NextGen 2024: Genetics in SJIA Session Part 3
NextGen 2024: Genetics in SJIA Session Part 3
- 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.
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

- · No conflicts of interest
- · IE. HLA-DRB1*15:01, *15:02, *15:03, etc.
- · DR15 ( DRB1*15:01 + DRB5*01:01 )
- · DQ6 ( DQA1*01:02 + DQB1*06:02 )
- · Cw7-B7 (C*07:02 + B* 07:02 )
- · Strongest genetic risk factor for MS
- · RA, SLE, narcolepsy and Goodpasture disease
- · ABPA, egg allergy, ragweed
- · Altered immunity against EBV
- · Myanmar 41-84%
- · China 23-27%
- · Europe 20-40%
- · South American 0-25%
- · USA
- · Asian 41%
- · African American 23-30%
- · European 29%
- · Hispanic 20%
- 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]
- 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]
- · 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
- · MHC presentation of altered peptide (neoantigen, hapten)
- · Novel antigenic pathogen or exposure
- · Cytokine shifting/skewing
- · Non-antigenic stimulation
- · Effect of linked non-classical HLA gene

D ISCLOSURES

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
· Common Eurasian ancestral haplotype
· Immunologically relevant


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

Wobma 𡪠0.49 in sJIA
Lerman 𡪠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

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

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?

W HAT C ONNECTS HLA-DRB1*15 WITH D RUG R EACTION /LD?
1. Antigen dependent
2. Antigen independent

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




















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