Cargando…
Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant
OBJECTIVE: To identify the functional single‐nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene. METHODS: Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joi...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175168/ https://www.ncbi.nlm.nih.gov/pubmed/29732726 http://dx.doi.org/10.1002/art.40545 |
_version_ | 1783361441539031040 |
---|---|
author | Shepherd, Colin Zhu, Dongxing Skelton, Andrew J. Combe, Jennifer Threadgold, Harrison Zhu, Linyi Vincent, Tonia L. Stuart, Paul Reynard, Louise N. Loughlin, John |
author_facet | Shepherd, Colin Zhu, Dongxing Skelton, Andrew J. Combe, Jennifer Threadgold, Harrison Zhu, Linyi Vincent, Tonia L. Stuart, Paul Reynard, Louise N. Loughlin, John |
author_sort | Shepherd, Colin |
collection | PubMed |
description | OBJECTIVE: To identify the functional single‐nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene. METHODS: Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA‐sequencing analysis was used to investigate differential expression of ALDH1A2 and other retinoic acid signaling pathway genes in cartilage. Expression of ALDH1A2 in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription–polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNA interference 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: ALDH1A2 expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several retinoic acid signaling genes was different in diseased cartilage compared to non‐diseased cartilage, with ALDH1A2 showing lower levels in OA cartilage. Experimental depletion of ALDH1A2 resulted in changes in the expression levels of 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. CONCLUSION: The ALDH1A2 locus seems to increase the risk of hand OA through decreased expression of ALDH1A2 in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk. |
format | Online Article Text |
id | pubmed-6175168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61751682018-10-15 Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant Shepherd, Colin Zhu, Dongxing Skelton, Andrew J. Combe, Jennifer Threadgold, Harrison Zhu, Linyi Vincent, Tonia L. Stuart, Paul Reynard, Louise N. Loughlin, John Arthritis Rheumatol Osteoarthritis OBJECTIVE: To identify the functional single‐nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene. METHODS: Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA‐sequencing analysis was used to investigate differential expression of ALDH1A2 and other retinoic acid signaling pathway genes in cartilage. Expression of ALDH1A2 in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription–polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNA interference 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: ALDH1A2 expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several retinoic acid signaling genes was different in diseased cartilage compared to non‐diseased cartilage, with ALDH1A2 showing lower levels in OA cartilage. Experimental depletion of ALDH1A2 resulted in changes in the expression levels of 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. CONCLUSION: The ALDH1A2 locus seems to increase the risk of hand OA through decreased expression of ALDH1A2 in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk. John Wiley and Sons Inc. 2018-08-23 2018-10 /pmc/articles/PMC6175168/ /pubmed/29732726 http://dx.doi.org/10.1002/art.40545 Text en © 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Osteoarthritis Shepherd, Colin Zhu, Dongxing Skelton, Andrew J. Combe, Jennifer Threadgold, Harrison Zhu, Linyi Vincent, Tonia L. Stuart, Paul Reynard, Louise N. Loughlin, John Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant |
title | Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant |
title_full | Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant |
title_fullStr | Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant |
title_full_unstemmed | Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant |
title_short | Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant |
title_sort | functional characterization of the osteoarthritis genetic risk residing at aldh1a2 identifies rs12915901 as a key target variant |
topic | Osteoarthritis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175168/ https://www.ncbi.nlm.nih.gov/pubmed/29732726 http://dx.doi.org/10.1002/art.40545 |
work_keys_str_mv | AT shepherdcolin functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT zhudongxing functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT skeltonandrewj functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT combejennifer functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT threadgoldharrison functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT zhulinyi functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT vincenttonial functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT stuartpaul functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT reynardlouisen functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant AT loughlinjohn functionalcharacterizationoftheosteoarthritisgeneticriskresidingataldh1a2identifiesrs12915901asakeytargetvariant |