Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis

Global IPF Consortium

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Abstract

RATIONALE: Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.

OBJECTIVE: 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 controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test.

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 OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 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 risk of IPF in the TERT and RTEL1 gene regions, 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; these genetic variants focus on biological mechanisms of host defense and cell senescence.

Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
DOIs
Publication statusAccepted/In press - 29 Apr 2019

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Idiopathic Pulmonary Fibrosis
Cell Aging
Genes
Alleles
Genome-Wide Association Study
Logistic Models
Lung
DNA

Cite this

@article{22a6703656094f619fa80ae7d65a2963,
title = "Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis",
abstract = "RATIONALE: Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.OBJECTIVE: 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 controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test.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 OR of 5.45 (95{\%} CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95{\%} CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 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 risk of IPF in the TERT and RTEL1 gene regions, 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; these genetic variants focus on biological mechanisms of host defense and cell senescence.",
author = "{Global IPF Consortium} and Camille Moore and Blumhagen, {Rachel Z} and Yang, {Ivana V} and Avram Walts and Julie Powers and Tarik Walker and Makenna Bishop and Pamela Russell and Brian Vestal and Jonathan Cardwell and Markin, {Cheryl R} and Mathai, {Susan K} and Schwarz, {Marvin I} and Steele, {Mark P} and Joyce Lee and Brown, {Kevin K} and Loyd, {James E} and Crapo, {James D} and Silverman, {Edwin K} and Cho, {Michael H} and James, {Judith A} and Guthridge, {Joel M} and Cogan, {Joy D} and Kropski, {Jonathan A} and Swigris, {Jeffrey J} and Carol Bair and {Soon Kim}, Dong and Wonjun Ji and Hocheol Kim and Song, {Jin Woo} and Maier, {Lisa A} and Pacheco, {Karin A} and Nikhil Hirani and Poon, {Azin S} and Feng Li and Jenkins, {R Gisli} and Rebecca Braybrooke and Gauri Saini and Maher, {Toby M} and Molyneaux, {Philip L} and Peter Saunders and Yingze Zhang and Gibson, {Kevin F} and Kass, {Daniel J} and Mauricio Rojas and John Sembrat and Wolters, {Paul J} and Collard, {Harold R} and Sundy, {John S} and Thomas O'Riordan and Strek, {Mary E} and Imre Noth and Shwu-Fan Ma and Porteous, {Mary K} and Kreider, {Maryl E} and Patel, {Namrata B} and Yoshikazu Inoue and Masaki Hirose and Toru Arai and Shinobu Akagawa and Oliver Eickelberg and Fernandez, {Isis Enlil} and J{\"u}rgen Behr and Nesrin Mogulkoc and Corte, {Tamera J} and Ian Glaspole and Sara Tomassetti and Claudia Ravaglia and Venerino Poletti and Bruno Crestani and Raphael Borie and Caroline Kannengiesser and Helen Parfrey and Christine Fiddler and Doris Rassl and Maria Molina-Molina and Carlos Machahua and {Montes Worboys}, Ana and Gunnar Gudmundsson and Isaksson, {Helgi J} and Lederer, {David J} and Podolanczuk, {Anna J} and Montesi, {Sydney B} and Elisabeth Bendstrup and Vivi Danchel and Moises Selman and Annie Pardo and Henry, {Michael T} and Keane, {Michael P} and Peter Doran and Martina Vaš{\'a}kov{\'a} and Martina Sterclova and Ryerson, {Christopher J} and Wilcox, {Pearce G} and Tsukasa Okamoto and Haruhiko Furusawa and Yasunari Miyazaki and Geoffrey Laurent and Svetlana Baltic and Cecilia Prele and Yuben Moodley and Shea, {Barry S} and Ken Ohta and Maho Suzukawa and Osamu Narumoto and Nathan, {Steven D} and Venuto, {Drew C} and Woldehanna, {Merte L} and Nurdan Kokturk and {de Andrade}, {Joao A} and Tracy Luckhardt and Tejaswini Kulkarni and Francesco Bonella and Donnelly, {Seamas C} and Aoife McElroy and Armstrong, {Michelle E} and Alvaro Aranda and Carbone, {Roberto G} and Francesco Puppo and Beckman, {Kenneth B} and Nickerson, {Deborah A} and Fingerlin, {Tasha E} and Schwartz, {David A}",
year = "2019",
month = "4",
day = "29",
doi = "10.1164/rccm.201810-1891OC",
language = "English",
journal = "American Journal of Respiratory Critical Care Medicine",
issn = "1073-449X",
publisher = "AMER THORACIC SOC",

}

TY - JOUR

T1 - Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis

AU - Global IPF Consortium

AU - Moore, Camille

AU - Blumhagen, Rachel Z

AU - Yang, Ivana V

AU - Walts, Avram

AU - Powers, Julie

AU - Walker, Tarik

AU - Bishop, Makenna

AU - Russell, Pamela

AU - Vestal, Brian

AU - Cardwell, Jonathan

AU - Markin, Cheryl R

AU - Mathai, Susan K

AU - Schwarz, Marvin I

AU - Steele, Mark P

AU - Lee, Joyce

AU - Brown, Kevin K

AU - Loyd, James E

AU - Crapo, James D

AU - Silverman, Edwin K

AU - Cho, Michael H

AU - James, Judith A

AU - Guthridge, Joel M

AU - Cogan, Joy D

AU - Kropski, Jonathan A

AU - Swigris, Jeffrey J

AU - Bair, Carol

AU - Soon Kim, Dong

AU - Ji, Wonjun

AU - Kim, Hocheol

AU - Song, Jin Woo

AU - Maier, Lisa A

AU - Pacheco, Karin A

AU - Hirani, Nikhil

AU - Poon, Azin S

AU - Li, Feng

AU - Jenkins, R Gisli

AU - Braybrooke, Rebecca

AU - Saini, Gauri

AU - Maher, Toby M

AU - Molyneaux, Philip L

AU - Saunders, Peter

AU - Zhang, Yingze

AU - Gibson, Kevin F

AU - Kass, Daniel J

AU - Rojas, Mauricio

AU - Sembrat, John

AU - Wolters, Paul J

AU - Collard, Harold R

AU - Sundy, John S

AU - O'Riordan, Thomas

AU - Strek, Mary E

AU - Noth, Imre

AU - Ma, Shwu-Fan

AU - Porteous, Mary K

AU - Kreider, Maryl E

AU - Patel, Namrata B

AU - Inoue, Yoshikazu

AU - Hirose, Masaki

AU - Arai, Toru

AU - Akagawa, Shinobu

AU - Eickelberg, Oliver

AU - Fernandez, Isis Enlil

AU - Behr, Jürgen

AU - Mogulkoc, Nesrin

AU - Corte, Tamera J

AU - Glaspole, Ian

AU - Tomassetti, Sara

AU - Ravaglia, Claudia

AU - Poletti, Venerino

AU - Crestani, Bruno

AU - Borie, Raphael

AU - Kannengiesser, Caroline

AU - Parfrey, Helen

AU - Fiddler, Christine

AU - Rassl, Doris

AU - Molina-Molina, Maria

AU - Machahua, Carlos

AU - Montes Worboys, Ana

AU - Gudmundsson, Gunnar

AU - Isaksson, Helgi J

AU - Lederer, David J

AU - Podolanczuk, Anna J

AU - Montesi, Sydney B

AU - Bendstrup, Elisabeth

AU - Danchel, Vivi

AU - Selman, Moises

AU - Pardo, Annie

AU - Henry, Michael T

AU - Keane, Michael P

AU - Doran, Peter

AU - Vašáková, Martina

AU - Sterclova, Martina

AU - Ryerson, Christopher J

AU - Wilcox, Pearce G

AU - Okamoto, Tsukasa

AU - Furusawa, Haruhiko

AU - Miyazaki, Yasunari

AU - Laurent, Geoffrey

AU - Baltic, Svetlana

AU - Prele, Cecilia

AU - Moodley, Yuben

AU - Shea, Barry S

AU - Ohta, Ken

AU - Suzukawa, Maho

AU - Narumoto, Osamu

AU - Nathan, Steven D

AU - Venuto, Drew C

AU - Woldehanna, Merte L

AU - Kokturk, Nurdan

AU - de Andrade, Joao A

AU - Luckhardt, Tracy

AU - Kulkarni, Tejaswini

AU - Bonella, Francesco

AU - Donnelly, Seamas C

AU - McElroy, Aoife

AU - Armstrong, Michelle E

AU - Aranda, Alvaro

AU - Carbone, Roberto G

AU - Puppo, Francesco

AU - Beckman, Kenneth B

AU - Nickerson, Deborah A

AU - Fingerlin, Tasha E

AU - Schwartz, David A

PY - 2019/4/29

Y1 - 2019/4/29

N2 - RATIONALE: Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.OBJECTIVE: 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 controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test.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 OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 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 risk of IPF in the TERT and RTEL1 gene regions, 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; these genetic variants focus on biological mechanisms of host defense and cell senescence.

AB - RATIONALE: Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.OBJECTIVE: 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 controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test.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 OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 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 risk of IPF in the TERT and RTEL1 gene regions, 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; these genetic variants focus on biological mechanisms of host defense and cell senescence.

U2 - 10.1164/rccm.201810-1891OC

DO - 10.1164/rccm.201810-1891OC

M3 - Article

JO - American Journal of Respiratory Critical Care Medicine

JF - American Journal of Respiratory Critical Care Medicine

SN - 1073-449X

ER -