The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis

被引：7

作者：

Cui, Jing ^{[1
]}

Diogo, Dorothee

Stahl, Eli A. ^{[4
]}

Canhao, Helena ^{[5
]}

Mariette, Xavier ^{[6
,7
]}

Greenberg, Jeffrey D. ^{[8
]}

Okada, Yukinori ^{[9
]}

Pappas, Dimitrios A. ^{[10
]}

Fulton, Robert S. ^{[11
]}

Tak, Paul P. ^{[12
]}

Nurmohamed, Michael T. ^{[14
]}

Lee, Annette ^{[15
]}

Larson, David E. ^{[11
]}

Kurreeman, Fina ^{[16
]}

Deluca, Tracie L. ^{[11
]}

O'Laughlin, Michelle ^{[11
]}

Fronick, Catrina C. ^{[11
]}

Fulton, Lucinda L. ^{[11
]}

Mardis, Elaine R.

van der Horst-Bruinsma, Irene E. ^{[14
]}

Wolbink, Gert-Jan ^{[14
]}

Gregersen, Peter K. ^{[15
]}

Kremer, Joel M. ^{[17
,18
]}

Crusius, J. Bart A. ^{[19
]}

de Vries, Niek ^{[13
]}

Huizinga, Tom W. J. ^{[16
]}

Fonseca, Joao Eurico ^{[20
,21
]}

Miceli-Richard, Corinne ^{[22
]}

Karlson, Elizabeth W. ^{[1
]}

Coenen, Marieke J. H. ^{[23
]}

Barton, Anne ^{[24
,25
]}

Plenge, Robert M. ^{[1
,2
,3
]}

Raychaudhuri, Soumya ^{[24
,25
,26
,27
]}

机构：

[1] Brigham & Womens Hosp, Harvard Med Sch, Boston, MA 02115 USA

[2] Merck & Co Inc, Boston, MA USA

[3] Broad Inst, Cambridge, MA USA

[4] Mt Sinai Sch Med, New York, NY USA

[5] Univ Nova Lisboa, P-1200 Lisbon, Portugal

[6] Univ Paris 11, INSERM U1184, Ctr Immunol Viral Infect, Paris, France

[7] Hop Bicetre, AP HP, Autoimmune Dis, Paris, France

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

[9] Osaka Univ, Grad Sch Med, Osaka, Japan

[10] Columbia Univ, New York, NY USA

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

[12] GlaxoSmithKline, Stevenage, Herts, England

[13] Univ Amsterdam, Amsterdam, Netherlands

[14] Reade, Amsterdam Rheumatol & Immunol Ctr, Amsterdam, Netherlands

[15] Feinstein Inst Med Res, Manhasset, NY USA

[16] Leiden Univ, Med Ctr, Leiden, Netherlands

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

[18] Ctr Rheumatol, Albany, NY USA

[19] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands

[20] Univ Lisbon, Lisbon, Portugal

[21] Hosp Santa Maria, Lisbon, Portugal

[22] Hop Cochin, AP HP, Serv Rhumatol, Paris, France

[23] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands

[24] Univ Manchester, Ctr Musculoskeletal Res, Manchester, Lancs, England

[25] Manchester Acad Hlth Sci Ctr, Cent Manchester NHS Fdn Trust, Manchester, Lancs, England

[26] Brigham & Womens Hosp, Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA

[27] Broad Inst, Cambridge, MA USA

来源：

ARTHRITIS & RHEUMATOLOGY | 2017年 / 69卷 / 04期

关键词：

DISEASE-ACTIVITY SCORES; ASSOCIATION; VALIDATION; CRITERIA;

D O I：

10.1002/art.39966

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Objective. In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. Methods. We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. Results. We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (P-enrichment = 0.15, based on phenotype permutations). Conclusion. Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling\

引用

页码：735 / 741

页数：7

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