Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes

被引：71

作者：

Hirschfield, G. M. ^{[3
,4
]}

Xie, G. ^{[1
,2
]}

Lu, E. ^{[5
]}

Sun, Y. ^{[1
,2
]}

Juran, B. D. ^{[6
]}

Chellappa, V. ^{[7
]}

Coltescu, C. ^{[3
]}

Mason, A. L. ^{[8
]}

Milkiewicz, P. ^{[9
]}

Myers, R. P. ^{[10
]}

Odin, J. A. ^{[11
]}

Luketic, V. A. ^{[12
]}

Bacon, B. ^{[13
]}

Bodenheimer, H. ^{[14
]}

Liakina, V. ^{[15
]}

Vincent, C. ^{[16
]}

Levy, C. ^{[17
]}

Pillai, S. ^{[7
]}

Lazaridis, K. N. ^{[6
]}

Amos, C. I. ^{[5
]}

Siminovitch, K. A. ^{[1
,2
,4
,18
,19
]}

机构：

[1] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[2] Toronto Gen Res Inst, Toronto, ON M5G 1X5, Canada

[3] Toronto Western Hosp, Ctr Liver, Toronto, ON M5T 2S8, Canada

[4] Univ Toronto, Dept Med, Toronto, ON, Canada

[5] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[6] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Ctr Basic Res Digest Dis, Rochester, MN USA

[7] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA

[8] Univ Alberta, Dept Med, Edmonton, AB, Canada

[9] Pomeranian Med Sch, Liver Unit, Szczecin, Poland

[10] Univ Calgary, Liver Unit, Calgary, AB, Canada

[11] Mt Sinai Sch Med, Div Liver Dis, New York, NY USA

[12] Virginia Commonwealth Univ, Dept Gastroenterol, Richmond, VA USA

[13] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO USA

[14] Albert Einstein Coll Med, Dept Med, New York, NY USA

[15] Vilnius State Univ, Ctr Gastroenterol & Dietet, Vilnius, Lithuania

[16] Univ Montreal, Ctr Hosp, St Luc Hosp, Montreal, PQ, Canada

[17] Univ Miami, Sch Med, Ctr Liver Dis, Div Hepatol, Miami, FL USA

[18] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A1, Canada

[19] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada

来源：

GENES AND IMMUNITY | 2012年 / 13卷 / 04期

基金：

美国国家卫生研究院;

关键词：

autoimmunity; fine mapping; sequence analysis; primary biliary cirrhosis; RISK ALLELES; T-CELLS; CYTOKINE; DIFFERENTIATION; AUTOIMMUNITY; DEFICIENCY; SUPPRESSOR; DISEASE; GAMMA;

D O I：

10.1038/gene.2011.89

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (50051) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 x 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 x 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 x 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC.

引用

页码：328 / 335

页数：8

共 25 条

[1]

SOCS1 is a critical inhibitor of interferon γ signaling and prevents the potentially fatal neonatal actions of this cytokine [J].

Alexander, WS ;

Starr, R ;

Fenner, JE ;

Scott, GL ;

Handman, E ;

Sprigg, NS ;

Corbin, JE ;

Cornish, AL ;

Darwiche, R ;

Owczarek, CM ;

Kay, TWH ;

Nicola, NA ;

Hertzog, PJ ;

Metcalf, D ;

Hilton, DJ .

CELL, 1999, 98 (05) :597-608

[2]

B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase [J].

Cariappa, Annaiah ;

Takematsu, Hiromu ;

Liu, Haoyuan ;

Diaz, Sandra ;

Haider, Khaleda ;

Boboila, Cristian ;

Kalloo, Geetika ;

Connole, Michelle ;

Shi, Hai Ning ;

Varki, Nissi ;

Varki, Ajit ;

Pillai, Shiv .

JOURNAL OF EXPERIMENTAL MEDICINE, 2009, 206 (01) :125-138

[3]

Regulation of Follicular B Cell Differentiation by the Related E26 Transformation-Specific Transcription Factors PU.1, Spi-B, and Spi-C [J].

DeKoter, Rodney P. ;

Geadah, Marc ;

Khoosal, Sonam ;

Xu, Li S. ;

Thillainadesan, Gobi ;

Torchia, Joseph ;

Chin, Shu Shien ;

Garrett-Sinha, Lee Ann .

JOURNAL OF IMMUNOLOGY, 2010, 185 (12) :7374-7384

[4]

Multiple common variants for celiac disease influencing immune gene expression [J].

Dubois, Patrick C. A. ;

Trynka, Gosia ;

Franke, Lude ;

Hunt, Karen A. ;

Romanos, Jihane ;

Curtotti, Alessandra ;

Zhernakova, Alexandra ;

Heap, Graham A. R. ;

Adany, Roza ;

Aromaa, Arpo ;

Bardella, Maria Teresa ;

van den Berg, Leonard H. ;

Bockett, Nicholas A. ;

de la Concha, Emilio G. ;

Dema, Barbara ;

Fehrmann, Rudolf S. N. ;

Fernandez-Arquero, Miguel ;

Fiatal, Szilvia ;

Grandone, Elvira ;

Green, Peter M. ;

Groen, Harry J. M. ;

Gwilliam, Rhian ;

Houwen, Roderick H. J. ;

Hunt, Sarah E. ;

Kaukinen, Katri ;

Kelleher, Dermot ;

Korponay-Szabo, Ilma ;

Kurppa, Kalle ;

MacMathuna, Padraic ;

Maki, Markku ;

Mazzilli, Maria Cristina ;

McCann, Owen T. ;

Mearin, M. Luisa ;

Mein, Charles A. ;

Mirza, Muddassar M. ;

Mistry, Vanisha ;

Mora, Barbara ;

Morley, Katherine I. ;

Mulder, Chris J. ;

Murray, Joseph A. ;

Nunez, Concepcion ;

Oosterom, Elvira ;

Ophoff, Roel A. ;

Polanco, Isabel ;

Peltonen, Leena ;

Platteel, Mathieu ;

Rybak, Anna ;

Salomaa, Veikko ;

Schweizer, Joachim J. ;

Sperandeo, Maria Pia .

NATURE GENETICS, 2010, 42 (04) :295-U42

[5]

Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency [J].

Ferreira, Ricardo C. ;

Pan-Hammarstrom, Qiang ;

Graham, Robert R. ;

Gateva, Vesela ;

Fontan, Gumersindo ;

Lee, Annette T. ;

Ortmann, Ward ;

Urcelay, Elena ;

Fernandez-Arquero, Miguel ;

Nunez, Concepcion ;

Jorgensen, Gudmundur ;

Ludviksson, Bjorn R. ;

Koskinen, Sinikka ;

Haimila, Katri ;

Clark, Hilary F. ;

Klareskog, Lars ;

Gregersen, Peter K. ;

Behrens, Timothy W. ;

Hammarstrom, Lennart .

NATURE GENETICS, 2010, 42 (09) :777-U69

[6]

SOCS1, a Negative Regulator of Cytokine Signals and TLR Responses, in Human Liver Diseases [J].

Fujimoto, Minoru ;

Naka, Tetsuji .

GASTROENTEROLOGY RESEARCH AND PRACTICE, 2010, 2010

[7]

Risk alleles for multiple sclerosis identified by a genomewide study [J].

Hafler, David A. ;

Compston, Alastair ;

Sawcer, Stephen ;

Lander, Eric S. ;

Daly, Mark J. ;

De Jager, Philip L. ;

de Bakker, Paul I. W. ;

Gabriel, Stacey B. ;

Mirel, Daniel B. ;

Ivinson, Adrian J. ;

Pericak-Vance, Margaret A. ;

Gregory, Simon G. ;

Rioux, John D. ;

McCauley, Jacob L. ;

Haines, Jonathan L. ;

Barcellos, Lisa F. ;

Cree, Bruce ;

Oksenberg, Jorge R. ;

Hauser, Stephen L. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 357 (09) :851-862

[8]

A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene [J].

Hakonarson, Hakon ;

Grant, Struan F. A. ;

Bradfield, Jonathan P. ;

Marchand, Luc ;

Kim, Cecilia E. ;

Glessner, Joseph T. ;

Grabs, Rosemarie ;

Casalunovo, Tracy ;

Taback, Shayne P. ;

Frackelton, Edward C. ;

Lawson, Margaret L. ;

Robinson, Luke J. ;

Skraban, Robert ;

Lu, Yang ;

Chiavacci, Rosetta M. ;

Stanley, Charles A. ;

Kirsch, Susan E. ;

Rappaport, Eric F. ;

Orange, Jordan S. ;

Monos, Dimitri S. ;

Devoto, Marcella ;

Qu, Hui-Qi ;

Polychronakos, Constantin .

NATURE, 2007, 448 (7153) :591-U7

[9]

Progress in the Genetics of Primary Biliary Cirrhosis [J].

Hirschfield, Gideon M. ;

Invernizzi, Pietro .

SEMINARS IN LIVER DISEASE, 2011, 31 (02) :147-156

[10]

Hirschfield GM, 2011, ISR MED ASSOC J, V13, P55

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