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


ABSTRACT: 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?

SUBMITTER: Cui J 

PROVIDER: S-EPMC6669377 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Cui Jing J   Diogo Dorothee D   Stahl Eli A EA   Canhao Helena H   Mariette Xavier X   Greenberg Jeffrey D JD   Okada Yukinori Y   Pappas Dimitrios A DA   Fulton Robert S RS   Tak Paul P PP   Nurmohamed Michael T MT   Lee Annette A   Larson David E DE   Kurreeman Fina F   Deluca Tracie L TL   O'Laughlin Michelle M   Fronick Catrina C CC   Fulton Lucinda L LL   Mardis Elaine R ER   van der Horst-Bruinsma Irene E IE   Wolbink Gert-Jan GJ   Gregersen Peter K PK   Kremer Joel M JM   Crusius J Bart A JB   de Vries Niek N   Huizinga Tom W J TW   Fonseca João Eurico JE   Miceli-Richard Corinne C   Karlson Elizabeth W EW   Coenen Marieke J H MJ   Barton Anne A   Plenge Robert M RM   Raychaudhuri Soumya S  

Arthritis & rheumatology (Hoboken, N.J.) 20170401 4


<h4>Objective</h4>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.<h4>Methods</h4>We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who we  ...[more]

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