-value: 0.045). <bold>Conclusion:</bold> PDE4D gene encodes a hydrolase of cyclic adenosine monophosphate and is a key regulator of airway smooth-muscle contractility. Genetic variants in PDE4D gene are associated with asthma susceptibility.