LAUSR

Background Increased nitric oxide (NO) and its generating enzyme, inducible nitric oxide synthase (iNOS), are observed in experimental models of idiopathic pulmonary fibrosis (IPF). Asymmetric dimethylarginine (ADMA) competitively inhibits iNOS and is hydrolysed by dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. Modulation of NO bioavailability via pharmacological/genetic knock-out of DDAH1 attenuates bleomycin-induced fibrosis in vivo. Using a candidate gene approach with an a priori hypothesis, we investigated the impact of DDAH1 variants associated with lower ADMA (thus indicative of DDAH1 over-activity) on lung function decline and survival in IPF. Methods Consecutive patients with a new diagnosis IPF were recruited from a tertiary UK ILD centre (n=70). Only Caucasian individuals were included, patients on anti-fibrotic agents were excluded. Clinical end points were: time to first FVC decline (≥10% relative change in FVC from baseline) and survival (months survived following presentation). DDAH1 tSNPs were identified in Caucasian individuals genotyped in the International HapMap Project. Those with minor allele frequency >40% in the IPF cohort and an association with lower ADMA levels in a normal cohort were selected – rs530006 and rs6576765. Survival curves and stepwise multivariate Cox proportional hazards analyses were performed. Results Baseline pulmonary function did not vary between genotypes. FVC decline differed between rs530006 genotypes (p<0.0039*, median months: GG 34.5; GT 38.6; TT 13.7) [figure 1], with minor homozygote carriage (p<0.0009*, HR 4.68, 95% CI 1.88 to 11.65) and remained significant on multivariate analysis (p<0.001*). Survival differed between rs530006 genotypes (p<0.0418*, median months: GG 42.4; GT 57.2; TT 26.0), with minor homozygote carriage (p<0.0118*, HR 2.43, 95% CI 1.22 to 4.86) and trended towards significance on multivariate analysis (p<0.054). FVC decline differed between rs6576765 genotypes (p<0.0249*, median months TT 20.7; TA 38.6; AA 33.4), with major homozygote carriage (p<0.0075*, HR 2.58, 95% CI 1.29 to 5.15) and on multivariate analysis (p<0.014*). Survival did not significantly differ between rs6576765 genotypes. Abstract S141 Figure 1. Time to first FVC decline (months taken for ≥10% relative change in FVC from baseline) by carriage of DDAH1 variant rs530006 genotypes; p<0.0039* (Mantel-Cox log-rank test) Conclusion Minor homozygote carriage of DDAH1 variant rs530006 was associated with accelerated disease progression and mortality in IPF. These findings require validation in a larger, replicate cohort of IPF patients. Identification of aggressive disease phenotypes may allow risk stratification and earlier therapeutic intervention in IPF.