Director, Center for Genomics & Human Genetics, The Feinstein Institute for Medical Research
Professor, Molecular Medicine, Hofstra North Shore-LIJ School of Medicine
Phone: (516) 562-1542/1134
Last year, the Royal Swedish Academy of Sciences presented Dr. Gregersen with the Crafoord prize for his genetic research in rheumatoid arthritis. The prestigious Crafoord prize is an annual science prize established in 1980 by Holger Crafoord, a Swedish Industrialist. The prize was presented in Stockholm by the king of Sweden on May 2, 2013.
In addition, he has spearheaded the development of a robotic biorepository and informatics resources to support these studies, including a large normal control registry (gapregistry.org) with a view toward understanding genotype-phenotype relationships in both normal and disease populations. He has longstanding interests related to the genetics of absolute pitch and synesthesia, as well as studies of immunological aspects of autism.
Dr. Gregersen’s ongoing studies in the laboratory include international collaborative efforts to achieve a comprehensive description of the genetics of autoimmune diseases, with a particular focus on rheumatoid arthritis and systemic lupus erythematosus. At least 46 genetic regions have been identified for rheumatoid arthritis, but it is likely that many more remain to be discovered.
In addition, Dr. Gregersen is pursuing functional studies of a number of newly defined risk genes for autoimmunity, particularly genes that regulate the thresholds for activation of the immune system. Several of these genes for autoimmunity are potential targets of new drugs that may be able to modify activation thresholds, in order to either enhance or reduce aspects of the immune response. These studies include work on the following genes:
CSK (c-Src tyrosine kinase)
Csk interacts with another protein, PTPN22, the gene that is known for associating strongly with multiple autoimmune diseases. Dr. Gregersen’s team recently demonstrated that variants in CSK are associated with systemic lupus erthematosus1. Strikingly, the CSK risk variant is associated with an increased ‘activation state’ of B lymphocytes in human blood. Furthermore, his team was able to demonstrate the disease associated CSK risk variant actually affects the proportions of developing B lymphocytes in human umbilical cord blood. Together, these observations suggest that the CSK variant increases susceptibility to lupus by affecting multiple aspects of B lymphocyte development and activation.
TNIP1 (TNFAIP3 interacting protein 1)
This gene is known to control signaling pathways that are critical to the immune response, and alterations in this gene can lead to autoimmunity in animals. In addition to associations with systemic lupus erythematosus and rheumatoid arthritis, Dr. Gregersen’s team recently identified a polymorphism in TNIP1 that is strongly associated with myasthenia gravis, an autoimmune disorder that affects the neuromuscular junction, causing weakness in patients. The relevant variants include an amino acid in the TNIP1 protein2, but also influence the amount of TNIP1 that is made. The exact mechanisms by which TNIP1 causes risk for autoimmunity are being pursued in the laboratory.
BLK (B lymphoid kinase)
Genetic variation in Blk is associated with rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome and systemic sclerosis, as well as several other autoimmune disorders. Dr. Gregersen’s team demonstrated that disease associated polymorphisms particularly affect BLK gene and protein expression levels in B lymphocytes early in development, isolated from human umbilical cord blood3. They are pursuing the hypothesis that quantitative changes in Blk may specifically affect subsets of B cells involved in making autoantibodies.
PTPN22 is an intracellular phosphatase that Dr. Gregersen’s team discovered in 2004 to be associated with rheumatoid arthritis. It is one of the leading genes that are involved across many autoimmune disorders, but in a rather complex pattern. An amino acid change (R620W) in PTPN22 while predisposing to several autoimmune disorders such as SLE and RA is protective against Crohn’s disease, as well as some infectious diseases such as tuberculosis. R620W exerts its pathogenic mutation by disrupting the interaction between PTPN22 and CSK. A small molecule that disrupts PTPN22-CSK binding could be a used to adjust the thresholds for immune activation and could be useful for temporary treatment of Crohn`s disease and/or infectious disorders. Therefore, in addition to studies of the function of PTPN22 in various immune cells, a current project is aimed toward designing a high throughput assay to screen for small molecules that mimic the R620W mutation.
Finally, Dr. Gregersen’s team is attempting to define the genetic basis of several rare but related cognitive traits that include absolute pitch and synesthesia. They have recently identified several chromosomal regions that contain the relevant genes5 and are working to narrow down the candidate genes in these regions. They have also developed an iPhone app (PitchMatch! – download is free) to assess pitch perception in the general population. These studies may lead to a better understanding of brain connectivity, with potential application to identifying factors that influence early childhood cognitive development, including autism.
Jan Freudenberg, MD
Paul Andrei Jicman
Computer Systems Analyst
Post Doc Fellow
Mary Keogh, ANP, RN
Nurse Manager, Tissue Bank
Marlena Kern, DNP, RN
Research Project Coordinator
Research Coordinator, Absolute Pitch
Wentian Li, PhD
Nataly Manjarrez-Ordana, PhD
Cathleen Mason, RN
Research Nurse, Tissue Bank
Michaela Oswald, PhD
Computer Systems Analyst
Computer Systems Analyst
Post Doc Fellow
Kim Simpfendorfer, PhD
Johns Hopkins University, Baltimore MD
Field of Study: Natural Sciences
Columbia University College of Physicians & Surgeons
Field of Study: Medicine
1988 Pfizer Scholars Award for New Faculty
2007 Klemperer Medal, New York Academy of Medicine
2007 ACR Distinguished Basic Investigator Award
2009 Association of American Physicians
2013 Crafoord Award from Royal Swedish Academy of Sciences for Arthritis Research
- Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, Simpfendorfer KR, Pirskanen-Matell R, Piehl F, Pan-Hammarstrom Q, Verschuuren JJ, Titulaer MJ, Niks EH, Marx A, Ströbel P, Tackenberg B, Pütz M, Maniaol A, Elsais A, Tallaksen C, Harbo HF, Lie BA, Raychaudhuri S, de Bakker PI, Melms A, Garchon HJ, Willcox N, Hammarstrom L, Seldin MF. Ann Neurol.”Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.” 2012 Dec;72(6):927-35. doi: 10.1002/ana.23691. Epub 2012 Oct 10.
- Manjarrez-Orduño N, Marasco E, Chung SA, Katz MS, Kiridly JF, Simpfendorfer KR, Freudenberg J, Ballard DH, Nashi E, Hopkins TJ, Cunninghame Graham DS, Lee AT, Coenen MJ, Franke B, Swinkels DW, Graham RR, Kimberly RP, Gaffney PM, Vyse TJ, Behrens TW, Criswell LA, Diamond B, Gregersen PK. “CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation.” Nat Genet. 2012 Nov;44(11):1227-30. doi: 10.1038/ng.2439. Epub 2012 Oct 7.
- Cho JH, Gregersen PK. “Genomics and the multifactorial nature of human autoimmune disease.” N Engl J Med. 2011 Oct 27;365(17):1612-23. doi: 10.1056/NEJMra1100030. Review. No abstract available. PMID: 22029983
- 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. “Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.” Nat Genet. 2010 Jun;42(6):508-14. doi: 10.1038/ng.582. Epub 2010 May 9.
- Gregersen PK, Amos CI, Lee AT, Lu Y, Remmers EF, Kastner DL, Seldin MF, Criswell LA, Plenge RM, Holers VM, Mikuls TR, Sokka T, Moreland LW, Bridges SL Jr, Xie G, Begovich AB, Siminovitch KA. “REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.” Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
- Gregersen PK, Olsson LM. “Recent advances in the genetics of autoimmune disease.” Annu Rev Immunol. 2009;27:363-91. doi: 10.1146/annurev.immunol.021908.132653/. Review. PMID: 19302045
- Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. “STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.” N Engl J Med. 2007 Sep 6;357(10):977-86.
- Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B, Liew A, Khalili H, Chandrasekaran A, Davies LR, Li W, Tan AK, Bonnard C, Ong RT, Thalamuthu A, Pettersson S, Liu C, Tian C, Chen WV, Carulli JP, Beckman EM, Altshuler D, Alfredsson L, Criswell LA, Amos CI, Seldin MF, Kastner DL, Klareskog L, Gregersen PK. “TRAF1-C5 as a risk locus for rheumatoid arthritis–a genomewide study.” N Engl J Med. 2007 Sep 20;357(12):1199-209. Epub 2007 Sep 5.