Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Detection of Potentially Disease Associated Copy Number Variants in Children with Rheumatoid Arthritis.

Prahalad1,  Sampath, Mulle2,  Jennifer Gladys, Dodd3,  Anne, Prozonic3,  Jennifer, Brown3,  Milton, Zeft4,  Andrew S., Bohnsack4,  John F.

Emory Children's Center, Atlanta, GA
Emory University, Atlanta, GA
Emory University
University of Utah, Salt Lake City, UT


Rheumatoid arthritis (RA) is a common chronic inflammatory arthropathy with a peak age of onset in the fifth decade. About 5% of children with juvenile idiopathic arthritis phenotypically resemble adult RA. We hypothesize that children with the RA phenotype are a genetically enriched early-onset disease cohort which could enable the identification of additional susceptibility factors for RA. Most studies to date have focused on adults with RA and on single nucleotide polymorphisms (SNPs). Copy number variants (CNVs), defined as duplications or deletions of DNA sequences, occur extensively throughout the human genome and have the potential to explain larger phenotypic effects than SNPs. We sought to identify CNVs which may influence susceptibility through disruption of genes in children with early onset RA.


Subjects were 13 children with very early onset of RA. The mean age of onset was 8 years (range 2 – 12.8 years). All subjects had at least two positive tests for rheumatoid factor and were positive for antibodies to cyclic citrullinated peptide (anti-CCP). We used a custom-designed oligonucleotide microarray (EmArray Cyto 180K, Agilent Technologies, Santa Clara, CA, USA) to detect CNVs. Following the manufacturer's protocol, DNA isolated from peripheral blood was hybridized to an array containing 180K oligonucleotides, including targeted coverage of known clinically relevant regions and a whole genome backbone with a resolution of ~75 kb. We eliminated common benign CNVs in the population using online databases ( and and our own internal laboratory database.


Three CNVs were identified. The first CNV was a 168-kb loss of chromosome 10, that includes the gene HPSE2 (heparanase 2) which cleaves heparan-sulfate proteoglycans into heparan-sulfate side chains and proteoglycans. Heparanase-2 is also implicated in the extravasation of leukocytes. Another CNV was a 106-kb gain of chromosome 18 involving ROCK1 which encodes a protein kinase that phosphorylates a large number of important signaling proteins, and is involved in regulation of lymphocyte migration. Both these CNVs were not observed in ~11,000 normal individuals in the Database of Genomic Variants (p <0.001 by Fisher's exact test). Both CNVs were confirmed by Affymetrix 6.0 Arrays. A third CNV was a 79.8-kb gain of chromosome 6 which involves HLA-DRB5, a paralog of HLA-DRB1 that is strongly associated with RA. This CNV has been reported previously. Common CNVs not associated with any phenotypes were observed in seven children. We also observed small deletions or gains in some children that were in regions with no relevant genes.


We have identified CNVs potentially associated with childhood presentation of RA. The genes identified are plausible candidates for RA. We are typing additional children with RA for CNVs using a higher density array. These preliminary findings support additional searches for CNVs in children with RA.

To cite this abstract, please use the following information:
Prahalad, Sampath, Mulle, Jennifer Gladys, Dodd, Anne, Prozonic, Jennifer, Brown, Milton, Zeft, Andrew S., et al; Detection of Potentially Disease Associated Copy Number Variants in Children with Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :250
DOI: 10.1002/art.28019

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