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