Male-biased association of endothelial nitric oxide synthase Asp298Glu substitution (NOS3-c.894G/T) with asthma risk and severity

Abstract

Objective

The nitric-oxide pathway plays a crucial role in the pathogeneses of asthma and NOS3-encoded endothelial nitric oxide synthase is one of the main components of the pathway. Variants of NOS3 are known to contribute to asthma development and pathophysiology.

Methods

We investigated the association of NOS3-c.894G/T (rs1799983) with asthma risk and severity by studying frequencies of its genotypes and alleles in 555 asthmatics (93 intermittent, 240 mild, 158 moderate, and 64 severe asthma cases) and 351 control participants using the PCR-FRLP method, logistic regression analysis and generalized ordered logit estimates.

Results

GT genotype (OR_adj: 1.39; CI: 1.04–1.85; p = 0.026), dominant model GT + TT (OR_adj: 1.41; CI: 1.07–1.87; p = 0.015), and T allele (OR_adj: 1.32; CI: 1.05–1.67; p = 0.018) was associated with increased ORs in asthmatics. Also, the frequency of GT + TT (OR_adj: 1.55; CI: 1.01–2.38; p = 0.044) was significantly higher in males. Furthermore, GT genotype (OR_adj: 1.39; CI: 1.04–1.85; p = 0.024), GT + TT (OR_adj: 1.42; CI: 1.07–1.87; p = 0.014), and T allele (OR_adj: 1.32; CI: 1.05–1.66; p = 0.018) in total population and GT + TT (OR_adj: 1.56; CI: 1.02–2.37; p = 0.04) in males were significantly associated with increased risk of severe, moderate, mild, intermittent asthma vs. controls. Also, GT genotype (OR_adj: 1.39; CI: 1.02–1.91; p = 0.039) was significantly more frequent in severe, moderate grades vs. lower severity grades in the total population. Frequencies of GT genotype (OR_adj: 1.77; CI: 1.05–3.00; p = 0.032) and GT + TT (OR_adj: 1.74; CI: 1.04–2.90; p = 0.036) in total population and GT genotype (OR_adj: 2.40; CI: 1.16–4.97; p = 0.018) and GT + TT (OR_adj: 2.30; CI: 1.12–4.74; p = 0.023) in male subpopulation were significantly higher in severe cases compared to lower grades.

Conclusions

NOS3-c.894G/T may be associated with asthma risk and its severer grades, with greater effects in men.

Keywords:

• Lung
• asthma
• endothelial nitric oxide synthase
• rs1799983
• genetic association

Availability of data and materials

All data are available upon formal asking from the corresponding author.

Consent to participate

All participants signed informed consent for participation and the use of data in research.

Disclosure statement

The authors have no competing interests to declare.

Ethics approval

Research protocols were approved by the medical ethics committee of the research council of the National Institute for Medical Research Development, Tehran, Iran (IR-NIMAD-REC-1396-032).

Additional information

Funding

This study was supported by the National Institute for Medical Research Development (NIMAD) of IRAN (Code: 957667).