title: Brief Report: The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis.
abstract: 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.
  
  
  
  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.
  
  
  
  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 (Penrichment= 0.15, based on phenotype permutations).
  
  
  
  Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with RA.
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Jing
authors: J
authors: Cui
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, and Broad Institute, Cambridge, Massachusetts.
authors: Dorothee
authors: D
authors: Diogo
authors: Mount Sinai School of Medicine, New York, New York.
authors: Eli A
authors: EA
authors: Stahl
authors: Universidade Nova de Lisboa, Lisbon, Portugal.
authors: Helena
authors: H
authors: Canhao
authors: Université Paris Sud, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Bicêtre Hospital, AP-HP, Paris, France.
authors: Xavier
authors: X
authors: Mariette
authors: New York University Hospital for Joint Diseases, New York, New York.
authors: Jeffrey D
authors: JD
authors: Greenberg
authors: Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Yukinori
authors: Y
authors: Okada
authors: Columbia University, New York, New York.
authors: Dimitrios A
authors: DA
authors: Pappas
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: Robert S
authors: RS
authors: Fulton
authors: University of Amsterdam, Amsterdam, The Netherlands.
authors: Paul P
authors: PP
authors: Tak
authors: Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.
authors: Michael T
authors: MT
authors: Nurmohamed
authors: Feinstein Institute for Medical Research, Manhasset, New York.
authors: Annette
authors: A
authors: Lee
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: David E
authors: DE
authors: Larson
authors: Leiden University Medical Centre, Leiden, The Netherlands.
authors: Fina
authors: F
authors: Kurreeman
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: Tracie L
authors: TL
authors: Deluca
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: Michelle
authors: M
authors: O'Laughlin
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: Catrina C
authors: CC
authors: Fronick
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: Lucinda L
authors: LL
authors: Fulton
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors: Elaine R
authors: ER
authors: Mardis
authors: Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.
authors: Irene E
authors: IE
authors: van der Horst-Bruinsma
authors: Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.
authors: Gert-Jan
authors: GJ
authors: Wolbink
authors: Feinstein Institute for Medical Research, Manhasset, New York.
authors: Peter K
authors: PK
authors: Gregersen
authors: Albany Medical College and the Center for Rheumatology, Albany, New York.
authors: Joel M
authors: JM
authors: Kremer
authors: VU University Medical Center, Amsterdam, The Netherlands.
authors: J Bart A
authors: JB
authors: Crusius
authors: University of Amsterdam, Amsterdam, The Netherlands.
authors: Niek
authors: N
authors: de Vries
authors: Leiden University Medical Centre, Leiden, The Netherlands.
authors: Tom W J
authors: TW
authors: Huizinga
authors: Universidade de Lisboa and Santa Maria Hospital, Lisbon, Portugal.
authors: João Eurico
authors: JE
authors: Fonseca
authors: Service de Rhumatologie, Hôpital Cochin, AP-HP, Paris, France.
authors: Corinne
authors: C
authors: Miceli-Richard
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Elizabeth W
authors: EW
authors: Karlson
authors: Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Marieke J H
authors: MJ
authors: Coenen
authors: Centre for Musculoskeletal Research, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Anne
authors: A
authors: Barton
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, and Broad Institute, Cambridge, Massachusetts.
authors: Robert M
authors: RM
authors: Plenge
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts, and Centre for Musculoskeletal Research, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Soumya
authors: S
authors: Raychaudhuri
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016366:Open Reading Frames; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D014409:Tumor Necrosis Factor-alpha