Utility of whole genome sequencing in assessing risk and clinically-relevant outcomes for pulmonary fibrosis.

Whole genome sequencing (WGS) can detect variants and estimate telomere length. The clinical utility of WGS in estimating risk, progression, and survival of pulmonary fibrosis patients is unknown. In this observational cohort study, we performed WGS on 949 idiopathic pulmonary fibrosis or familial pulmonary fibrosis patients to determine rare and common variant genotypes, estimate telomere length, and assess the association of genomic factors with clinical outcomes. WGS estimates of telomere length correlated with quantitative PCR (R=0.65) and Southern blot (R=0.71) measurements. Rare, deleterious, qualifying variants were found in 14% of the total cohort, with a five-fold increase in those with a family history of disease versus those without (25% versus 5%). Most rare qualifying variants (85%) were found in telomere-related genes and were associated with shorter telomere lengths. Rare qualifying variants have a greater effect on telomere length than a polygenic risk score (PRS) calculated using 20 common variants previously associated with telomere length. The common variant PRS predicted telomere length only in sporadic disease. Reduced transplant-free survival was associated with rare qualifying variants, shorter qPCR-measured telomere lengths, and the absence of MUC5B promoter (rs35705950) SNP, but not with WGS-estimated telomere length or the common variant PRS. Disease progression was associated with both measures of telomere length (qPCR-measured and WGS-estimated), rare qualifying variants, and the common variant PRS. As a single test, WGS can inform pulmonary fibrosis genetic-mediated risk, evaluate functional effect of telomere-related variants by estimating telomere length, and prognosticate clinically relevant disease outcomes.