Resequencing Study Con fi rms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fi brosis, a progressive fi brotic 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 betweendiseaseand 1 )individualcommonvariantsvialogisticregression and 2 ) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically signi fi cant 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% con fi dence interval, 4.91 – 6.06) for one copyoftheriskalleleand18.68(95%con fi denceinterval,13.34 – 26.17)for twocopiesoftheriskallele( P =9.60 3 10 2 295 ).Inadditiontoidentifying forthe fi rsttimethatrarevariationin FAM13A isassociatedwithdisease, we con fi rmed 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 fi brosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. S.D.N., D.C.V., M.L.W., N.K., J.A.d.A., T.L., T.K., F.B., S.C.D., A.M., M.E.A., A.A., R.G.C., T.W., M.B., G.L., S.B., C.P., and F.P. provided data and samples. S.K.M., M.I.S., M.P.S, J.L., K.K.B., J.E.L., and D.A.S. coordinated the clinical evaluations and integrated the findings with clinical aspects of idiopathic pulmonary fibrosis. I.V.Y. and A.W. supervised and coordinated the laboratory work. A.W. performed the DNA preparation. D.A.N. supervised the targeted resequencing. K.B.B. supervised the AIMS genotyping. T.E.F. and D.A.S. developed the conceptual approaches to data analysis, and T.E.F. planned and supervised the analysis. C.M., R.Z.B., P.R., B.V., and J.C. performed the data cleaning and analysis. C.M., R.Z.B., T.E.F., and D.A.S. wrote the manuscript.