OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.
OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.
Authors: Halima Moncrieffe; Anne Hinks; Simona Ursu; Laura Kassoumeri; Angela Etheridge; Mike Hubank; Paul Martin; Tracey Weiler; David N Glass; Susan D Thompson; Wendy Thomson; Lucy R Wedderburn Journal: Pharmacogenet Genomics Date: 2010-11 Impact factor: 2.089
Authors: Altan Ercan; Jing Cui; Melissa M Hazen; Franak Batliwalla; Louise Royle; Pauline M Rudd; Jonathan S Coblyn; Nancy Shadick; Michael E Weinblatt; Peter Gregersen; David M Lee; Peter A Nigrovic Journal: Arthritis Res Ther Date: 2012-03-05 Impact factor: 5.156
Authors: Jeffrey R Curtis; Annette H van der Helm-van Mil; Rachel Knevel; Tom W Huizinga; Douglas J Haney; Yijing Shen; Saroja Ramanujan; Guy Cavet; Michael Centola; Lyndal K Hesterberg; David Chernoff; Kerri Ford; Nancy A Shadick; Max Hamburger; Roy Fleischmann; Edward Keystone; Michael E Weinblatt Journal: Arthritis Care Res (Hoboken) Date: 2012-12 Impact factor: 4.794
Authors: Anne Barton; Steve Eyre; Xiayi Ke; Anne Hinks; John Bowes; Edward Flynn; Paul Martin; Anthony G Wilson; Ann W Morgan; Paul Emery; Sophia Steer; Lynne J Hocking; David M Reid; Pille Harrison; Paul Wordsworth; Wendy Thomson; Jane Worthington Journal: Hum Mol Genet Date: 2009-04-09 Impact factor: 6.150
Authors: A N Burska; K Roget; M Blits; L Soto Gomez; F van de Loo; L D Hazelwood; C L Verweij; A Rowe; G N Goulielmos; L G M van Baarsen; F Ponchel Journal: Pharmacogenomics J Date: 2014-03-04 Impact factor: 3.550
Authors: Rita A Moura; Cláudia Quaresma; Ana R Vieira; Maria J Gonçalves; Joaquim Polido-Pereira; Vasco C Romão; Nádia Martins; Helena Canhão; João E Fonseca Journal: PLoS One Date: 2017-09-08 Impact factor: 3.240
Authors: Jing Cui; Eli A Stahl; Saedis Saevarsdottir; Corinne Miceli; Dorothee Diogo; Gosia Trynka; Towfique Raj; Maša Umiċeviċ Mirkov; Helena Canhao; Katsunori Ikari; Chikashi Terao; Yukinori Okada; Sara Wedrén; Johan Askling; Hisashi Yamanaka; Shigeki Momohara; Atsuo Taniguchi; Koichiro Ohmura; Fumihiko Matsuda; Tsuneyo Mimori; Namrata Gupta; Manik Kuchroo; Ann W Morgan; John D Isaacs; Anthony G Wilson; Kimme L Hyrich; Marieke Herenius; Marieke E Doorenspleet; Paul-Peter Tak; J Bart A Crusius; Irene E van der Horst-Bruinsma; Gert Jan Wolbink; Piet L C M van Riel; Mart van de Laar; Henk-Jan Guchelaar; Nancy A Shadick; Cornelia F Allaart; Tom W J Huizinga; Rene E M Toes; Robert P Kimberly; S Louis Bridges; Lindsey A Criswell; Larry W Moreland; João Eurico Fonseca; Niek de Vries; Barbara E Stranger; Philip L De Jager; Soumya Raychaudhuri; Michael E Weinblatt; Peter K Gregersen; Xavier Mariette; Anne Barton; Leonid Padyukov; Marieke J H Coenen; Elizabeth W Karlson; Robert M Plenge Journal: PLoS Genet Date: 2013-03-28 Impact factor: 5.917