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Lookup NU author(s): Dr Colin Shepherd,
Dr Dongxing Zhu,
Dr Louise Reynard,
Professor John LoughlinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Objective: To identify the functional single nucleotide polymorphisms (SNPs) and mechanisms conferring increased hand osteoarthritis (OA) risk at the ALDH1A2 locus, which is a retinoic acid (RA) regulatory gene. Methods: Tissues from 247 knee, hip or hand OA patients who had undergone joint surgery were included. RNA-sequencing was used to investigate differential expression of ALDH1A2 and other RA signalling pathway genes in cartilage. ALDH1A2 expression in multiple joint tissues was quantified by qPCR. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNAi were assessed in primary human chondrocytes. In silico and in vitro analyses were used to pinpoint which among 62 highly correlated SNPs could account for the association at the locus. Results: We observed ALDH1A2 expression across multiple joint tissues, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several RA signalling genes was different in diseased versus non-diseased cartilage, with ALDH1A2 showing lower levels in OA samples. Experimental ALDH1A2 depletion impacted upon a number of chondrogenic markers, including SOX9. In addition, reduced expression of the OA risk-conferring allele was witnessed in a number of joint tissues, with the strongest effect in cartilage. The intronic SNP rs12915901 recapitulated the AEI observed in patient tissues, while the ETS transcription factors were identified as potential mediators of this effect. Conclusions: The ALDH1A2 locus seems to increase hand OA risk through decreased expression of ALDH1A2 in joint tissues depending on rs12915901, a mechanism that can now be targeted to modulate OA risk.
Author(s): Shepherd C, Zhu D, Skelton AJ, Combe J, Threadgold H, Zhu L, Vincent TL, Stuart P, Reynard LN, Loughlin J
Publication type: Article
Publication status: Published
Journal: Arthritis & Rheumatology
Print publication date: 01/10/2018
Online publication date: 06/05/2018
Acceptance date: 26/04/2018
Date deposited: 06/06/2018
ISSN (print): 2326-5191
ISSN (electronic): 2326-5205
Publisher: John Wiley & Sons, Inc.
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