Robert Plenge
Brigham and Women's Hospital
Div. of Rheumatology, Immunology & Allergy
77 Ave. Louis Pasteur, NRB
Boston, MA 02115
Tel: 617-525-4451
Fax: 617-525-4488
Email: rplenge@partners.org
Visit my lab page here.
Dysregulation of the immune system is a fundamental disease mechanism, yet is incompletely understood. The Plenge laboratory applies human genetics as a tool to understand dysregulation of the immune system in the context of human disease. In particular, we have focused on a common autoimmune disease, rheumatoid arthritis (RA), which is diagnosed in up to 1% of the adult population worldwide.
There are several areas of investigation that I believe are critical to my laboratory’s core mission of improving care of patients who suffer from RA and other immune-mediated diseases:
(1) Discover RA risk alleles. We employ and develop state-of-the-art genomics technology to identify new RA risk loci. Examples include genome-wide association studies and next-generation sequencing technology. Through international collaborations, we have identified over 30 regions of the genome that are unambiguously associated with risk of RA.
(2) Understand molecular mechanisms of RA risk alleles. Having identified RA risk alleles, a next critical step is to understand how these alleles disrupt normal immune function. In this way, we hope to gain insight into fundamental mechanisms that lead to RA, which in turn could help guide the development of novel RA therapies. Our genetic studies have demonstrated the importance of T-cell activation by antigen presenting cells (PTPN22, STAT, and CTLA4 genes); the role of the NF-κB signaling (CD40, TRAF1, TNFRSF14, TNFAIP3, and REL genes); and the roles for citrullination (PADI4), natural killer cells (CD244), and chemotaxis (CCL21). We use primary immune cells from healthy subjects, as well as human cell lines, to study the mechanism of action of RA risk alleles; we are planning to also use human stem cells, too.
(3) Translate genetic discoveries to improve patient care. Finally, we are constantly striving to understand how these risk alleles can improve patient care. One approach is to determine how RA risk alleles subset patients in meaningful ways (e.g., response to anti-TNF therapy, risk of cardiovascular disease). We work with an informatics team (www.i2b2.org) and as part of an international collaboration to investigate these clinical applications.
References:
Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG; BIRAC Consortium, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, van der Schoot CE, van Riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP; YEAR Consortium, Wijmenga C, Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010 Jun;42(6):508-14. Epub 2010 May 9.
Raychaudhuri S, Thomson BP, Remmers EF, Eyre S, Hinks A, Guiducci C, Catanese JJ, Xie G, Stahl EA, Chen R, Alfredsson L, Amos CI, Ardlie KG; BIRAC Consortium, Barton A, Bowes J, Burtt NP, Chang M, Coblyn J, Costenbader KH, Criswell LA, Crusius JB, Cui J, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Kurreeman FA, Lee AT, Liu X, Li Y, Martin P, Morgan AW, Padyukov L, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth P; YEAR Consortium, Altshuler D, Karlson EW, Toes RE, de Vries N, Begovich AB, Siminovitch KA, Worthington J, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk. Nature Genetics 2009, Dec; 41(12):1313-8.
Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, Padyukov L, Kurreeman FAS, Chang M, Catanese JJ, Ding B, Wong SL, van der Helm-van Mil AHM, Neale BM, Coblyn J, Cui J, Criswell LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, Huizinga TWJ,
Shadick NA, Weinblatt ME, Worthington J, Seielstad M, Toes REM, Karlson EW, Begovich AB, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nature Genetics 2008; 40(10):1216-23.
Plenge RM*, Seielstad M*, Padyukov L, Lee AT, Remmers EF, Ding B, Liew A, Khalili H, Chandrasekaran A, Davies LRL, Li W, Tan AKS, Bonnard C, Ong RTH, Thalamuthu A, Pettersson S, Liu C, Tian C, Chen WV, Carulli J, Altshuler D, Alfredsson L, Criswell LA, Amos CI, Seldin MF, W, Kastner DA, Klareskog L*, Gregersen PK*. Genome-wide search
dentifies TRAF1-C5 as Rheumatoid Arthritis Risk Locus. New Eng J Med 2007; 357(12):1199-209. *contributed equally
Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PIW, Maller J, Pe’er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M, Barry R, Winslow W, Healy C, Graham RR, Izmailova E, Roubenoff R, Parker AN, Coblyn J, Weinblatt ME, Glass R, Karlson EW, Maher N, Hafler DA, Lee DM, Brenner MB, Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Gabriel SB, Purcell S, Klareskog L, Gregersen PK, Shadick NA, Daly MJ, Altshuler D. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nature Genetics 2007; 39(12):1477-82.
Last Update: 1/14/2013