Abstract
Background 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.
Methods In this observational cohort study, we performed WGS on 949 patients with idiopathic pulmonary fibrosis or familial pulmonary fibrosis to determine rare and common variant genotypes, estimate telomere length and assess the association of genomic factors with clinical outcomes.
Results 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 had a greater effect on telomere length than a polygenic risk score calculated using 20 common variants previously associated with telomere length. The common variant polygenic risk score predicted telomere length only in sporadic disease. Reduced transplant-free survival was associated with rare qualifying variants, shorter quantitative PCR-measured telomere lengths and absence of the MUC5B promoter (rs35705950) single nucleotide polymorphism, but not with WGS-estimated telomere length or the common variant polygenic risk score. Disease progression was associated with both measures of telomere length (quantitative PCR measured and WGS estimated), rare qualifying variants and the common variant polygenic risk score.
Conclusion As a single test, WGS can inform pulmonary fibrosis genetic-mediated risk, evaluate the functional effect of telomere-related variants by estimating telomere length, and prognosticate clinically relevant disease outcomes.
Abstract
Whole genome sequencing yields rare and common variant genotypes and telomere length estimation to characterise disease risk and provide prognostic information regarding survival and progression for pulmonary fibrosis patients. https://bit.ly/3A8uVBe
Footnotes
Author contributions: Study design: C.K. Garcia, D. Zhang; patient recruitment or data sharing: C.K. Garcia, C.A. Newton, I. Noth, F.J. Martinez, G. Raghu; genetic analysis : D. Zhang, G. Povysil, B. Wang; clinical analyses: C.A. Newton; interpretation of results: D. Zhang, C.A. Newton, D. Goldstein, C.K. Garcia; manuscript preparation: D. Zhang, C.K. Garcia. All authors contributed to the manuscript review and approved the submitted draft.
Conflict of interest: D. Zhang has received consulting fees from Boehringer Ingelheim and is supported by grants from the Stony Wold-Herbert Fund and the NHLBI (HL105323). C.A. Newton has received consulting fees from Boehringer Ingelheim and is supported by a career development award from the NHLBI. I. Noth has received consulting fees from Boehringer Ingelheim, Genentech and Sanofi-Aventis. F.J. Martinez reports grants from the NIH/NHLBI, Afferent/Merck, Bayer, Biogen, Nitto, Patara/Respivant, Promedior/Roche and Veracyte; consulting fees from Abvie, Boehringer Ingelheim, BMS, Bridge Biotherapeutics, CSL Behring, DevPro, Genentech, IQVIA, Lung Therapeutics, Sanofi, Shionogi, twoXAR and Veracyte; travel support from Boehringer Ingelheim, CSL Behring and Patara/Respivant; participation on advisory boards for Biogen and Boehringer Ingelheim; and honoraria from United Therapeutics. D. Goldstein is an employee of Actio Biosciences; La Jolla, CA, USA. C.K. Garcia reports support from NIH, the Department of Defense and Boehringer Ingelheim outside the scope of this work, lecture honoraria from Three Lakes Foundation and Stanford University, and other support from AstraZeneca. B. Wang, G. Povysil and G. Raghu have nothing to disclose.
Support statement: National Institutes of Health grant support include R01HL093096 (C.K. Garcia), K23HL148498 and UL1TR001105 (C.A. Newton), Stony Wold-Herbert Fund and T32HL105323 (D. Zhang). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 28, 2022.
- Accepted August 12, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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