Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

• Klíčová slova
• TOPMed, genetic association studies, interstitial lung disease, telomerase, whole-genome sequencing,
• MeSH
• exom MeSH
• idiopatická plicní fibróza * genetika   MeSH
• lidé MeSH
• sekvenování celého genomu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

• Klíčová slova
• disease risk alleles, genetic variants, idiopathic pulmonary fibrosis, rare variants, targeted resequencing,
• MeSH
• ABC transportéry genetika   MeSH
• celogenomová asociační studie MeSH
• DNA-helikasy genetika   MeSH
• exoribonukleasy genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetická variace MeSH
• idiopatická plicní fibróza genetika   MeSH
• interakce hostitele a patogenu genetika   MeSH
• lidé MeSH
• logistické modely MeSH
• mucin 5B genetika   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protein A asociovaný s plicním surfaktantem genetika   MeSH
• protein C asociovaný s plicním surfaktantem genetika   MeSH
• proteiny aktivující GTPasu genetika   MeSH
• proteiny vázající telomery genetika   MeSH
• RNA genetika   MeSH
• sekvenční analýza DNA MeSH
• stárnutí buněk genetika   MeSH
• studie případů a kontrol MeSH
• telomerasa genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCA3 protein, human MeSH Prohlížeč
• DNA-helikasy MeSH
• exoribonukleasy MeSH
• FAM13A protein, human MeSH Prohlížeč
• MUC5B protein, human MeSH Prohlížeč
• mucin 5B MeSH
• poly(A)-specific ribonuclease MeSH Prohlížeč
• protein A asociovaný s plicním surfaktantem MeSH
• protein C asociovaný s plicním surfaktantem MeSH
• proteiny aktivující GTPasu MeSH
• proteiny vázající telomery MeSH
• RNA MeSH
• RTEL1 protein, human MeSH Prohlížeč
• SFTPA2 protein, human MeSH Prohlížeč
• SFTPC protein, human MeSH Prohlížeč
• telomerasa MeSH
• telomerase RNA MeSH Prohlížeč
• TERT protein, human MeSH Prohlížeč
• TINF2 protein, human MeSH Prohlížeč