Polymorphisms in candidate genes for the nitric oxide pathway in sickle cell patients with acute chest syndrome and asthma

Sickle cell disease (SCD) is one of the most common genetic diseases, affecting one in 600 African Americans. Acute chest syndrome (ACS) is the leading cause of mortality and the second most common cause of hospitalizations in patients with SCD accounting for nearly half of premature deaths. A number of recent studies have reported that asthma may increase the risk of ACS in children with sickle cell disease. Nitric oxide is thought to play a key role in the pathogenesis of ACS. The main objectives of this study were to test the hypotheses that polymorphisms in candidate genes; Arginase 1, nitric oxide synthase (NOS) genes; NOS1 and NOS3, associate with ACS in SCD patients and to characterize the association between physician-diagnosed asthma and ACS. A total of 134 participants between 5-21 years of age with SCD were enrolled. Associations between acute chest syndrome and asthma with the following polymorphisms were explored: the AAT in intron 13 (formerly intron 20) of the NOS1; T-786C and G894T and the repeat polymorphism in intron 4 of NOS3; and ARG I Pvu polymorphism. African Americans (n=74) comprised a cohort of healthy controls owing to non-Hardy-Weinberg equilibrium (HWE) in some variants.;Physician-diagnosed asthma was determined by chart review, parental report, and medication use. Eighty five percent of participants with asthma had at least on episode of ACS compared to 14.6% of participants without ACS; adjusted odds ratio (OR) (95%CI) 5.46 (2.20,13.5), P = < 0.0001. Physician-diagnosed asthma correlated with the number of episodes of ACS (P < 0.001). The NOS1 AAT repeat polymorphism associated with the risk of ACS (P = 0.001) in patients without physician-diagnosed asthma. No associations were found between the NOS3 T-786C polymorphism and ACS. Carriers of the ARG I minor allele were less likely to have asthma, 22/79 (28%) compared to WT homozygotes 6/47 (13%); p = 0.04.;Findings from this study suggest that asthma is a major risk factor for ACS. The NOS1 AAT repeat polymorphism may contribute to ACS in SCD patients without asthma. Studies that further characterize the association between asthma, ACS, and NOS genes in children with sickle cell disease are warranted.