Session Type: ACR Concurrent Abstract Session
Session Time: 9:00AM-10:30AM
Background/Purpose: Heritability of hand osteoarthritis (OA) has been estimated to be as high as 65%. Despite having a strong genetic component, genome-wide linkage and association studies of hand OA have identified few replicated genetic loci. Other mechanisms such as DNA methylation, which affects gene expression without altering the DNA sequence, may be involved. We therefore aimed to identify differentially methylated loci across the genome that are associated with hand OA.
Methods: Analyses were based on the Framingham Study, a community-based study in the US in which subjects were studied irrespective of OA status. Peripheral blood samples were collected on 2,846 individuals from the second generation cohort. Genomic DNA was extracted from the buffy coat, bisulfite converted, and assayed with the Illumina Infinium Human Methylation450 Beadchip. Standard quality-control procedures were conducted, leaving 2,648 samples and 485,513 CpG probes for analysis. There were 1,261 individuals from this generation cohort without rheumatoid arthritis who obtained bilateral posteroanterior hand radiographs. We derived a summary index score for hand OA by summing semi-quantitative Kellgren-Lawrence (KL) scores at the 2nd-5th distal interphalangeal, 2nd-5th proximal interphalangeal, 1st-5th metacarpophalangeal, thumb interphalangeal, and 1st carpometacarpal joints (possible range=0 to 120). We implemented linear mixed effects regression models to test the effect of a hand OA summary index score on DNA methylation level at each CpG probe. All regression models were adjusted for age, sex, principal components, and estimated cell counts as fixed effects, and familial relationships and chip identifiers as random effects.
Results: A total of 1,073 individuals with hand OA assessments and DNA methylation data were included in the analysis. Mean age was 66±8 years and 57% were women. Mean summary index score for hand OA was 8±12. We applied a conservative Bonferroni correction for ~490,000 probes and identified 7 differentially methylated regions that met genome-wide significance (p<1×10-7), including cg12762517, cg21838477, cg05400732, cg04299389, cg20277504, cg13225177, and cg20205818 (Table 1). Our top finding, cg12762517, is located in PARP3, which catalyzes poly-ADP-ribosylation of nuclear proteins needed for DNA repair and regulation of apoptosis. None of the other findings has been previously associated with hand OA; however, cg0500732 resides within ARHGEF3, a Rho gunanine nucleotide exchange factor that may play a role bone cell biology.
Conclusion: We identified 7 differentially methylated regions associated with hand OA at genome-wide significance. None of these regions has been previously associated with OA, though ARHGEF3 has been implicated in osteoporosis, suggesting that regulation of bone mineral density may play an important role in hand OA pathogenesis.
To cite this abstract in AMA style:Yau MS, Joehanes R, Hsu YH, Kiel DP, Felson DT. Genome-Wide DNA Methylation Association Study of Hand Osteoarthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/genome-wide-dna-methylation-association-study-of-hand-osteoarthritis/. Accessed June 5, 2020.
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