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.

Contact Us

Susan Bozak

Staff Assistant
9000 Rockville Pike
Building: 10, Room: 6N204
Bethesda MD 20892

Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:

Staff

Tenure Track Investigator, Head
301-435-4037
Postdoctoral Fellow
301-451-4362
Biologist
301-496-9896
Postbaccalaureate Fellow
Postdoctoral Fellow (Visiting)
301-451-4362

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Clinical Trials

RECRUITING

Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still's Disease, and Related Conditions

ClinicalTrials.gov Identifier: NCT03510442

The purpose of this protocol is to study the natural history, genetics and pathophysiology of systemic juvenile idiopathic arthritis (sJIA), adult-onset Still s disease (AOSD) and related inflammatory conditions. One of seven subtypes of juvenile idiopathic arthritis (JIA), sJIA contributes disproportionately to the morbidity and mortality of JIA and is considered by many to be the most severe JIA subtype. sJIA typically presents with fever of unknown origin and arthritis, together with evanescent skin rash, serositis, hepatosplenomegaly and lymphadenopathy. It is strongly associated with macrophage activation syndrome (MAS), which has a high fatality rate when untreated. AOSD is phenotypically similar to sJIA in presentation, progression and association with MAS, however it develops after the 16th birthday. The causes sJIA and AOSD are poorly understood.

Scientific Publications

Selected Recent 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 Rheumatol.
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 Res (Hoboken).
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
Nat Genet.
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
Curr Rheumatol Rev.
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
Ann Rheum Dis.
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 Immun.
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
Ann Rheum Dis.
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
J Allergy Clin Immunol.
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.
Proc Natl Acad Sci U S A.
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
Curr Opin Rheumatol.
2015 Jul;
27(4).
doi: 10.1097/BOR.0000000000000189
PMID: 26002026

Advances in the genetically complex autoinflammatory diseases.

Ombrello MJ
Semin Immunopathol.
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 Dermatol.
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 Pract Res Clin Rheumatol.
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
Proc Natl Acad Sci U S A.
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
Proc Natl Acad Sci U S A.
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
Nat Immunol.
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
Am J Hum Genet.
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
N Engl J Med.
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
Nat Rev Rheumatol.
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
Nat Genet.
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 Clin Appl.
2009 Jul;
3(7).
doi: 10.1002/prca.200800073
PMID: 21136990

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