Leukotriene pathway polymorphisms are associated with altered cysteinyl leukotriene production in children with acute asthma.

ABSTRACT

Cysteinyl leukotrienes (cysLTs) are pro-inflammatory mediators with increasing evidence for a role in childhood acute asthma. This study examined the influence of polymorphisms in cysLT pathway genes on urinary leukotriene E(4) (uLTE(4)) levels and clinical status in acute asthmatic children. Children aged 2-16 years were recruited during an asthma attack (n=205). Where possible, asthma severity scores were assigned, ALOX5AP G-336A, ALOX5 G-1708A, LTC4S A-444C and G-1072A, GPX4 C718T, and CYSTLTR1 T927C genotypes were determined and uLTE(4) was measured in acute and convalescent samples. uLTE(4) levels were higher acutely compared with convalescence (acute GM 115.7pg/mg creatinine; 95% CI 88.6-151.1, convalescence GM 66.4pg/mg creatinine; 95% CI 51.5-85.6; n=50 paired samples, p=0.003) and paired sample analysis showed genotype-specific effects with significantly increased uLTE(4) for LTC(4)S-444AA (acute GM 127.9pg/mg creatinine; 95% CI 91.8-178.3, convalescence GM 68.2pg/mg creatinine; 95% CI 50.5-92.0; n=32, p=0.002), LTC(4)S-1072 GG (acute GM 126.7pg/mg creatinine; 95% CI 95.4-168.3, convalescence GM 78.9pg/mg creatinine; 95% CI 59.7-104.1; n=39, p=0.019) and CYSLTR1 927 TT/T_ (acute GM 96.8pg/mg creatinine; 95% CI 73.8-126.9, convalescence GM 62.4pg/mg creatinine; 95% CI 46.8-83.3; n=28, p=0.036) but not AC/CC, GA/AA, or TC/CC/C_, respectively. When we compared the allele frequencies of the CYSLTR1 SNP between asthmatics and non-asthmatics, the 927C allele was found to be a risk allele for asthma (OR=2.13, 95% CI 1.06-4.26, p=0.033). Genotypes were not associated with acute or convalescent uLTE(4) levels alone and neither the SNPs nor uLTE(4) correlated with acute asthma severity. Leukotriene pathway gene polymorphisms may influence the magnitude of cysLT production during an attack, yet their influence alone may not be substantial enough to alter the severity of exacerbations.