Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

Daneil C. Feldmann; Masouda Rahim; Mathijs A.M. Suijkerbuijk; Mary Jessica N. Laguette; Paweł Cieszczyk; Krzysztof Ficek; Kinga Huminska-Lisowska; Charlotte K. Häger; Evalena Stattin; Kjell G. Nilsson; Javier Alvarez-Rumero; Nir Eynon; Julian Feller; Oren Tirosh; Michael Posthumus; Emile R. Chimusa; Malcolm Collins; Alison V. September

doi:10.1002/jor.25192

Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

Daneil C. Feldmann, Masouda Rahim, Mathijs A.M. Suijkerbuijk, Mary Jessica N. Laguette, Paweł Cieszczyk, Krzysztof Ficek, Kinga Huminska-Lisowska, Charlotte K. Häger, Evalena Stattin, Kjell G. Nilsson, Javier Alvarez-Rumero, Nir Eynon, Julian Feller, Oren Tirosh, Michael Posthumus, Emile R. Chimusa, Malcolm Collins, Alison V. September^*

^*Corresponding author for this work

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

6 Citations (Scopus)

Abstract

Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.

Original language	English
Pages (from-to)	1604-1612
Number of pages	9
Journal	Journal of Orthopaedic Research
Volume	40
Issue number	7
Early online date	18 Oct 2021
DOIs	https://doi.org/10.1002/jor.25192
Publication status	Published - Jul 2022

Bibliographical note

Funding Information:
K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011‐69X‐21877‐01‐6, K2014‐99X‐21876‐04‐4), Västerbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL‐358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO‐2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020‐MSCA‐RISE‐2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town.

Funding Information:
K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011-69X-21877-01-6, K2014-99X-21876-04-4), Västerbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL-358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO-2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020-MSCA-RISE-2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town.

Publisher Copyright:
© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.

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10.1002/jor.25192

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Feldmann, D. C., Rahim, M., Suijkerbuijk, M. A. M., Laguette, M. J. N., Cieszczyk, P., Ficek, K., Huminska-Lisowska, K., Häger, C. K., Stattin, E., Nilsson, K. G., Alvarez-Rumero, J., Eynon, N., Feller, J., Tirosh, O., Posthumus, M., Chimusa, E. R., Collins, M., & September, A. V. (2022). Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury. Journal of Orthopaedic Research, 40(7), 1604-1612. https://doi.org/10.1002/jor.25192

@article{5ec90a7a9d764056a24e36c58abc1a31,

title = "Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury",

abstract = "Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.",

author = "Feldmann, {Daneil C.} and Masouda Rahim and Suijkerbuijk, {Mathijs A.M.} and Laguette, {Mary Jessica N.} and Pawe{\l} Cieszczyk and Krzysztof Ficek and Kinga Huminska-Lisowska and H{\"a}ger, {Charlotte K.} and Evalena Stattin and Nilsson, {Kjell G.} and Javier Alvarez-Rumero and Nir Eynon and Julian Feller and Oren Tirosh and Michael Posthumus and Chimusa, {Emile R.} and Malcolm Collins and September, {Alison V.}",

note = "Funding Information: K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011‐69X‐21877‐01‐6, K2014‐99X‐21876‐04‐4), V{\"a}sterbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL‐358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO‐2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020‐MSCA‐RISE‐2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town. Funding Information: K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011-69X-21877-01-6, K2014-99X-21876-04-4), V{\"a}sterbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL-358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO-2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020-MSCA-RISE-2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town. Publisher Copyright: {\textcopyright} 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.",

year = "2022",

month = jul,

doi = "10.1002/jor.25192",

language = "English",

volume = "40",

pages = "1604--1612",

journal = "Journal of Orthopaedic Research",

issn = "0736-0266",

publisher = "Wiley-Blackwell",

number = "7",

}

Feldmann, DC, Rahim, M, Suijkerbuijk, MAM, Laguette, MJN, Cieszczyk, P, Ficek, K, Huminska-Lisowska, K, Häger, CK, Stattin, E, Nilsson, KG, Alvarez-Rumero, J, Eynon, N, Feller, J, Tirosh, O, Posthumus, M, Chimusa, ER, Collins, M & September, AV 2022, 'Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury', Journal of Orthopaedic Research, vol. 40, no. 7, pp. 1604-1612. https://doi.org/10.1002/jor.25192

TY - JOUR

T1 - Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

AU - Feldmann, Daneil C.

AU - Rahim, Masouda

AU - Suijkerbuijk, Mathijs A.M.

AU - Laguette, Mary Jessica N.

AU - Cieszczyk, Paweł

AU - Ficek, Krzysztof

AU - Huminska-Lisowska, Kinga

AU - Häger, Charlotte K.

AU - Stattin, Evalena

AU - Nilsson, Kjell G.

AU - Alvarez-Rumero, Javier

AU - Eynon, Nir

AU - Feller, Julian

AU - Tirosh, Oren

AU - Posthumus, Michael

AU - Chimusa, Emile R.

AU - Collins, Malcolm

AU - September, Alison V.

N1 - Funding Information: K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011‐69X‐21877‐01‐6, K2014‐99X‐21876‐04‐4), Västerbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL‐358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO‐2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020‐MSCA‐RISE‐2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town. Funding Information: K.G.N. is a consultant for Zimmer. Additionally, he received grants from both Zimmer and Link. Also, he is a speaker for Zimmer, Smith&Nephew and DePuy. No further declarations for any of the other authors. This study was funded in part by funds from the National Research Foundation (NRF) of South Africa (Grant: CPRR160426163211) and the University of Cape Town, South Africa. In Sweden, financial support was obtained from the Swedish research Council (Grants Nos. K2011-69X-21877-01-6, K2014-99X-21876-04-4), Västerbotten County Council (Grant No. ALF VLL548501 and Strategic funding VLL-358901; Project No.7002795). For Poland, the study was supported by the National Science Centre of Poland (No. UMO-2016/21/B/NZ7/01068). In Australia, funding was received from the Perpetual Trustees Grant and the Epworth Research Institute Grant. M.A.M.S and M.R were financially supported by the European Union funded project RUBICON H2020-MSCA-RISE-2015–690850, in addition MR was funded by the Harry Crossley Postdoctoral fellowship. D.C.F was funded by the NRF South African Doctoral Scholarship, and in part by the University of Cape Town. Publisher Copyright: © 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.

PY - 2022/7

Y1 - 2022/7

N2 - Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.

AB - Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.

UR - http://www.scopus.com/inward/record.url?scp=85117215269&partnerID=8YFLogxK

U2 - 10.1002/jor.25192

DO - 10.1002/jor.25192

M3 - Article

C2 - 34664319

AN - SCOPUS:85117215269

SN - 0736-0266

VL - 40

SP - 1604

EP - 1612

JO - Journal of Orthopaedic Research

JF - Journal of Orthopaedic Research

IS - 7

ER -

Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

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