NextGen 2024: Genetics in SJIA Session Part 2

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