The Translational Genetics and Genomics Unit (TGGU) is a research group focused on understanding the mechanisms that underlie inflammatory and autoimmune disease. The unit applies integrated genomic approaches to investigate autoinflammatory and rheumatic diseases, seeking to understand the mechanisms through which disease-associated genetic variants participate in disease pathophysiology. The unit's goal is to advance our knowledge of rheumatic disease pathophysiology and inflammatory biology.
The goals of the unit are to:
- Use genetics, genomics and bioinformatics approaches to identify the genetic basis of complex autoinflammatory and autoimmune diseases.
- Determine mechanisms through which disease-associated variants participate in pathophysiology of autoinflammatory phenotypes.
- Search for novel genetic causes of autoinflammation and autoimmunity.
A major focus of the TGGU is on investigating and understanding genetically-complex diseases, such as Still's disease/systemic juvenile arthritis and Behçet's disease. Working with large international collaborations, we are engaged in integrated genomic investigations of well-phenotyped patient collections. We are also seeking to better understand the mechanisms of seemingly unprovoked inflammation through the study of individuals and families with monogenic inflammatory diseases, such as PLCG2 associated antibody deficiency and immune dysregulation (PLAID), together with phenotypically-similar but genetically-complex disorders, such as common variable immune deficiency. Through the biologic knowledge that such studies produce, we hope to identify novel therapeutic targets to ultimately improve the lives of individuals affected by chronic inflammatory and rheumatic diseases.
Another interest of the group is to determine the role of major histocompatibility complex (MHC) proteins in complex autoinflammatory diseases. Because of their role in presenting peptide antigens to T cells, MHC molecules are traditionally considered to be part of the adaptive immune system, a notion supported by their association with numerous autoimmune diseases. In contrast, autoinflammatory diseases are those in which inflammation develops in the absence of overt evidence of autoimmunity. While there is little evidence that autoimmunity is involved in the inflammatory phenotypes of either Behçet's disease or Still's disease, classical MHC alleles have been identified as risk factors in both cases. This has led the unit to consider mechanisms through which these molecules may influence inflammation without triggering autoimmunity.
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Studies Seeking Patients
Demirkaya E, Zhou Q, Smith CK, Ombrello MJ, Deuitch N, Tsai WL, Hoffmann P, Remmers EF, Takeuchi M, Park YH, Chae JJ, Barut K, Simsek D, Adrovic A, Sahin S, Caliskan S, Chandrasekharappa SC, Hasni SA, Ombrello AK, Gadina M, Kastner DL, Kaplan MJ, Kasapcopur O and Aksentijevich I. Deficiency of Complement 1r subcomponent in early-onset SLE: Role for disease-modifying alleles in a monogenic disease. Arthritis Rheumatol 2017.
Ogdie A, Sparks JA, Angeles-Han ST, Bush K, Castelino FV, Golding A, Jiang Y, Kahlenberg JM, Kim AHJ, Lee YC, Machireddy K, Ombrello MJ, Shah AA, Wallace ZS, Nigrovic PA, and Makris UE, for the American College of Rheumatology Early Career Investigator Subcommittee of the Committee on Research. Barriers and facilitators of mentoring for trainees and early career investigators in rheumatology research: current state, identification of needs, and roadmap to an inter-institutional adult rheumatology mentoring program. Arthritis Care Res (Hoboken) 2017.
Takeuchi M, Mizuki M, Meguro A, Ombrello MJ, Kirino Y, Satorius C, Le, J, Blake M, Erer B, Kawagoe T, Ustek D, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Sousa I, Davatchi F, Francisco V, Shahram F, Abdollahi BS, Nadji A, Shafiee NM, Ghaderibarmi F, Ohno S, Ueda A, Ishigatsubo Y, Gadina M, Oliveira SA, Gul A, Kastner DL, Remmers EF. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat Genet 2017;49(3):438-443.
Tejada CI, Broadaway KA, Brown MR, Ponder LA, Ombrello MJ, Pichavant MR, Wang G, Angeles-Han ST, Hersh AO, Bohnsack JF, Conneely KN, Epstein P, Prahalad S. Investigation of Associations between Autoimmunity Associated Variants in PDCD1 and Juvenile Idiopathic Arthritis. Curr Rheumatol Rev 2017.
Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom A, Foell D, Martini A, Gattorno M, Ozen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MOE, Oliveira S, Yeung RSM, Rosenberg A, Wedderburn LR, Anton J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr R, Achkar JP, Kamboh MI, Kaufman K, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology study group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis, Childhood Arthritis Prospective Study group, Randomized Placebo Phase Study of Rilonacept in sJIA investigators, Sparks-Childhood Arthritis Response to Medication Study group, Biologically Based Outcome Predictors in JIA group, Langefeld CD, Thompson SD, Zeggini E, Kastner DL, Woo P, and Thomson W. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis 2017;76(5):906-913.
Erer B, Takeuchi M, Ustek D, Tugal-Tulkun I, Seyahi E, Ozyazgan Y, Duymaz-Tozkir J, Gül A, Kastner DL, Remmers EF, Ombrello MJ. Evaluation of KIR3DL1/KIR3DS1 polymorphisms in Behçet’s disease. Genes Immun 2016;17(7):396-399.
Takeuchi M, Ombrello MJ, Kirino Y, Erer B, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Watts N, Gül A, Kastner DL, Remmers EF. A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet’s disease in HLA-B*51 carriers. Ann Rheum Dis 2016;75(12):2208-2211.
Muñoz-Cano R, Pascal M, Bartra J, Picado C, Valero A, Kim DK, Brooks S, Ombrello MJ, Metcalfe DD, Rivera J, Olivera A. Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis. J Allergy Clin Immunol. 2016;137(1):137-46.
Ombrello MJ, Remmers EF, Tachmazidou I, Grom A, Foell D, Haas JP, Martini A, Gattorno M, Ozen S, Prahalad S, Zeft AS, Bohnsack JF, Mellins ED, Ilowite NT, Russo R, Len C, Hilario MOE, Oliveira S, Yeung RSM, Rosenberg A, Wedderburn LR, Anton J, Schwarz T, Hinks A, Bilginer Y, Park J, Cobb J, Satorius C, Han B, Baskin E, Signa S, Duerr R, Achkar JP, Kamboh MI, Kaufman K, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology study group, Childhood Arthritis Prospective Study group, Randomized Placebo Phase Study of Rilonacept in sJIA investigators, Sparks-Childhood Arthritis Response to Medication Study group, Biologically Based Outcome Predictors in JIA group, de Bakker PIW, Raychaudhuri S, Langefeld CD, Thompson SD, Zeggini E, Thomson W, Kastner DL, and Woo P, on behalf of the International Childhood Arthritis Genetics Consortium. HLA-DRB1*11 and variants of the class II HLA locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 2015;112(52):15970-5.
Ombrello MJ, Kastner DL, Remmers EF. Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics. Curr Opin Rheumatol 2015;27(4):349-56.
Ombrello MJ. Advances in the genetically complex autoinflammatory diseases. Semin Immunopathol 2015;37(4):403-6.
Aderibigbe OM, Priel DL, Lee CC, Ombrello MJ, Prajapati VH, Liang MG, Lyons JJ, Kuhns DB, Cowen EW, Milner JD. Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations. JAMA Dermatol 2015;151(6):627-34.
Ombrello MJ, Sikora KA, Kastner DL. Genetics, genomics, and their relevance to pathology and therapy. Best Pract Res Clin Rheumatol. 2014 Apr;28(2):175-89. doi: 10.1016/j.berh.2014.05.001.
Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF. Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 2014 May 12. [Epub ahead of print]
Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius CL, Maskeri B, Mullikin JC, Sun HW, Gutierrez-Cruz G, Kim Y, Wilson AF, Kastner DL, Gül A, Remmers EF. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proc Natl Acad Sci U S A 2013;110(20):8134-9.
Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius CL, Maskeri B, Mullikin JC, Sun HW, Gutierrez-Cruz G, Kim Y, Wilson AF, Kastner DL, Gül A, Remmers EF. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8134-9. doi: 10.1073/pnas.1306352110. Epub 2013 Apr 30.
Ombrello MJ, Kastner DL, Milner JD. HOIL and water: the two faces of HOIL-1 deficiency. Nat Immunol. 2012;13(12):1133-5.
Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A, Martins MS, Bunney TD, Santich BH, Moir S, Kuhns DB, Priel DA, Ombrello A, Stone D, Ombrello MJ, Khan J, Milner J, Kastner DL, Aksentijevich I. A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency. Am J Hum Genet 2012;91(4):713-20.
Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, Subramanian N, Bunney TD, Baxendale RW, Martins MS, Romberg N, Komarow H, Aksentijevich I, Kim HS, Ho J, Cruse G, Jung MY, Gilfillan AM, Metcalfe DD, Nelson C, O'Brien M, Wisch L, Stone K, Douek DC, Gandhi C, Wanderer AA, Lee H, Nelson SF, Shianna KV, Cirulli ET, Goldstein DB, Long EO, Moir S, Meffre E, Holland SM, Kastner DL, Katan M, Hoffman HM, Milner JD. Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions. N Engl J Med 2012;366(4):330-8.
Ombrello MJ and Kastner DL. Autoinflammation in 2010: Expanding Clinical Spectrum and Broadening Therapeutic Horizons. Nat Rev Rheumatol 2011;7(2):82-4.
Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, Le JM, Yang B, Korman BD, Cakiris A, Aglar O, Emrence Z, Azakli H, Ustek D, Tugal-Tutkun I, Akman-Demir G, Chen W, Amos CI, Dizon MB, Kose AA, Azizlerli G, Erer B, Brand OJ, Kaklamani VG, Kaklamanis P, Ben-Chetrit E, Stanford M, Fortune F, Ghabra M, Ollier WE, Cho YH, Bang D, O'Shea J, Wallace GR, Gadina M, Kastner DL, Gül A. Genome-wide Association Study Identifies Variants in the MHC Class I, IL10, and IL23R-IL12RB2 Regions Associated with Behçet's Disease. Nat Genet 2010;42(8):698-702.
Low JM, Chauhan AK, Gibson DS, Zhu M, Chen S, Rooney M, Ombrello MJ, Moore TL. Proteomic Analysis of Circulating Immune Complexes in Juvenile Idiopathic Arthritis Reveals Disease-Associated Proteins. Proteomics Clin Appl 2009;3(7):829-40.