NextGen 2024: Genetics in SJIA Session Part 3

NextGen 2024: Genetics in SJIA Session Part 3

@SJIA_Foundation
@SJIA_Foundation
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3 months ago 578
AI Summary
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Key Insights
  • HLA-DRB1*15 is a common class II HLA allele group and a component of the common Eurasian ancestral haplotype.
  • HLA-DRB1*15 carriage varies by geography and ancestry with varying rates across regions.
  • HLA-DRB1*15 alleles are not associated with systemic juvenile idiopathic arthritis (sJIA) in both case-control populations and ImmunoChip studies.
  • Still's-Lung Disease and Drug Reactions are associated with HLA-DRB1*15 alleles, with the majority of Still's-Lung Disease cases carrying HLA-DRB1*15.
  • Coexistence of Lung Disease and Drug Reaction with shared HLA-DRB1*15 association suggests shared pathophysiology, but a specific mechanism remains unclear.
#stillsdisease #sjiafoundation #sjia #genetics #curesjia

NextGen 2024: Genetics in SJIA Session Part 3

@SJIA_Foundation3 months ago

What is the role of

HLA-DRB1*15 in Still's disease

Michael Ombrello

Translational Genetics and Genomics Section NIAMS Intramural Research Program

                      D ISCLOSURES

                      • · No conflicts of interest

                                          W HAT ARE H UMAN L EUKOCYTE A NTIGEN (HLA) P ROTEINS ?

                                                              W HAT ARE H UMAN L EUKOCYTE A NTIGEN (HLA) P ROTEINS ?

                                                              A family of proteins expressed on the surface of antigen presenting cells to display protein fragments (peptides or antigens) in a standardized way that enables T cell surveillance

                                                                                  W HAT IS HLA-DRB1*15?

                                                                                                      W HAT IS HLA-DRB1*15?

                                                                                                      · A common class II HLA allele group

                                                                                                      • · IE. HLA-DRB1*15:01, *15:02, *15:03, etc.

                                                                                                      · Common Eurasian ancestral haplotype

                                                                                                      • · DR15 ( DRB1*15:01 + DRB5*01:01 )
                                                                                                      • · DQ6 ( DQA1*01:02 + DQB1*06:02 )
                                                                                                      • · Cw7-B7 (C*07:02 + B* 07:02 )

                                                                                                      · Immunologically relevant

                                                                                                      • · Strongest genetic risk factor for MS
                                                                                                      • · RA, SLE, narcolepsy and Goodpasture disease
                                                                                                      • · ABPA, egg allergy, ragweed
                                                                                                      • · Altered immunity against EBV

                                                                                                                          W HAT IS THE R ELATIONSHIP BETWEEN HLA-DRB1*15 AND S YSTEMIC JIA?

                                                                                                                                              HLA-DRB1*15 A LLELES A RE N OT A SSOCIATED WITH S JIA

                                                                                                                                              9 independent case-control populations

                                                                                                                                                                  HLA-DRB1*15 D OES NOT A SSOCIATE WITH S JIA IN I MMUNO C HIP S TUDY

                                                                                                                                                                  Both of these studies were stringently controlled for ancestry at a genetic level

                                                                                                                                                                                      HLA-DRB1*15 C ARRIAGE V ARIES BY G EOGRAPHY AND A NCESTRY

                                                                                                                                                                                      Distribution of HLA-DRI5 in Europe; the Near East and North Africa

                                                                                                                                                                                      · HLA-DRB1*15 carriage rates

                                                                                                                                                                                      • · Myanmar 41-84%
                                                                                                                                                                                      • · China 23-27%
                                                                                                                                                                                      • · Europe 20-40%
                                                                                                                                                                                      • · South American 0-25%
                                                                                                                                                                                      • · USA
                                                                                                                                                                                      • · Asian 41%
                                                                                                                                                                                      • · African American 23-30%
                                                                                                                                                                                      • · European 29%
                                                                                                                                                                                      • · Hispanic 20%

                                                                                                                                                                                      Wobma 🡪 0.49 in sJIA

                                                                                                                                                                                      Lerman 🡪 0.74 in sJIA

                                                                                                                                                                                    allelefrequencies.net/hla6004a.asp?all_name=DRB1*15 Eupedia.com/genetics/HLA-DR_distribution_maps.shtml

                                                                                                                                                                                                        W HAT IS THE R ELATIONSHIP BETWEEN HLA-DRB1*15 AND S TILL ' S -L UNG D ISEASE ?

                                                                                                                                                                                                                            S TILL ' S -L UNG D ISEASE IS A SSOCIATED WITH HLA-DRB1*15 A LLELES

                                                                                                                                                                                                                            • 1. Still's-LD carriage of HLA-DRB1*15 = 82%
                                                                                                                                                                                                                            • 2. Still's-LD (n=47) vs. INCHARGE sJIA
                                                                                                                                                                                                                            • · HLA-DRB1*15 had an OR of 14.1 [6.4, 31]
                                                                                                                                                                                                                            • 3. Still's-LD (n=47) vs. 'drug tolerant' sJIA (n=31)
                                                                                                                                                                                                                            • · HLA-DRB1*15 had an OR 57.6 [11.5, 288]

                                                                                                                                                                                                                                                Thank you to Dr. Correia Marques for sharing this informative figure!

                                                                                                                                                                                                                                                                    W HAT IS THE R ELATIONSHIP BETWEEN HLA-DRB1*15 AND D RUG R EACTIONS ?

                                                                                                                                                                                                                                                                                        D RUG R EACTIONS IN S TILL ' S D ISEASE A SSOCIATE WITH HLA-DRB1*15 A LLELES

                                                                                                                                                                                                                                                                                        • 1. Drug reaction carriage of HLA-DRB1*15 = 82%
                                                                                                                                                                                                                                                                                        • 2. Drug reaction, no LD (n=18) vs. INCHARGE sJIA
                                                                                                                                                                                                                                                                                        • · HLA-DRB1*15 had an OR 11.0 [4, 30.1]
                                                                                                                                                                                                                                                                                        • 3. Still's with drug reaction (n=65) vs. 'drug tolerant' sJIA (n=31)
                                                                                                                                                                                                                                                                                        • · HLA-DRB1*15 had an OR 54.9 [11.6, 261]

                                                                                                                                                                                                                                                                                        Unique combination of immediate and delayed-type reactions

                                                                                                                                                                                                                                                                                                            Thank you to Dr. Correia Marques for sharing this informative figure!

                                                                                                                                                                                                                                                                                                            HLA-DRB1*15 in drug reaction (surrogate): 78/92 (84.8%)

                                                                                                                                                                                                                                                                                                                                W HAT C ONNECTS HLA-DRB1*15 WITH D RUG R EACTION /LD?

                                                                                                                                                                                                                                                                                                                                • · Coexistant LD and drug reaction with shared HLA association suggests shared pathophysiology, but a specific mechanism unclear
                                                                                                                                                                                                                                                                                                                                • 1. Reaction to the drug (active ingredient)
                                                                                                                                                                                                                                                                                                                                • 2. Reaction to the drug (not active ingredient)
                                                                                                                                                                                                                                                                                                                                • 3. Still's disease-specific compensatory shift (biologic effect of drug)
                                                                                                                                                                                                                                                                                                                                • 4. Related to viral infection, exogenous modifier or new exposure
                                                                                                                                                                                                                                                                                                                                • 5. Related to another gene co-inherited on DR15 haplotype
                                                                                                                                                                                                                                                                                                                                • 6. Something beyond the bounds of my imagination

                                                                                                                                                                                                                                                                                                                                                    W HAT C ONNECTS HLA-DRB1*15 WITH D RUG R EACTION /LD?

                                                                                                                                                                                                                                                                                                                                                    1. Antigen dependent

                                                                                                                                                                                                                                                                                                                                                    • · MHC presentation of altered peptide (neoantigen, hapten)
                                                                                                                                                                                                                                                                                                                                                    • · Novel antigenic pathogen or exposure

                                                                                                                                                                                                                                                                                                                                                    2. Antigen independent

                                                                                                                                                                                                                                                                                                                                                    • · Cytokine shifting/skewing
                                                                                                                                                                                                                                                                                                                                                    • · Non-antigenic stimulation
                                                                                                                                                                                                                                                                                                                                                    • · Effect of linked non-classical HLA gene

                                                                                                                                                                                                                                                                                                                                                                        Still's disease!

                                                                                                                                                                                                                                                                                                                                                                                            Acknowledgements

                                                                                                                                                                                                                                                                                                                                                                                            Translational Genetics and Genomics Section, NIAMS

                                                                                                                                                                                                                                                                                                                                                                                            Hiroto Nakano, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                            Mariana Correia Marques, MD

                                                                                                                                                                                                                                                                                                                                                                                            Kathleen Baysac, PhD

                                                                                                                                                                                                                                                                                                                                                                                            Anthony Cruz

                                                                                                                                                                                                                                                                                                                                                                                            Brooke Boyd

                                                                                                                                                                                                                                                                                                                                                                                            Mallika Datta

                                                                                                                                                                                                                                                                                                                                                                                            Ann Marie Szymanski, MD

                                                                                                                                                                                                                                                                                                                                                                                            Alana Platukus

                                                                                                                                                                                                                                                                                                                                                                                            Danielle Rubin

                                                                                                                                                                                                                                                                                                                                                                                            Charles Fisher

                                                                                                                                                                                                                                                                                                                                                                                            Alexis Bailey

                                                                                                                                                                                                                                                                                                                                                                                            Emily Shuldiner

                                                                                                                                                                                                                                                                                                                                                                                            Victoria Arthur, PhD

                                                                                                                                                                                                                                                                                                                                                                                            Andrew Patt, PhD

                                                                                                                                                                                                                                                                                                                                                                                            Elizabeth Baskin

                                                                                                                                                                                                                                                                                                                                                                                          Office of the Clincal Director, NIAMS

                                                                                                                                                                                                                                                                                                                                                                                          Michelle Millwood Carol Lake Ly-Lan Bergeron Estefania De Los Santos

                                                                                                                                                                                                                                                                                                                                                                                          Biodata Mining Section, NIAMS

                                                                                                                                                                                                                                                                                                                                                                                          Zuoming Deng, PhD Stephen Brooks, PhD

                                                                                                                                                                                                                                                                                                                                                                                          Inflammatory Disease Section, NHGRI

                                                                                                                                                                                                                                                                                                                                                                                          Amanda Ombrello, MD

                                                                                                                                                                                                                                                                                                                                                                                          Elaine Remmers, PhD

                                                                                                                                                                                                                                                                                                                                                                                          Daniel Kastner, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                          University of Cincinnati/ CCHMC

                                                                                                                                                                                                                                                                                                                                                                                          Grant Schulert, MD PhD Alexei Grom, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                          Stanford University

                                                                                                                                                                                                                                                                                                                                                                                          Elizabeth Mellins, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                          Vivian Saper, MD

                                                                                                                                                                                                                                                                                                                                                                                          Children's Hospital of Philadelphia

                                                                                                                                                                                                                                                                                                                                                                                          Scott Canna, MD

                                                                                                                                                                                                                                                                                                                                                                                          University of California San Francisco

                                                                                                                                                                                                                                                                                                                                                                                          Jill Hollenbach, PhD

                                                                                                                                                                                                                                                                                                                                                                                        We appreciate the selfless contributions of our patients and their families to our studies of sJIA and AOSD.

                                                                                                                                                                                                                                                                                                                                                                                        Boston Children's Hospital

                                                                                                                                                                                                                                                                                                                                                                                        Lauren Henderson, MD

                                                                                                                                                                                                                                                                                                                                                                                      INCHARGE Consortium

                                                                                                                                                                                                                                                                                                                                                                                      Jordi Anton, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                      John Bohnsack, MD

                                                                                                                                                                                                                                                                                                                                                                                      Dirk Föll, MD

                                                                                                                                                                                                                                                                                                                                                                                      Marco Gattorno MD

                                                                                                                                                                                                                                                                                                                                                                                      Alexei Grom, MD

                                                                                                                                                                                                                                                                                                                                                                                      Johannes-Peter Haas MD PhD

                                                                                                                                                                                                                                                                                                                                                                                      Cladio Len MD

                                                                                                                                                                                                                                                                                                                                                                                      Alberto Martini MD

                                                                                                                                                                                                                                                                                                                                                                                      Kirsten Minden, MD

                                                                                                                                                                                                                                                                                                                                                                                      Elizabeth Mellins MD

                                                                                                                                                                                                                                                                                                                                                                                      Sheila Oliviera, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                      Seza Ozen, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                      Sampath Prahalad, MD

                                                                                                                                                                                                                                                                                                                                                                                      Elaine Remmers, PhD

                                                                                                                                                                                                                                                                                                                                                                                      Angela Rosen-Wolff, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                      Alan Rosenberg, MD

                                                                                                                                                                                                                                                                                                                                                                                      Klaus Tenbrock, MD

                                                                                                                                                                                                                                                                                                                                                                                      Susan Thompson, PhD

                                                                                                                                                                                                                                                                                                                                                                                      Wendy Thomson, PhD

                                                                                                                                                                                                                                                                                                                                                                                      Lucy Wedderburn, MD PhD

                                                                                                                                                                                                                                                                                                                                                                                      Patricia Woo, MBBS PhD

                                                                                                                                                                                                                                                                                                                                                                                      Rae Yeung, MD PhD

What is the role of 
HLA-DRB1*15 in Still’s 
disease
Michael Ombrello
Translational Genetics an…
1/20
DISCLOSURES
•No conflicts of interest
2/20
WHAT ARE HUMAN LEUKOCYTE
ANTIGEN (HLA) PROTEINS?
3/20
WHAT ARE HUMAN LEUKOCYTE ANTIGEN
(HLA) PROTEINS?
A family of proteins expressed on the surface of…
4/20
WHAT IS HLA-DRB1*15?
5/20
WHAT IS HLA-DRB1*15?
• A common class II HLA allele group
• IE. HLA-DRB1*15:01, *15:02, *15:03, e…
6/20
WHAT IS THE RELATIONSHIP BETWEEN
HLA-DRB1*15 AND SYSTEMIC
JIA?
7/20
HLA-DRB1*15 ALLELES ARE NOT
ASSOCIATED WITH SJIA
Ombrello MJ et al, 2015 (PMID 26598658)
9 indep…
8/20
HLA-DRB1*15 DOES NOT ASSOCIATE
WITH SJIA IN IMMUNOCHIP STUDY
Unpublished Data
Both of these stud…
9/20
HLA-DRB1*15 CARRIAGE VARIES BY
GEOGRAPHY AND ANCESTRY
• HLA-DRB1*15 carriage rates
• Myanmar 41-…
10/20
WHAT IS THE RELATIONSHIP BETWEEN
HLA-DRB1*15 AND STILL’S-LUNG
DISEASE?
11/20
STILL’S-LUNG DISEASE IS ASSOCIATED WITH
HLA-DRB1*15 ALLELES
1. Still’s-LD carriage of HLA-DRB1*15…
12/20
3
6
1 0
0
7 3
Lerman 2023
Drug reaction
Lung disease
HLA-DRB1*15+
All negative
3
1
5
1…
13/20
WHAT IS THE RELATIONSHIP BETWEEN
HLA-DRB1*15 AND DRUG
REACTIONS?
14/20
DRUG REACTIONS IN STILL’S DISEASE ASSOCIATE
WITH HLA-DRB1*15 ALLELES
1. Drug reaction carriage of…
15/20
HLA-DRB1*15 in drug reaction (surrogate): 78/92 (84.8%)
3
6
1 0
0
7 3
Lerman 2023
Drug react…
16/20
WHAT CONNECTS HLA-DRB1*15 WITH
DRUG REACTION/LD?
•Coexistant LD and drug reaction with shared HLA…
17/20
WHAT CONNECTS HLA-DRB1*15 WITH
DRUG REACTION/LD?
1. Antigen dependent
• MHC presentation of alte…
18/20
Still’s disease!
19/20
Acknowledgements
Translational Genetics and Genomics Section, NIAMS
 Hiroto Nakano, MD PhD
 Mari…
20/20


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