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:

Image & Media Gallery

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

Inflammatory conditions can cause symptoms like fevers, arthritis, and rash. Systemic juvenile idiopathic arthritis (sJIA) is one of these conditions. So is adult-onset Still's disease (AOSD). Their causes are unknown. Researchers want to learn more about these conditions. This includes genetic changes and environmental factors.

The objective of this trial is to study sJIA and AOSD in children and adults over time. Patients enrolled in this protocol will undergo screening history, physical examination, and laboratory evaluation. At times, we may ask for permission to evaluate additional family members. We will collect peripheral blood samples for genetic and functional studies from affected patients, unrelated healthy volunteers, and in some cases, patients' family members. We will ask permission to perform whole genome/exome sequencing. We also may ask some patients to undergo skin biopsy for research purposes.

Scientific Publications

Selected Recent Publications

Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

Saper VE, Ombrello MJ, Tremoulet AH, Montero-Martin G, Prahalad S, Canna S, Shimizu C, Deutsch G, Tan SY, Remmers EF, Monos D, Hahn T, Phadke OK, Cassidy E, Ferguson I, Mallajosyula V, Xu J, Rosa Duque JS, Chua GT, Ghosh D, Szymanski AM, Rubin D, Burns JC, Tian L, Fernandez-Vina MA, Mellins ED, Hollenbach JA, Drug Hypersensitivity Consortium., INCHARGE Consortium.
Ann Rheum Dis.
2022 Mar;
81(3).
doi: 10.1136/annrheumdis-2021-220578
PMID: 34789453

A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies.

Skeens E, Pantouris G, Shah D, Manjula R, Ombrello MJ, Maluf NK, Bhandari V, Lisi GP, Lolis EJ
Front Mol Biosci.
2022;
9().
doi: 10.3389/fmolb.2022.783669
PMID: 35252348

2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis.

Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT
Arthritis Rheumatol.
2022 Apr;
74(4).
doi: 10.1002/art.42037
PMID: 35233993

2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging.

Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT
Arthritis Care Res (Hoboken).
2022 Apr;
74(4).
doi: 10.1002/acr.24839
PMID: 35233989

2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis.

Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT
Arthritis Care Res (Hoboken).
2022 Apr;
74(4).
doi: 10.1002/acr.24853
PMID: 35233986

2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging.

Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT
Arthritis Rheumatol.
2022 Apr;
74(4).
doi: 10.1002/art.42036
PMID: 35233961

Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

Saper VE, Ombrello MJ, Tremoulet AH, Montero-Martin G, Prahalad S, Canna S, Shimizu C, Deutsch G, Tan SY, Remmers EF, Monos D, Hahn T, Phadke OK, Cassidy E, Ferguson I, Mallajosyula V, Xu J, Rosa Duque JS, Chua GT, Ghosh D, Szymanski AM, Rubin D, Burns JC, Tian L, Fernandez-Vina MA, Mellins ED, Hollenbach JA, Drug Hypersensitivity Consortium., INCHARGE Consortium.
Ann Rheum Dis.
2022 Mar;
81(3).
doi: 10.1136/annrheumdis-2021-220578
PMID: 34789453

COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome?

Ombrello MJ, Schulert GS
Transl Res.
2021 Jun;
232().
doi: 10.1016/j.trsl.2021.03.002
PMID: 33684592

Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease.

Nagai H, Kirino Y, Nakano H, Kunishita Y, Henmi R, Szymanski AM, Yoshimi R, Ombrello MJ, Nakajima H
Rheumatology (Oxford).
2021 Aug 2;
60(8).
doi: 10.1093/rheumatology/keaa814
PMID: 33550379

Clinical characteristics and comorbidities in adult-onset Still's disease using a large US administrative claims database.

Lenert A, Oh G, Ombrello MJ, Kim S
Rheumatology (Oxford).
2020 Jul 1;
59(7).
doi: 10.1093/rheumatology/kez622
PMID: 31965185

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis.

Ringold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA, Becker ML, Colbert RA, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Horonjeff J, Nigrovic PA, Ombrello MJ, Passo MH, Stoll ML, Rabinovich CE, Schneider R, Halyabar O, Hays K, Shah AA, Sullivan N, Szymanski AM, Turgunbaev M, Turner A, Reston J
Arthritis Rheumatol.
2019 Jun;
71(6).
doi: 10.1002/art.40884
PMID: 31021537

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

Angeles-Han ST, Ringold S, Beukelman T, Lovell D, Cuello CA, Becker ML, Colbert RA, Feldman BM, Holland GN, Ferguson PJ, Gewanter H, Guzman J, Horonjeff J, Nigrovic PA, Ombrello MJ, Passo MH, Stoll ML, Rabinovich CE, Sen HN, Schneider R, Halyabar O, Hays K, Shah AA, Sullivan N, Szymanski AM, Turgunbaev M, Turner A, Reston J
Arthritis Rheumatol.
2019 Jun;
71(6).
doi: 10.1002/art.40885
PMID: 31021511

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

Arthur VL, Shuldiner E, Remmers EF, Hinks A, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Oliveira S, Yeung RSM, Rosenberg AM, Wedderburn LR, Anton J, Haas JP, Rösen-Wolff A, Minden K, Szymanski AM, INCHARGE Consortium., Thomson W, Kastner DL, Woo P, Ombrello MJ
Arthritis Rheumatol.
2018 Aug;
70(8).
doi: 10.1002/art.40498
PMID: 29609200

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

Key Publications

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

Arthur VL, Shuldiner E, Remmers EF, Hinks A, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Oliveira S, Yeung RSM, Rosenberg AM, Wedderburn LR, Anton J, Haas JP, Rösen-Wolff A, Minden K, Szymanski AM, INCHARGE Consortium., Thomson W, Kastner DL, Woo P, Ombrello MJ
Arthritis Rheumatol.
2018 Aug;
70(8).
doi: 10.1002/art.40498
PMID: 29609200

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

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

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

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

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

News & Highlights

NIAMS-Related Article | January 13, 2022

Genetic Sequencing Solves Drug Reaction Mystery

A researcher from Stanford University asked IRP investigator Michael Ombrello, M.D., to help her team follow a new lead in the mystery of why some patients with a rare inflammatory condition called Still’s disease were coming down with a life-threatening lung ailment.