Overview

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.

Image & Media Gallery

Scientific Publications

 

 

Brief Report: Deficiency of Complement 1r Subcomponent in Early-Onset Systemic Lupus Erythematosus: The Role of Disease-Modifying Alleles in a Monogenic Disease.

Demirkaya E, Zhou Q, Smith CK, Ombrello MJ, Deuitch N, Tsai WL, Hoffmann P, Remmers EF, Takeuchi M, Park YH, Chae J, Barut K, Simsek D, Adrovic A, Sahin S, Caliskan S, Chandrasekharappa SC, Hasni SA, Ombrello AK, Gadina M, Kastner DL, Kaplan MJ, Kasapcopur O, Aksentijevich I
Arthritis & rheumatology (Hoboken, N.J.).
2017 Sep;
69(9).
doi: 10.1002/art.40158
PMID: 28544690

Barriers and Facilitators of Mentoring for Trainees and Early Career Investigators in Rheumatology Research: Current State, Identification of Needs, and Road Map to an Inter-Institutional Adult Rheumatology Mentoring Program.

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, Makris UE, American College of Rheumatology Early Career Investigator Subcommittee of the Committee on Research.
Arthritis care & research.
2018 Mar;
70(3).
doi: 10.1002/acr.23286
PMID: 28544766

Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

Takeuchi M, Mizuki N, 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, Gül A, Kastner DL, Remmers EF
Nature genetics.
2017 Mar;
49(3).
doi: 10.1038/ng.3786
PMID: 28166214

Case-control Association Study of Autoimmunity Associated Variants in PDCD1 and Juvenile Idiopathic Arthritis.

Tejeda C, Broadaway AK, Ombrello MJ, Brown MR, Ponder LA, Pichavant MR, Wang G, Angeles-Han S, Hersh A, Bohnsack J, Conneely KN, Epstein M, Prahalad S
Current rheumatology reviews.
2017;
13(3).
doi: 10.2174/1573397113666170104123113
PMID: 28056736

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.

Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg AM, Wedderburn LR, Anton J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group., Langefeld CD, Thompson S, Zeggini E, Kastner DL, Woo P, Thomson W
Annals of the rheumatic diseases.
2017 May;
76(5).
doi: 10.1136/annrheumdis-2016-210324
PMID: 27927641

Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet's disease.

Erer B, Takeuchi M, Ustek D, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Duymaz-Tozkir J, Gül A, Kastner DL, Remmers EF, Ombrello MJ
Genes and immunity.
2016 Dec;
17(7).
doi: 10.1038/gene.2016.36
PMID: 27708262

A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers.

Takeuchi M, Ombrello MJ, Kirino Y, Erer B, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Watts NR, Gül A, Kastner DL, Remmers EF
Annals of the rheumatic diseases.
2016 Dec;
75(12).
doi: 10.1136/annrheumdis-2015-209059
PMID: 27217550

Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis.

Muñoz-Cano R, Pascal M, Bartra J, Picado C, Valero A, Kim DK, Brooks S, Ombrello M, Metcalfe DD, Rivera J, Olivera A
The Journal of allergy and clinical immunology.
2016 Jan;
137(1).
doi: 10.1016/j.jaci.2015.05.042
PMID: 26194548

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.

Ombrello MJ, Remmers EF, Tachmazidou I, Grom A, Foell D, Haas JP, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Mellins ED, Ilowite NT, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg A, Wedderburn LR, Anton J, Schwarz T, Hinks A, Bilginer Y, Park J, Cobb J, Satorius CL, Han B, Baskin E, Signa S, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group., Childhood Arthritis Prospective Study (CAPS) Group., Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators., Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group., Biologically Based Outcome Predictors in JIA (BBOP) Group., de Bakker PI, Raychaudhuri S, Langefeld CD, Thompson S, Zeggini E, Thomson W, Kastner DL, Woo P, International Childhood Arthritis Genetics (INCHARGE) Consortium.
Proceedings of the National Academy of Sciences of the United States of America.
2015 Dec 29;
112(52).
doi: 10.1073/pnas.1520779112
PMID: 26598658

Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics.

Ombrello MJ, Kastner DL, Remmers EF
Current opinion in rheumatology.
2015 Jul;
27(4).
doi: 10.1097/BOR.0000000000000189
PMID: 26002026

Advances in the genetically complex autoinflammatory diseases.

Ombrello MJ
Seminars in immunopathology.
2015 Jul;
37(4).
doi: 10.1007/s00281-015-0498-0
PMID: 26077134

Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations.

Aderibigbe OM, Priel DL, Lee CC, Ombrello MJ, Prajapati VH, Liang MG, Lyons JJ, Kuhns DB, Cowen EW, Milner JD
JAMA dermatology.
2015 Jun;
151(6).
doi: 10.1001/jamadermatol.2014.5641
PMID: 25760457

Genetics, genomics, and their relevance to pathology and therapy.

Ombrello MJ, Sikora KA, Kastner DL
Best practice & research. Clinical rheumatology.
2014 Apr;
28(2).
doi: 10.1016/j.berh.2014.05.001
PMID: 24974057

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity.

Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF
Proceedings of the National Academy of Sciences of the United States of America.
2014 Jun 17;
111(24).
doi: 10.1073/pnas.1406575111
PMID: 24821759

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease.

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
Proceedings of the National Academy of Sciences of the United States of America.
2013 May 14;
110(20).
doi: 10.1073/pnas.1306352110
PMID: 23633568

Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency.

Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, Abhyankar A, Israël L, Trevejo-Nunez G, Bogunovic D, Cepika AM, MacDuff D, Chrabieh M, Hubeau M, Bajolle F, Debré M, Mazzolari E, Vairo D, Agou F, Virgin HW, Bossuyt X, Rambaud C, Facchetti F, Bonnet D, Quartier P, Fournet JC, Pascual V, Chaussabel D, Notarangelo LD, Puel A, Israël A, Casanova JL, Picard C
Nature immunology.
2012 Dec;
13(12).
doi: 10.1038/ni.2457
PMID: 23104095

A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency.

Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A, Martins MS, Bunney TD, Santich BH, Moir S, Kuhns DB, Long Priel DA, Ombrello A, Stone D, Ombrello MJ, Khan J, Milner JD, Kastner DL, Aksentijevich I
American journal of human genetics.
2012 Oct 5;
91(4).
doi: 10.1016/j.ajhg.2012.08.006
PMID: 23000145

Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

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
The New England journal of medicine.
2012 Jan 26;
366(4).
doi: 10.1056/NEJMoa1102140
PMID: 22236196

Autoinflammation in 2010: expanding clinical spectrum and broadening therapeutic horizons.

Ombrello MJ, Kastner DL
Nature reviews. Rheumatology.
2011 Feb;
7(2).
doi: 10.1038/nrrheum.2010.229
PMID: 21289614

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease.

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
Nature genetics.
2010 Aug;
42(8).
doi: 10.1038/ng.625
PMID: 20622878

Proteomic analysis of circulating immune complexes in juvenile idiopathic arthritis reveals disease-associated proteins.

Low JM, Chauhan AK, Gibson DS, Zhu M, Chen S, Rooney ME, Ombrello MJ, Moore TL
Proteomics. Clinical applications.
2009 Jul;
3(7).
doi: 10.1002/prca.200800073
PMID: 21136990

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Last Updated: May 2020