TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits

被引：110

作者：

Diogo, Dorothee ^{[1
,2
,3
,4
]}

Bastarache, Lisa ^{[5
]}

Liao, Katherine P. ^{[1
]}

Graham, Robert R. ^{[6
]}

Fulton, Robert S. ^{[7
]}

Greenberg, Jeffrey D. ^{[8
]}

Eyre, Steve ^{[9
]}

Bowes, John ^{[9
]}

Cui, Jing ^{[1
]}

Lee, Annette ^{[10
]}

Pappas, Dimitrios A. ^{[1
,11
]}

Kremer, Joel M. ^{[12
,13
]}

Barton, Anne ^{[9
]}

Coenen, Marieke J. H. ^{[14
]}

Franke, Barbara ^{[15
]}

Kiemeney, Lambertus A. ^{[16
]}

Mariette, Xavier ^{[17
,18
]}

Richard-Miceli, Corrine ^{[17
,18
]}

Canhao, Helena ^{[19
,20
]}

Fonseca, Joao E. ^{[19
,20
]}

de Vries, Niek ^{[21
]}

Tak, Paul P. ^{[21
]}

Crusius, J. Bart A. ^{[22
]}

Nurmohamed, Michael T. ^{[23
]}

Kurreeman, Fina ^{[24
]}

Mikuls, Ted R. ^{[25
,26
]}

Okada, Yukinori ^{[1
,2
,3
]}

Stahl, Eli A. ^{[1
,2
,3
]}

Larson, David E. ^{[7
]}

Deluca, Tracie L. ^{[7
]}

O'Laughlin, Michelle ^{[7
]}

Fronick, Catrina C. ^{[7
]}

Fulton, Lucinda L. ^{[7
]}

Kosoy, Roman ^{[27
]}

Ransom, Michael ^{[27
]}

Bhangale, Tushar R. ^{[6
]}

Ortmann, Ward ^{[6
]}

Cagan, Andrew ^{[28
]}

Gainer, Vivian ^{[28
]}

Karlson, Elizabeth W. ^{[1
]}

Kohane, Isaac ^{[28
]}

Murphy, Shawn N. ^{[28
]}

Martin, Javier ^{[29
]}

Zhernakova, Alexandra ^{[24
,30
]}

Klareskog, Lars ^{[31
,32
]}

Padyukov, Leonid ^{[31
,32
]}

Worthington, Jane ^{[9
]}

Mardis, Elaine R. ^{[7
]}

Seldin, Michael F. ^{[25
,26
]}

Gregersen, Peter K. ^{[10
]}

机构：

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA USA

[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA USA

[3] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[4] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA

[5] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA

[6] Genentech Inc, ITGR Human Genet Grp, San Francisco, CA 94080 USA

[7] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA

[8] NYU, Hosp Joint Dis, New York, NY USA

[9] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Epidemiol Unit, Manchester, Lancs, England

[10] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA

[11] Columbia Univ, Coll Phys & Surg, New York, NY USA

[12] Albany Med Coll, Albany, NY 12208 USA

[13] Ctr Rheumatol, Albany, NY USA

[14] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[15] Radboud Univ Nijmegen, Med Ctr, Donders Ctr Neurosci, Dept Psychiat & Human Genet, NL-6525 ED Nijmegen, Netherlands

[16] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands

[17] Univ Paris Sud, Orsay, France

[18] Hop Bicetre, INSERM, AP HP, U1012, Paris, France

[19] Univ Lisbon, Fac Med, Inst Mol Med, Rheumatol Res Unit, P-1699 Lisbon, Portugal

[20] Hosp Santa Maria, CHLN, Dept Rheumatol, Lisbon, Portugal

[21] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, Amsterdam Rheumatol & Immunol Ctr, NL-1105 AZ Amsterdam, Netherlands

[22] Vrije Univ Amsterdam, Med Ctr, Dept Med Microbiol & Infect Control, Immunogenet Lab, Amsterdam, Netherlands

[23] Amsterdam Rheumatol & Immunol Ctr, Dept Rheumatol, Amsterdam, Netherlands

[24] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

[25] Omaha VA, Div Rheumatol & Immunol, Omaha, NE USA

[26] Univ Nebraska Med Ctr, Omaha, NE USA

[27] Univ Calif Davis, Dept Biochem & Mol Med, Davis, CA 95616 USA

[28] Partners Healthcare, Informat Syst, Charlestown, MA USA

[29] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain

[30] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

[31] Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden

[32] Karolinska Univ Hosp Solna, Stockholm, Sweden

[33] Vanderbilt Univ, Dept Med, Nashville, TN USA

来源：

PLOS ONE | 2015年 / 10卷 / 04期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; RARE VARIANTS; COMMON VARIANTS; CROHNS-DISEASE; SUSCEPTIBILITY LOCI; MEDICAL-RECORDS; LIPID-LEVELS; ANTI-TNF; RISK; GENES;

D O I：

10.1371/journal.pone.0122271

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein- coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2x10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6x10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, P-omnibus = 6x10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P-omnibus = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.

引用

页数：21

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