Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia

被引：86

作者：

Fingerlin, Tasha E. ^{[1
,2
]}

Zhang, Weiming ^{[2
]}

Yang, Ivana V. ^{[3
]}

Ainsworth, Hannah C. ^{[4
,5
]}

Russell, Pamela H. ^{[6
]}

Blumhagen, Rachel Z. ^{[1
,2
]}

Schwarz, Marvin I. ^{[3
]}

Brown, Kevin K. ^{[1
]}

Steele, Mark P. ^{[7
]}

Loyd, James E. ^{[7
]}

Cosgrove, Gregory P. ^{[1
]}

Lynch, David A. ^{[1
]}

Groshong, Steve ^{[1
]}

Collard, Harold R. ^{[8
]}

Wolters, Paul J. ^{[8
]}

Bradford, Williamson Z. ^{[9
]}

Kossen, Karl ^{[9
]}

Seiwert, Scott D. ^{[9
]}

du Bois, Roland M. ^{[10
,11
]}

Garcia, Christine Kim ^{[12
]}

Devine, Megan S. ^{[12
]}

Gudmundsson, Gunnar ^{[13
,14
]}

Isaksson, Helgi J. ^{[13
,14
]}

Kaminski, Naftali ^{[15
]}

Zhang, Yingze ^{[15
]}

Gibson, Kevin F. ^{[15
]}

Lancaster, Lisa H. ^{[7
]}

Maher, Toby M. ^{[10
,11
]}

Molyneaux, Philip L. ^{[10
,11
]}

Wells, Athol U. ^{[10
,11
]}

Moffatt, Miriam F. ^{[10
,11
]}

Selman, Moises ^{[16
]}

Pardo, Annie ^{[17
]}

Kim, Dong Soon ^{[18
]}

Crapo, James D. ^{[1
]}

Make, Barry J. ^{[1
]}

Regan, Elizabeth A. ^{[1
]}

Walek, Dinesha S. ^{[19
]}

Daniel, Jerry J. ^{[19
]}

Kamatani, Yoichiro ^{[20
]}

Zelenika, Diana ^{[21
]}

Murphy, Elissa ^{[3
]}

Smith, Keith ^{[3
]}

McKean, David ^{[3
]}

Pedersen, Brent S. ^{[3
]}

Talbert, Janet ^{[3
]}

Powers, Julia ^{[3
]}

Markin, Cheryl R. ^{[7
]}

Beckman, Kenneth B. ^{[19
]}

Lathrop, Mark ^{[20
,21
]}

机构：

[1] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO USA

[2] Univ Colorado, Dept Biostat & Informat, Aurora, CO USA

[3] Univ Colorado, Sch Med, Dept Med, Aurora, CO USA

[4] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA

[5] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA

[6] Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO USA

[7] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA

[8] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[9] InterMune, Brisbane, CA USA

[10] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[11] Royal Brompton Hosp, Natl Inst Hlth Res, Biomed Res Unit, London SW3 6LY, England

[12] Univ Texas Southwestern, Dept Med, Dallas, TX USA

[13] Landspitali Univ Hosp, Reykjavik, Iceland

[14] Univ Iceland, Fac Med, Reykjavik, Iceland

[15] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA

[16] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico

[17] Univ Nacl Autonoma Mexico, Mexico City 04510, DF, Mexico

[18] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea

[19] Univ Minnesota, Genom Ctr, Minneapolis, MN USA

[20] Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France

[21] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France

[22] Univ Colorado, Sch Med, Dept Immunol, Aurora, CO USA

来源：

BMC GENETICS | 2016年 / 17卷

关键词：

Pulmonary fibrosis; HLA association; Imputation; Gene expression; RNA-Seq; SURFACTANT PROTEIN-C; ENDOPLASMIC-RETICULUM STRESS; MUC5B PROMOTER POLYMORPHISM; GENOTYPE IMPUTATION; ASSOCIATION; MUTATIONS; SUSCEPTIBILITY; RISK; ALVEOLITIS; APOPTOSIS;

D O I：

10.1186/s12863-016-0377-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P-meta = 3.7 x 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 x 10(-7) and DQB1*06:02 P = 6.1 x 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 x 10(-16)). Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.

引用

页数：12

共 53 条

[1]

Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[2]

American Thoracic Society

[3]

European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias, 2002, AM J RESP CRIT CARE, V165, P277, DOI [10.1164/ajrccm.165.2.ats01, DOI 10.1164/AJRCCM.165.2.ATS01]

[4]

MICA polymorphisms and decreased expression of the MICA receptor NKG2D contribute to idiopathic pulmonary fibrosis susceptibility [J].

Aquino-Galvez, Arnoldo ;

Perez-Rodriguez, Martha ;

Camarena, Angel ;

Falfan-Valencia, Ramces ;

Ruiz, Victor ;

Montano, Martha ;

Barrera, Lourdes ;

Sada-Ovalle, Isabel ;

Ramirez, Remedios ;

Granados, Julio ;

Pardo, Annie ;

Selman, Moises .

HUMAN GENETICS, 2009, 125 (5-6) :639-648

[5]

Telomerase mutations in families with idiopathic pulmonary fibrosis [J].

Armanios, Mary Y. ;

Chen, Julian J. -L. ;

Cogan, Joy D. ;

Alder, Jonathan K. ;

Ingersoll, Roxann G. ;

Markin, Cheryl ;

Lawson, William E. ;

Xie, Mingyi ;

Vulto, Irma ;

Phillips, John A., III ;

Lansdorp, Peter M. ;

Greider, Carol W. ;

Loyd, James E. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (13) :1317-1326

[6]

Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls [J].

Arnett, Frank C. ;

Gourh, Pravitt ;

Shete, Sanjay ;

Ahn, Chul W. ;

Honey, Robert E. ;

Agarwal, Sandeep K. ;

Tan, Filemon K. ;

McNearney, Terry ;

Fischbach, Michael ;

Fritzler, Marvin J. ;

Mayes, Maureen D. ;

Reveille, John D. .

ANNALS OF THE RHEUMATIC DISEASES, 2010, 69 (05) :822-827

[7]

Occupational and environmental risk factors for idiopathic pulmonary fibrosis: A multicenter case-control study [J].

Baumgartner, KB ;

Samet, JM ;

Coultas, DB ;

Stidley, CA ;

Hunt, WC ;

Colby, TV ;

Waldron, JA .

AMERICAN JOURNAL OF EPIDEMIOLOGY, 2000, 152 (04) :307-315

[8]

Cigarette smoking: A risk factor for idiopathic pulmonary fibrosis [J].

Baumgartner, KB ;

Samet, JM ;

Stidley, CA ;

Colby, TV ;

Waldron, JA ;

Coultas, DB ;

Davis, GS ;

Garcia, JGN ;

Hunninghake, GW ;

Kallay, MC ;

King, TE ;

Krowka, MJ ;

Rennard, SI ;

Ryu, JH ;

Sherman, CB ;

Smith, LJ ;

Toews, G ;

Winterbauer, RH .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 155 (01) :242-248

[9]

The MUC5B Variant Is Associated with Idiopathic Pulmonary Fibrosis but Not with Systemic Sclerosis Interstitial Lung Disease in the European Caucasian Population [J].

Borie, Raphael ;

Crestani, Bruno ;

Dieude, Philippe ;

Nunes, Hilario ;

Allanore, Yannick ;

Kannengiesser, Caroline ;

Airo, Paolo ;

Matucci-Cerinic, Marco ;

Wallaert, Benoit ;

Israel-Biet, Dominique ;

Cadranel, Jacques ;

Cottin, Vincent ;

Gazal, Steven ;

Peljto, Anna L. ;

Varga, John ;

Schwartz, David A. ;

Valeyre, Dominique ;

Grandchamp, Bernard .

PLOS ONE, 2013, 8 (08)

[10]

Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia [J].

Cogan, Joy D. ;

Kropski, Jonathan A. ;

Zhao, Min ;

Mitchell, Daphne B. ;

Rives, Lynette ;

Markin, Cheryl ;

Gamett, Errine T. ;

Montgomery, Keri H. ;

Mason, Wendi R. ;

McKean, David F. ;

Powers, Julia ;

Murphy, Elissa ;

Olson, Lana M. ;

Choi, Leena ;

Cheng, Dong-Sheng ;

Blue, Elizabeth Marchani ;

Young, Lisa R. ;

Lancaster, Lisa H. ;

Steele, Mark P. ;

Brown, Kevin K. ;

Schwarz, Marvin I. ;

Fingerlin, Tasha E. ;

Schwartz, David A. ;

Lawson, William E. ;

Loyd, James E. ;

Zhao, Zhongming ;

Phillips, John A., III ;

Blackwell, Timothy S. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2015, 191 (06) :646-655

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