Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy

Louis Y El Khoury; Rebecca Rickaby; Tom Samiric; Stuart M Raleigh

doi:10.1016/j.jsams.2017.08.016

Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy

Louis Y El Khoury, Rebecca Rickaby, Tom Samiric, Stuart M Raleigh

Research output: Contribution to journal › Article › peer-review

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Abstract

OBJECTIVES: Patellar tendinopathy (PT) is a debilitating and prevalent condition that tends to affect those who are physically active or engaged in jumping sports. Although tendinopathies are known to have a genetic basis, the role of DNA methylation as an epigenetic factor and risk determinant for human PT has never been described. We sought to determine whether differences existed between the methylation profiles of both the TIMP2 and ADAMTS4 gene promoter sequences in a cohort of males having undergone surgery for patellar tendinopathy compared to controls.

DESIGN: Case-control epigenetic study using DNA from 10 males with PT and 10 males with healthy tendons.

METHODS: We used PCR and targeted pyrosequencing to interrogate the methylation profiles of CpG sites upstream of both the TIMP2 (4 sites) and ADAMTS4 (6 sites) genes. We compared methylation differences between the two groups using t-tests.

RESULTS: We report no significant (p>0.05) methylation differences within the TIMP2 gene promoter between the PT group and controls across the 4 CpG sites investigated. In contrast, we detected a significant (p=0.016) difference in the methylation status of 1 CpG site, approximately 3kb upstream of the ADAMTS4 gene between the PT group and controls.

CONCLUSIONS: To our knowledge, this is the first study to investigate how DNA methylation impacts on the risk of human tendinopathy. Our data indicate that the methylation status of the ADAMTS4 gene is altered in patellar tendinopathy and we speculate on how this change might modify the patellar tendon extra-cellular matrix environment.

Original language	English
Pages (from-to)	378-382
Number of pages	5
Journal	Journal of Science and Medicine in Sport
Volume	21
Issue number	4
Early online date	30 Aug 2017
DOIs	https://doi.org/10.1016/j.jsams.2017.08.016
Publication status	Published - Apr 2018
Externally published	Yes

Bibliographical note

NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Science and Medicine in Sport. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Science and Medicine in Sport, [21, 4, (2018)] DOI: 10.1016/j.jsams.2017.08.016

© 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

ADAMTS4 Protein
Case-Control Studies
CpG Islands
DNA Methylation
Epigenesis, Genetic
Humans
Male
Patellar Ligament
Promoter Regions, Genetic
Tendinopathy
Tissue Inhibitor of Metalloproteinase-2
Journal Article

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10.1016/j.jsams.2017.08.016

Post-PrintAccepted author manuscript, 812 KBLicence: CC BY-NC-ND

http://nectar.northampton.ac.uk/9782/

Stuart Raleigh
- Research Centre for Sport, Exercise and Life Sciences - Associate Professor (Research)
Person: Teaching and Research

Cite this

@article{5e59a2d293ee42b7b9478ba75d7e7764,

title = "Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy",

abstract = "OBJECTIVES: Patellar tendinopathy (PT) is a debilitating and prevalent condition that tends to affect those who are physically active or engaged in jumping sports. Although tendinopathies are known to have a genetic basis, the role of DNA methylation as an epigenetic factor and risk determinant for human PT has never been described. We sought to determine whether differences existed between the methylation profiles of both the TIMP2 and ADAMTS4 gene promoter sequences in a cohort of males having undergone surgery for patellar tendinopathy compared to controls.DESIGN: Case-control epigenetic study using DNA from 10 males with PT and 10 males with healthy tendons.METHODS: We used PCR and targeted pyrosequencing to interrogate the methylation profiles of CpG sites upstream of both the TIMP2 (4 sites) and ADAMTS4 (6 sites) genes. We compared methylation differences between the two groups using t-tests.RESULTS: We report no significant (p>0.05) methylation differences within the TIMP2 gene promoter between the PT group and controls across the 4 CpG sites investigated. In contrast, we detected a significant (p=0.016) difference in the methylation status of 1 CpG site, approximately 3kb upstream of the ADAMTS4 gene between the PT group and controls.CONCLUSIONS: To our knowledge, this is the first study to investigate how DNA methylation impacts on the risk of human tendinopathy. Our data indicate that the methylation status of the ADAMTS4 gene is altered in patellar tendinopathy and we speculate on how this change might modify the patellar tendon extra-cellular matrix environment.",

keywords = "ADAMTS4 Protein, Case-Control Studies, CpG Islands, DNA Methylation, Epigenesis, Genetic, Humans, Male, Patellar Ligament, Promoter Regions, Genetic, Tendinopathy, Tissue Inhibitor of Metalloproteinase-2, Journal Article",

author = "{El Khoury}, {Louis Y} and Rebecca Rickaby and Tom Samiric and Raleigh, {Stuart M}",

note = "NOTICE: this is the author{\textquoteright}s version of a work that was accepted for publication in Journal of Science and Medicine in Sport. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Science and Medicine in Sport, [21, 4, (2018)] DOI: 10.1016/j.jsams.2017.08.016 {\textcopyright} 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ ",

year = "2018",

month = apr,

doi = "10.1016/j.jsams.2017.08.016",

language = "English",

volume = "21",

pages = "378--382",

journal = "Journal of Science and Medicine and Sport",

issn = "1440-2440",

publisher = "Elsevier",

number = "4",

}

TY - JOUR

T1 - Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy

AU - El Khoury, Louis Y

AU - Rickaby, Rebecca

AU - Samiric, Tom

AU - Raleigh, Stuart M

N1 - NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Science and Medicine in Sport. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Science and Medicine in Sport, [21, 4, (2018)] DOI: 10.1016/j.jsams.2017.08.016 © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

PY - 2018/4

Y1 - 2018/4

N2 - OBJECTIVES: Patellar tendinopathy (PT) is a debilitating and prevalent condition that tends to affect those who are physically active or engaged in jumping sports. Although tendinopathies are known to have a genetic basis, the role of DNA methylation as an epigenetic factor and risk determinant for human PT has never been described. We sought to determine whether differences existed between the methylation profiles of both the TIMP2 and ADAMTS4 gene promoter sequences in a cohort of males having undergone surgery for patellar tendinopathy compared to controls.DESIGN: Case-control epigenetic study using DNA from 10 males with PT and 10 males with healthy tendons.METHODS: We used PCR and targeted pyrosequencing to interrogate the methylation profiles of CpG sites upstream of both the TIMP2 (4 sites) and ADAMTS4 (6 sites) genes. We compared methylation differences between the two groups using t-tests.RESULTS: We report no significant (p>0.05) methylation differences within the TIMP2 gene promoter between the PT group and controls across the 4 CpG sites investigated. In contrast, we detected a significant (p=0.016) difference in the methylation status of 1 CpG site, approximately 3kb upstream of the ADAMTS4 gene between the PT group and controls.CONCLUSIONS: To our knowledge, this is the first study to investigate how DNA methylation impacts on the risk of human tendinopathy. Our data indicate that the methylation status of the ADAMTS4 gene is altered in patellar tendinopathy and we speculate on how this change might modify the patellar tendon extra-cellular matrix environment.

AB - OBJECTIVES: Patellar tendinopathy (PT) is a debilitating and prevalent condition that tends to affect those who are physically active or engaged in jumping sports. Although tendinopathies are known to have a genetic basis, the role of DNA methylation as an epigenetic factor and risk determinant for human PT has never been described. We sought to determine whether differences existed between the methylation profiles of both the TIMP2 and ADAMTS4 gene promoter sequences in a cohort of males having undergone surgery for patellar tendinopathy compared to controls.DESIGN: Case-control epigenetic study using DNA from 10 males with PT and 10 males with healthy tendons.METHODS: We used PCR and targeted pyrosequencing to interrogate the methylation profiles of CpG sites upstream of both the TIMP2 (4 sites) and ADAMTS4 (6 sites) genes. We compared methylation differences between the two groups using t-tests.RESULTS: We report no significant (p>0.05) methylation differences within the TIMP2 gene promoter between the PT group and controls across the 4 CpG sites investigated. In contrast, we detected a significant (p=0.016) difference in the methylation status of 1 CpG site, approximately 3kb upstream of the ADAMTS4 gene between the PT group and controls.CONCLUSIONS: To our knowledge, this is the first study to investigate how DNA methylation impacts on the risk of human tendinopathy. Our data indicate that the methylation status of the ADAMTS4 gene is altered in patellar tendinopathy and we speculate on how this change might modify the patellar tendon extra-cellular matrix environment.

KW - ADAMTS4 Protein

KW - Case-Control Studies

KW - CpG Islands

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Humans

KW - Male

KW - Patellar Ligament

KW - Promoter Regions, Genetic

KW - Tendinopathy

KW - Tissue Inhibitor of Metalloproteinase-2

KW - Journal Article

U2 - 10.1016/j.jsams.2017.08.016

DO - 10.1016/j.jsams.2017.08.016

M3 - Article

C2 - 28888475

VL - 21

SP - 378

EP - 382

JO - Journal of Science and Medicine and Sport

JF - Journal of Science and Medicine and Sport

SN - 1440-2440

IS - 4

ER -

Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy

Abstract

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