TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis.

Post hoc exploratory analysis of IPFnet PANTHER-IPF trial (NCT00650091) with replication in INSPIRE and UChicago cohorts. Participants were individuals with idiopathic pulmonary fibrosis who self-reported as non-Hispanic white. Genotyped SNPs in TOLLIP and MUC5B; primary analysis used multivariable Cox regression to test SNP-treatment interactions for a composite endpoint-free survival (death, transplantation, hospitalization, or >10% decline in FVC).

N-acetylcysteine (NAC) therapy; dosage and duration not specified in provided text.

Significant genotype–treatment interaction between NAC and rs3750920 (TOLLIP). In PANTHER, NAC reduced composite endpoint risk in rs3750920 TT genotype (HR 0.14; 95% CI 0.02–0.83; P=0.03) and showed a non-significant trend toward higher risk in rs3750920 CC genotype (HR 3.23; 95% CI 0.79–13.16; P=0.10). Replication in INSPIRE/UChicago showed TT genotype with NAC linked to reduced risk (HR 0.23; 95% CI 0.06–0.93; P=0.04); CT and CC genotypes linked to increased risk (CT: HR 2.18; 95% CI 1.14–4.13; P=0.02; CC: HR 3.11; 95% CI 1.25–7.72; P=0.01). Authors conclude NAC may be efficacious for IPF individuals with rs3750920 TT genotype but associated with harm for rs3750920 CC genotype. A genotype-stratified prospective clinical trial is warranted before recommending off-label NAC for IPF.

Post hoc exploratory analysis; not randomized by genotype, potential genotype-frequency bias; race/ethnicity self-reported; ~50% genetic-consent rate reducing power; small genotype-stratified event counts; replication cohorts had missing hospitalization data and potential disease-stage differences; results may not generalize to all IPF patients.