Whole Exome Trio Sequencing Implicates DOCK2 in Juvenile Idiopathic Arthritis

Laura A McIntosh^1,2, Yoshinori Fukui³, Thomas A. Griffin⁴, Kenneth Kaufman^1,2,5, Jarek Meller^6,7, Sherry Thornton⁸, Halima Moncrieffe^1,2 and Susan D Thompson^1,2, ¹Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ²Department of Pediatrics, University of Cincinnati, Cincinnati, OH, ³Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan, ⁴Levine Children’s Hospital at Carolinas Medical Center, Charlotte, NC, ⁵US Department of Veterans Affairs Medical Center, Cincinnati, OH, ⁶Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, ⁷Department of Environmental Health, University of Cincinnati, Cincinnati, OH, ⁸Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Arthritis, genetics, juvenile idiopathic arthritis (JIA), mouse model and neutrophils

Session Information

Date: Tuesday, October 23, 2018

Title: Pediatric Rheumatology – Basic Science Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood and has a strong genetic component to disease risk. Genome-wide association studies have been the primary method for understanding genetic risk in complex diseases, including JIA, but they do not fully explain disease inheritance. This study focuses on identifying de novo mutations (DNMs) among sporadic oligoarticular and rheumatoid factor-negative (RF^–) polyarticular JIA patients that may contribute to disease pathogenesis.

Methods: Whole exome sequencing (WES) and downstream bioinformatic analyses were used to identify rare, nonsynonymous DNMs among 10 oligoarticular or RF^– polyarticular JIA patient-parent trios. All cases met either the International League of Associations for Rheumatology (ILAR) or the American College of Rheumatology (ACR) classification for JIA. Analysis of these mutations implicated a role for DOCK2 in JIA. The impact of DOCK2 genetic deficiency in C57BL/6 mice on arthritis development and progression was evaluated using the autoantibody-induced, K/BxN serum-transfer model.

Results: Sanger sequencing confirmed 15 nonsynonymous DNMs identified by WES among 8 JIA trios. One DNM was located in DOCK2, whose gene product complexes with the gene products of two JIA-associated loci identified by association testing. In mice, DOCK2 deficiency resulted in decreased clinical measures of disease, while also reducing histopathological features in the forepaws, metacarpophalangeal joints, and knee joints induced by the K/BxN serum-transfer model. DOCK2 expression drives neutrophil infiltration into the hindpaws that can further exacerbate disease.

Conclusion: DOCK2 is a molecular determinant of autoantibody-induced arthritis that augments disease severity and pathology through a mechanism resulting in neutrophil infiltration. Furthermore, this study demonstrates the value of rare variant detection in understanding the genetic architecture of JIA.

Disclosure: L. A. McIntosh, None; Y. Fukui, None; T. A. Griffin, None; K. Kaufman, None; J. Meller, None; S. Thornton, None; H. Moncrieffe, None; S. D. Thompson, None.

To cite this abstract in AMA style:

McIntosh LA, Fukui Y, Griffin TA, Kaufman K, Meller J, Thornton S, Moncrieffe H, Thompson SD. Whole Exome Trio Sequencing Implicates DOCK2 in Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/whole-exome-trio-sequencing-implicates-dock2-in-juvenile-idiopathic-arthritis/. Accessed .

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