TY - JOUR
T1 - Utility of whole genome sequencing in assessing risk and clinically relevant outcomes for pulmonary fibrosis
AU - Zhang, David
AU - Newton, Chad A.
AU - Wang, Binhan
AU - Povysil, Gundula
AU - Noth, Imre
AU - Martinez, Fernando J.
AU - Raghu, Ganesh
AU - Goldstein, David
AU - Garcia, Christine Kim
N1 - Publisher Copyright:
Copyright ©The authors 2022.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
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U2 - 10.1183/13993003.00577-2022
DO - 10.1183/13993003.00577-2022
M3 - Article
C2 - 36028256
AN - SCOPUS:85144598636
SN - 0903-1936
VL - 60
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 6
M1 - 2200577
ER -