title: 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.
authors.affiliation: School of Paediatrics and Child Health, University of Western Australia, GPO Box D184, Perth, WA 6840, Australia.
authors.forename: Joelene A
authors.initials: JA
authors.lastname: Bizzintino
authors.forename: Siew-Kim
authors.initials: SK
authors.lastname: Khoo
authors.forename: Guicheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Martin
authors.forename: Kristina
authors.initials: K
authors.lastname: Rueter
authors.forename: Gary C
authors.initials: GC
authors.lastname: Geelhoed
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Laing
authors.forename: Peter N
authors.initials: PN
authors.lastname: Le Souëf
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hayden
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003545:Cysteine / Q000096:biosynthesis*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D017999:Leukotriene E4 / Q000652:urine; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018077:Receptors, Leukotriene / Q000235:genetics*
chemical_list: D015289:Leukotrienes; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D017999:Leukotriene E4; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D003545:Cysteine; C083169:leukotriene D4 receptor