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    NextGen 2024: Genetics in SJIA Session Part 2

    NextGen 2024: Genetics in SJIA Session Part 2

    S
    @SJIA_Foundation
    8 Followers
    5 months ago 351

    AIAI Summary

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    Key Insights

    #Sjiafoundation#Sjia#Curesjia#Genetics
    Recent discoveries in 
genomics of sJIA
Mariana Correia Marques, MD
Lawrence Shulman Scholar in Translational Research
Translational Genetics and Genomics Section
National Institute of Arthritis and Musculoskeletal and Skin Diseases
    1/19
    Disclosures
•None
    2/19
    What insights can we gain from genetics?
Disease 
development
Disease 
prognosis
Treatment 
response
    3/19
    Impact on genetics on the risk of 
developing disease
Rare 
variants
High impact
Common 
variants
Low impact
Low-frequency 
variants
Medium impact
Variant 
Frequency
Variant
Impact
    4/19
    Impact on genetics on the risk of 
developing disease
Rare 
variants
High impact
Common 
variants
Low impact
Low-frequency 
variants
Medium impact
Variant 
Frequency
Variant
Impact
    5/19
    Common variants – Candidate Gene Studies
Marques, Ombrello, Schulert, 2024, Expert Rev. Clin. Immunol.
    6/19
    Common variants - GWAS
Ombrello et al, 2015, PNAS
Ombrello et al, 2017, ARD
Arthur et al, 2018, A&R
Nakano et at, ACR Convergence 2022
• HLA-DRB1*11 and MHC class II locus – strongest 
association with sJIA – (OR 2.3)
• Implicated adaptive immune system in sJIA
• sJIA has different genetic architecture from other 
forms of JIA
• SNPs in the IL1RN promoter region associated with 
lower IL1RN expression also associated with sJIA 
(OR 1.3)
❖ Regulatory haplotype of CXC4 is associated with 
sJIA and is correlated with neutrophil and monocyte 
migration
    7/19
    Impact on genetics on the risk of 
developing disease
Rare 
variants
High impact
Common 
variants
Low impact
Low-frequency 
variants
Medium impact
Variant 
Frequency
Variant
Impact
    8/19
    Rare / Low frequency variants
Marques et al, 2024, A&R
• Rare/ultra-rare variants in HLH genes 
associated with sJIA in general
• STXBP2 and UNC13D individually 
associated with sJIA
• sJIA patients more often carried 2 
variants in HLH genes
• PRF1 A91V not associated with sJIA 
or MAS
    9/19
    Impact on genetics on the risk of 
developing disease
Rare 
variants
High impact
Common 
variants
Low impact
Low-frequency 
variants
Medium impact
Variant 
Frequency
Variant
Impact
    10/19
    Manki et al, 2006, Allergol Int
Alansari et al, 2023, J Rheum Dis
• 12 girls 1 boy who met ILAR criteria for sJIA
• Fever + symmetrical polyarthritis + 
maculopapular rash
• 8/13 + ANA, 5/13 + RF
• Segregated with homozygous LACC1 variant
• Same variant also reported in IBD with severe 
arthropathy
• Other variants in LACC1 associated with 
non-systemic JIA
Rare variants causing monogenic disease
LACC1 p.C284R
CASP1 IRAK2* MEFV TNFRSF1A SLC29A3
Proposed Genes that could cause sJIA Mimickers 
Wakil et al, 2015, A&R
Jorgensen et al, 2020, Rheumatology
Marques et al, 2024 ACR convergence*
    11/19
    What insights can we gain from genetics?
Disease 
development
Disease 
prognosis
Treatment 
response
    12/19
    Treatment response
IL1RN promoter 
SNPs
IL1RA IL1RA
risk of sJIA response to anakinra
    13/19
    Treatment response
IL1RN promoter 
SNPs
IL1RA IL1RA
risk of sJIA response to anakinra
    14/19
    Treatment response
IL1RN promoter 
SNPs
IL1RA IL1RA
risk of sJIA response to anakinra
    15/19
    Treatment response
IL1RN promoter 
SNPs
IL1RA IL1RA
risk of sJIA response to anakinra
    16/19
    What insights can we gain from genetics?
Disease 
development
Disease 
prognosis
Treatment 
response
    17/19
    Disease prognosis
HLH variants 
associated with risk of 
MAS
HLA-DRB1*15 
associated with lung 
disease and reactions 
to biologics
Dr. Cron Dr. Ombrello
    18/19
    The NIAMS Still’s Disease Team
Dale Kobrin, MD
Rheumatology Fellow
Ly-Lan Bergeron, PA
Physician Assistant
Carol Lake, FNP
Nurse Practitioner
Michelle Millwood, BSN
Research Nurse
THANK
YOU! We appreciate the contributions of our patients 
and their families to our studies of sJIA and AOSD.
Estefania De Los Santos
Patient Care Coordinator
Translational Genetics and Genomics Section, NIAMS
Michael Ombrello, MD
Dale Kobrin, MD
Navid Chowdhury
Anthony Cruz
Brooke Boyd
Sophia Chou
Mallika Datta
Elizabeth Schmitz
Alana Platukus
Biodata Mining Section, NIAMS
Zuoming Deng, PhD
Stephen Brooks, PhD
Translational Immunology Section, NIAMS
Massimo Gadina, PhD
Shajia Lu
Genome Technology Section, NIAMS
Stefania Dell’Orso, PhD
Michael Ombrello, MD
Principal Investigator
    19/19

    NextGen 2024: Genetics in SJIA Session Part 2

    • 1. Recent discoveries in genomics of sJIA Mariana Correia Marques, MD Lawrence Shulman Scholar in Translational Research Translational Genetics and Genomics Section National Institute of Arthritis and Musculoskeletal and Skin Diseases
    • 2. Disclosures •None
    • 3. What insights can we gain from genetics? Disease development Disease prognosis Treatment response
    • 4. Impact on genetics on the risk of developing disease Rare variants High impact Common variants Low impact Low-frequency variants Medium impact Variant Frequency Variant Impact
    • 5. Impact on genetics on the risk of developing disease Rare variants High impact Common variants Low impact Low-frequency variants Medium impact Variant Frequency Variant Impact
    • 6. Common variants – Candidate Gene Studies Marques, Ombrello, Schulert, 2024, Expert Rev. Clin. Immunol.
    • 7. Common variants - GWAS Ombrello et al, 2015, PNAS Ombrello et al, 2017, ARD Arthur et al, 2018, A&R Nakano et at, ACR Convergence 2022 • HLA-DRB1*11 and MHC class II locus – strongest association with sJIA – (OR 2.3) • Implicated adaptive immune system in sJIA • sJIA has different genetic architecture from other forms of JIA • SNPs in the IL1RN promoter region associated with lower IL1RN expression also associated with sJIA (OR 1.3) ❖ Regulatory haplotype of CXC4 is associated with sJIA and is correlated with neutrophil and monocyte migration
    • 8. Impact on genetics on the risk of developing disease Rare variants High impact Common variants Low impact Low-frequency variants Medium impact Variant Frequency Variant Impact
    • 9. Rare / Low frequency variants Marques et al, 2024, A&R • Rare/ultra-rare variants in HLH genes associated with sJIA in general • STXBP2 and UNC13D individually associated with sJIA • sJIA patients more often carried 2 variants in HLH genes • PRF1 A91V not associated with sJIA or MAS
    • 10. Impact on genetics on the risk of developing disease Rare variants High impact Common variants Low impact Low-frequency variants Medium impact Variant Frequency Variant Impact
    • 11. Manki et al, 2006, Allergol Int Alansari et al, 2023, J Rheum Dis • 12 girls 1 boy who met ILAR criteria for sJIA • Fever + symmetrical polyarthritis + maculopapular rash • 8/13 + ANA, 5/13 + RF • Segregated with homozygous LACC1 variant • Same variant also reported in IBD with severe arthropathy • Other variants in LACC1 associated with non-systemic JIA Rare variants causing monogenic disease LACC1 p.C284R CASP1 IRAK2* MEFV TNFRSF1A SLC29A3 Proposed Genes that could cause sJIA Mimickers Wakil et al, 2015, A&R Jorgensen et al, 2020, Rheumatology Marques et al, 2024 ACR convergence*
    • 12. What insights can we gain from genetics? Disease development Disease prognosis Treatment response
    • 13. Treatment response IL1RN promoter SNPs IL1RA IL1RA risk of sJIA response to anakinra
    • 14. Treatment response IL1RN promoter SNPs IL1RA IL1RA risk of sJIA response to anakinra
    • 15. Treatment response IL1RN promoter SNPs IL1RA IL1RA risk of sJIA response to anakinra
    • 16. Treatment response IL1RN promoter SNPs IL1RA IL1RA risk of sJIA response to anakinra
    • 17. What insights can we gain from genetics? Disease development Disease prognosis Treatment response
    • 18. Disease prognosis HLH variants associated with risk of MAS HLA-DRB1*15 associated with lung disease and reactions to biologics Dr. Cron Dr. Ombrello
    • 19. The NIAMS Still’s Disease Team Dale Kobrin, MD Rheumatology Fellow Ly-Lan Bergeron, PA Physician Assistant Carol Lake, FNP Nurse Practitioner Michelle Millwood, BSN Research Nurse THANK YOU! We appreciate the contributions of our patients and their families to our studies of sJIA and AOSD. Estefania De Los Santos Patient Care Coordinator Translational Genetics and Genomics Section, NIAMS Michael Ombrello, MD Dale Kobrin, MD Navid Chowdhury Anthony Cruz Brooke Boyd Sophia Chou Mallika Datta Elizabeth Schmitz Alana Platukus Biodata Mining Section, NIAMS Zuoming Deng, PhD Stephen Brooks, PhD Translational Immunology Section, NIAMS Massimo Gadina, PhD Shajia Lu Genome Technology Section, NIAMS Stefania Dell’Orso, PhD Michael Ombrello, MD Principal Investigator


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