Identification and evaluation of 41 risk loci for juvenile idiopathic arthritis informs precision medicine: mechanistic implications of DNA topology and an HLA-A*02:01-ERAP2 interaction
- 1Wake Forest University School of Medicine, USA
Abstract
Juvenile idiopathic arthritis (JIA), the most common class of pediatric rheumatic diseases, can lead to joint damage and extra-articular features including uveitis. Early treatment can improve functional outcomes; but many patients do not respond to first-line treatments. We present a JIA Immunochip-based association analysis of rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. This study spans 3,939 cases and 14,412 controls, including 1,123 cases and 1,356 controls not previously analyzed. We identify 41 (14 novel) JIA risk regions and report a JIA polygenic risk score that also associates with age of onset. Functional mechanisms presented include: a novel interaction between HLA-A*02:01 and ERAP2, cluster-based approach for functional amino acid discovery within HLA-DRB1, and sequence-dependent DNA topology for variant prioritization. We present a comprehensive list of curated gene-drug/small molecule interactions for clinically focused studies. These findings provide a deepened understanding of the genetics of JIA and potential mechanisms to inform precision medicine.
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BibTeX
@misc{ainsworth2026identification,
title = {{Identification and evaluation of 41 risk loci for juvenile idiopathic arthritis informs precision medicine: mechanistic implications of DNA topology and an HLA-A*02:01-ERAP2 interaction}},
author = {H. C. Ainsworth and E. S. Khvatkova and M. Sudman and M. C. Marion and K. Jiang and J. F. Bohnsack and M. E. Comeau and P. M. Gaffney and J.-P. Haas and T. D. Howard and K. Hyrich and J. A. James and P. A. Nigrovic and E. B. Nordal and A. M. Rosenberg and M. Rygg and S. L. Smith and V. Videm and L. R. Wedderburn and C. A. Wise and R. S. Yeung and S. D. Thompson and G. S. Schulert and S. Prahalad and J. Bowes and S. T. Angeles-Han and J. N. Jarvis and C. D. Langefeld},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.26363161},
url = {https://www.medrxiv.org/content/10.64898/2026.09.16.26363161v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Identification and evaluation of 41 risk loci for juvenile idiopathic arthritis informs precision medicine: mechanistic implications of DNA topology and an HLA-A*02:01-ERAP2 interaction
AU - H. C. Ainsworth
AU - E. S. Khvatkova
AU - M. Sudman
AU - M. C. Marion
AU - K. Jiang
AU - J. F. Bohnsack
AU - M. E. Comeau
AU - P. M. Gaffney
AU - J.-P. Haas
AU - T. D. Howard
AU - K. Hyrich
AU - J. A. James
AU - P. A. Nigrovic
AU - E. B. Nordal
AU - A. M. Rosenberg
AU - M. Rygg
AU - S. L. Smith
AU - V. Videm
AU - L. R. Wedderburn
AU - C. A. Wise
AU - R. S. Yeung
AU - S. D. Thompson
AU - G. S. Schulert
AU - S. Prahalad
AU - J. Bowes
AU - S. T. Angeles-Han
AU - J. N. Jarvis
AU - C. D. Langefeld
PY - 2026
DA - 2026/09/16
PB - medRxiv
DO - 10.64898/2026.09.16.26363161
UR - https://www.medrxiv.org/content/10.64898/2026.09.16.26363161v1
AB - Juvenile idiopathic arthritis (JIA), the most common class of pediatric rheumatic diseases, can lead to joint damage and extra-articular features including uveitis. Early treatment can improve functional outcomes; but many patients do not respond to first-line treatments. We present a JIA Immunochip-based association analysis of rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. This study spans 3,939 cases and 14,412 controls, including 1,123 cases and 1,356 controls not previously analyzed. We identify 41 (14 novel) JIA risk regions and report a JIA polygenic risk score that also associates with age of onset. Functional mechanisms presented include: a novel interaction between HLA-A*02:01 and ERAP2, cluster-based approach for functional amino acid discovery within HLA-DRB1, and sequence-dependent DNA topology for variant prioritization. We present a comprehensive list of curated gene-drug/small molecule interactions for clinically focused studies. These findings provide a deepened understanding of the genetics of JIA and potential mechanisms to inform precision medicine.
ER -