Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence

Background: Inducible nitric oxide (NO) synthase (iNOS, encoded by NOS2A) produces NO in response to environmental stimuli, which can result in nitrosative stress. Because nitrosative stress affects respiratory health, we hypothesized that variants in NOS2A are associated with asthma incidence and lung function growth during adolescence. Method: In this prospective study, spirometric testing was performed at school and a presence or abscence of asthma was ascertained annually by questionnaire among children participating in the southern California Children’s Health Study. We genotyped 24 SNPs of the NOS2A region (with 7 promoter SNPs in one haplotype block), spanning 20kb upstream and 10kb downstream. Association between the NOS2A region and asthma or lung function growth was tested using genetic block-specific principal component and haplotype analyses. This study was restricted to children with Latino and Caucasian ancestry for analyses of both asthma (N=1,596) and lung function growth (N=2,108). Result: A pair of "yin-yang"; haplotypes in the promoter region showed strong association with new-onset asthma and lung function growth. The "yin" haplotype (H0111101) was associated with 44% increased asthma risk (p-value=0.003) and reduced FEV1 growth from 10-18 years of age (-29.46 ml, p-value=0.07), whereas, the "yang"; (H1000010) haplotype was associated with 23% reduced asthma risk (p-value=0.13) and better FEV1 growth (43.84 ml, p-value=0.01). Furthermore, the increased asthma risk associated with H0111101 was restricted to children with GSTM1 "null" genotype (interaction p-value=0.002, HR, 1.89, 95%CI, 1.34-2.60). Conclusion: Common haplotypes in the NOS2A promoter are associated with new-onset asthma and lung function growth. These effects are stronger in adolescents with the GSTM1 ‘null’ genotype.