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Prioritization of PLEC and GRINA as osteoarthritis risk genes through the identification and characterization of novel methylation quantitative trait loci.

Arthritis & Rheumatology 2019 Februrary 8
OBJECTIVE: To identify methylation quantitative trait loci (mQTLs) correlating with osteoarthritis (OA) risk alleles and to undertake mechanistic characterization as a means of target gene prioritization.

METHODS: We used genome-wide genotyping and cartilage DNA methylation array data in a discovery screen of novel OA risk loci. This was followed by methylation, gene expression and genotyping studies in additional cartilage samples, accompanied by in-silico analyses.

RESULTS: We identified four novel OA mQTLs. The most significant contains nine CpG sites where methylation correlates with OA risk genotype, with five of the CpGs having P-values < 1x10-10 . The nine CpGs reside in an interval of only 7.7 kb within the PLEC gene and form two distinct clusters. We were able to prioritise PLEC and the adjacent gene GRINA as independent targets of the OA risk. We identified PLEC and GRINA expression quantitative trait loci (eQTL) operating in cartilage and methylation-expression QTLs (meQTLs) operating on the two genes. Both genes also demonstrated differential expression between OA hip and non-OA hip cartilage.

CONCLUSIONS: PLEC encodes plectin, a cytoskeletal protein that maintains tissue integrity by regulating intracellular signalling in response to mechanical stimuli. GRINA encodes the glutamate ionotropic receptor TMBIM3, which regulates cell survival. Based on our results, we hypothesise that in a joint predisposed to OA, expression of these genes alters in order to combat aberrant bio-mechanics and that this is epigenetically regulated. However, carriage of the OA risk-conferring allele at this locus hinders this response and contributes to disease development. This article is protected by copyright. All rights reserved.

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