Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

被引：164

作者：

LeMaire, Scott A. ^{[2
]}

McDonald, Merry-Lynn N. ^{[3
]}

Guo, Dong-chuan ^{[1
]}

Russell, Ludivine ^{[2
]}

Miller, Charles C., III ^{[4
]}

Johnson, Ralph J. ^{[1
]}

Bekheirnia, Mir Reza ^{[3
]}

Franco, Luis M. ^{[3
]}

Nguyen, Mary ^{[2
]}

Pyeritz, Reed E. ^{[5
]}

Bavaria, Joseph E. ^{[6
]}

Devereux, Richard ^{[7
]}

Maslen, Cheryl ^{[8
]}

Holmes, Kathryn W. ^{[9
]}

Eagle, Kim ^{[10
]}

Body, Simon C. ^{[11
]}

Seidman, Christine ^{[12
]}

Seidman, J. G. ^{[12
]}

Isselbacher, Eric M. ^{[13
]}

Bray, Molly ^{[14
]}

Coselli, Joseph S. ^{[2
]}

Estrera, Anthony L. ^{[4
]}

Safi, Hazim J. ^{[4
]}

Belmont, John W. ^{[3
]}

Leal, Suzanne M. ^{[3
]}

Milewicz, Dianna M. ^{[1
,15
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Div Med Genet, Dept Internal Med, Houston, TX USA

[2] Baylor Coll Med, Div Cardiothorac Surg, Michael E DeBakey Dept Surg, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[4] Univ Texas Hlth Sci Ctr Houston, Dept Cardiothorac & Vasc Surg, Houston, TX USA

[5] Univ Penn, Dept Med, Div Med Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Surg, Div Cardiovasc Surg, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Weill Cornell Med Coll, Dept Med, Greenberg Div Cardiol, New York, NY USA

[8] Oregon Hlth & Sci Univ, Div Cardiovasc Med, Dept Mol & Med Genet, Portland, OR 97201 USA

[9] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[10] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA

[11] Harvard Univ, Sch Med, Dept Anesthesiol, Boston, MA USA

[12] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[13] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[14] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[15] St Lukes Episcopal Hosp, Texas Heart Inst, Med Serv, Houston, TX USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 10期

基金：

美国国家卫生研究院;

关键词：

MARFAN-SYNDROME; MOUSE MODEL; MUTATIONS; DISEASE; VALVE; ADULTS;

D O I：

10.1038/ng.934

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 x 10(-5) in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

引用

页码：996 / U109

页数：7

共 27 条

[1] A haplotype map of the human genome [J].

Altshuler, D ;

Brooks, LD ;

Chakravarti, A ;

Collins, FS ;

Daly, MJ ;

Donnelly, P ;

Gibbs, RA ;

Belmont, JW ;

Boudreau, A ;

Leal, SM ;

Hardenbol, P ;

Pasternak, S ;

Wheeler, DA ;

Willis, TD ;

Yu, FL ;

Yang, HM ;

Zeng, CQ ;

Gao, Y ;

Hu, HR ;

Hu, WT ;

Li, CH ;

Lin, W ;

Liu, SQ ;

Pan, H ;

Tang, XL ;

Wang, J ;

Wang, W ;

Yu, J ;

Zhang, B ;

Zhang, QR ;

Zhao, HB ;

Zhao, H ;

Zhou, J ;

Gabriel, SB ;

Barry, R ;

Blumenstiel, B ;

Camargo, A ;

Defelice, M ;

Faggart, M ;

Goyette, M ;

Gupta, S ;

Moore, J ;

Nguyen, H ;

Onofrio, RC ;

Parkin, M ;

Roy, J ;

Stahl, E ;

Winchester, E ;

Ziaugra, L ;

Shen, Y .

NATURE, 2005, 437 (7063) :1299-1320

[2] FBN1 Mutations in Patients With Descending Thoracic Aortic Dissections [J].

Brautbar, Ariel ;

LeMaire, Scott A. ;

Franco, Luis M. ;

Coselli, Joseph S. ;

Milewicz, Dianna M. ;

Belmont, John W. .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2010, 152A (02) :413-416

[3] The bicuspid aortic valve [J].

Braverman, AC ;

Güven, H ;

Beardslee, MA ;

Makan, M ;

Kates, AM ;

Moon, MR .

CURRENT PROBLEMS IN CARDIOLOGY, 2005, 30 (09) :470-522

[4] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[5] Rationale and design of the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) [J].

Eagle, Kim A. .

AMERICAN HEART JOURNAL, 2009, 157 (02) :319-326

[6] Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections [J].

Guo, Dong-Chuan ;

Pannu, Hariyadarshi ;

Tran-Fadulu, Van ;

Papke, Christina L. ;

Yu, Robert K. ;

Avidan, Nili ;

Bourgeois, Scott ;

Estrera, Anthony L. ;

Safi, Hazim J. ;

Sparks, Elizabeth ;

Amor, David ;

Ades, Lesley ;

McConnell, Vivienne ;

Willoughby, Colin E. ;

Abuelo, Dianne ;

Willing, Marcia ;

Lewis, Richard A. ;

Kim, Dong H. ;

Scherer, Steve ;

Tung, Poyee P. ;

Ahn, Chul ;

Buja, L. Maximilian ;

Raman, C. S. ;

Shete, Sanjay S. ;

Milewicz, Dianna M. .

NATURE GENETICS, 2007, 39 (12) :1488-1493

[7] Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome [J].

Habashi, JP ;

Judge, DP ;

Holm, TM ;

Cohn, RD ;

Loeys, BL ;

Cooper, TK ;

Myers, L ;

Klein, EC ;

Liu, GS ;

Calvi, C ;

Podowski, M ;

Neptune, ER ;

Halushka, MK ;

Bedja, D ;

Gabrielson, K ;

Rifkin, DB ;

Carta, L ;

Ramirez, F ;

Huso, DL ;

Dietz, HC .

SCIENCE, 2006, 312 (5770) :117-121

[8]

Hiratzka LF, 2010, CIRCULATION, V121, pE266, DOI 10.1161/CIR.0b013e3181d4739e

[9] Noncanonical TGFβ Signaling Contributes to Aortic Aneurysm Progression in Marfan Syndrome Mice [J].

Holm, Tammy M. ;

Habashi, Jennifer P. ;

Doyle, Jefferson J. ;

Bedja, Djahida ;

Chen, YiChun ;

van Erp, Christel ;

Lindsay, Mark E. ;

Kim, David ;

Schoenhoff, Florian ;

Cohn, Ronald D. ;

Loeys, Bart L. ;

Thomas, Craig J. ;

Patnaik, Samarjit ;

Marugan, Juan J. ;

Judge, Daniel P. ;

Dietz, Harry C. .

SCIENCE, 2011, 332 (6027) :358-361

[10] Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections [J].

Kuang, Shao-Qing ;

Guo, Dong-Chuan ;

Prakash, Siddharth K. ;

McDonald, Merry-Lynn N. ;

Johnson, Ralph J. ;

Wang, Min ;

Regalado, Ellen S. ;

Russell, Ludivine ;

Cao, Jiu-Mei ;

Kwartler, Callie ;

Fraivillig, Kurt ;

Coselli, Joseph S. ;

Safi, Hazim J. ;

Estrera, Anthony L. ;

Leal, Suzanne M. ;

LeMaire, Scott A. ;

Belmont, John W. ;

Milewicz, Dianna M. .

PLOS GENETICS, 2011, 7 (06)

← 1 2 3 →