A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes

Weihua Meng (Lead / Corresponding author), Kaanan P. Shah, Samuella Pollack, Liro Toppila, Harry Hebert, Mark I McCarthy, Leif C. Groop, Emma Ahlqvist, Valeriya Lyssenko, Elisabet Argardh, Mark Daniell, Georgia Kaidonis, Jamie E Craig, Paul Mitchell, Gerald Liew, Annette Kifley, Jie Jin Wang, Richard A. Jensen, Alan Penman, Heather Hancock & 19 others Ching J. Chen, Adolfo Correa, Jane Z Kuo, Xiaohui Li, Yii-Der Ida Chen, Jerome I. Rotter, Ronald Klein, Barbara E. Klein, Tien Y Wong, Andrew D. Morris, Alexander S. F. Doney, Helen M. Colhoun, Alkes L Price, Kathryn P. Burdon, Per-Henrik Groop, Nina Sandholm, Michael A Grassi, Lucia Sobrin, Colin Palmer

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Abstract

Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.

Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant SNPs were taken forward for meta-analysis using multiple Caucasian cohorts.

Results: 560 cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a P value of 4.05 x 10-9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising P values (P values = 7.41 x 10-8 and 1.23 x 10-8, respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (P=0.003 and 0.007, respectively) while the P value of rs3913535 was not significant (P=0.429).
Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
Original languageEnglish
Pages (from-to)e811-e819
Number of pages9
JournalActa Ophthalmologica
Volume96
Issue number7
Early online date4 Sep 2018
DOIs
Publication statusPublished - 1 Nov 2018

Fingerprint

NADPH Oxidase
Genome-Wide Association Study
Diabetic Retinopathy
Type 2 Diabetes Mellitus
Scotland
Genes
Single Nucleotide Polymorphism
Meta-Analysis
Research
Light Coagulation
Lasers
Genome

Keywords

  • diabetes
  • diabetic complications
  • diabetic retinopathy
  • genome-wide association study
  • NOX4

Cite this

Meng, Weihua ; Shah, Kaanan P. ; Pollack, Samuella ; Toppila, Liro ; Hebert, Harry ; McCarthy, Mark I ; Groop, Leif C. ; Ahlqvist, Emma ; Lyssenko, Valeriya ; Argardh, Elisabet ; Daniell, Mark ; Kaidonis, Georgia ; Craig, Jamie E ; Mitchell, Paul ; Liew, Gerald ; Kifley, Annette ; Wang, Jie Jin ; Jensen, Richard A. ; Penman, Alan ; Hancock, Heather ; Chen, Ching J. ; Correa, Adolfo ; Kuo, Jane Z ; Li, Xiaohui ; Chen, Yii-Der Ida ; Rotter, Jerome I. ; Klein, Ronald ; Klein, Barbara E. ; Wong, Tien Y ; Morris, Andrew D. ; Doney, Alexander S. F. ; Colhoun, Helen M. ; Price, Alkes L ; Burdon, Kathryn P. ; Groop, Per-Henrik ; Sandholm, Nina ; Grassi, Michael A ; Sobrin, Lucia ; Palmer, Colin. / A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes. In: Acta Ophthalmologica. 2018 ; Vol. 96, No. 7. pp. e811-e819.
@article{1d6bc493ba5f4952b996d006299969e5,
title = "A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes",
abstract = "Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant SNPs were taken forward for meta-analysis using multiple Caucasian cohorts.Results: 560 cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a P value of 4.05 x 10-9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising P values (P values = 7.41 x 10-8 and 1.23 x 10-8, respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (P=0.003 and 0.007, respectively) while the P value of rs3913535 was not significant (P=0.429).Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.",
keywords = "diabetes, diabetic complications, diabetic retinopathy, genome-wide association study, NOX4",
author = "Weihua Meng and Shah, {Kaanan P.} and Samuella Pollack and Liro Toppila and Harry Hebert and McCarthy, {Mark I} and Groop, {Leif C.} and Emma Ahlqvist and Valeriya Lyssenko and Elisabet Argardh and Mark Daniell and Georgia Kaidonis and Craig, {Jamie E} and Paul Mitchell and Gerald Liew and Annette Kifley and Wang, {Jie Jin} and Jensen, {Richard A.} and Alan Penman and Heather Hancock and Chen, {Ching J.} and Adolfo Correa and Kuo, {Jane Z} and Xiaohui Li and Chen, {Yii-Der Ida} and Rotter, {Jerome I.} and Ronald Klein and Klein, {Barbara E.} and Wong, {Tien Y} and Morris, {Andrew D.} and Doney, {Alexander S. F.} and Colhoun, {Helen M.} and Price, {Alkes L} and Burdon, {Kathryn P.} and Per-Henrik Groop and Nina Sandholm and Grassi, {Michael A} and Lucia Sobrin and Colin Palmer",
note = "Funding: Wellcome Trust (90532; 98381)",
year = "2018",
month = "11",
day = "1",
doi = "10.1111/aos.13769",
language = "English",
volume = "96",
pages = "e811--e819",
journal = "Acta Ophthalmologica",
issn = "1755-375X",
publisher = "Wiley",
number = "7",

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Meng, W, Shah, KP, Pollack, S, Toppila, L, Hebert, H, McCarthy, MI, Groop, LC, Ahlqvist, E, Lyssenko, V, Argardh, E, Daniell, M, Kaidonis, G, Craig, JE, Mitchell, P, Liew, G, Kifley, A, Wang, JJ, Jensen, RA, Penman, A, Hancock, H, Chen, CJ, Correa, A, Kuo, JZ, Li, X, Chen, Y-DI, Rotter, JI, Klein, R, Klein, BE, Wong, TY, Morris, AD, Doney, ASF, Colhoun, HM, Price, AL, Burdon, KP, Groop, P-H, Sandholm, N, Grassi, MA, Sobrin, L & Palmer, C 2018, 'A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes', Acta Ophthalmologica, vol. 96, no. 7, pp. e811-e819. https://doi.org/10.1111/aos.13769

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes. / Meng, Weihua (Lead / Corresponding author); Shah, Kaanan P.; Pollack, Samuella ; Toppila, Liro; Hebert, Harry; McCarthy, Mark I; Groop, Leif C.; Ahlqvist, Emma; Lyssenko, Valeriya; Argardh, Elisabet; Daniell, Mark ; Kaidonis, Georgia; Craig, Jamie E; Mitchell, Paul; Liew, Gerald; Kifley, Annette ; Wang, Jie Jin; Jensen, Richard A.; Penman, Alan ; Hancock, Heather ; Chen, Ching J.; Correa, Adolfo; Kuo, Jane Z; Li, Xiaohui; Chen, Yii-Der Ida; Rotter, Jerome I.; Klein, Ronald; Klein, Barbara E.; Wong, Tien Y; Morris, Andrew D.; Doney, Alexander S. F.; Colhoun, Helen M.; Price, Alkes L; Burdon, Kathryn P.; Groop, Per-Henrik; Sandholm, Nina; Grassi, Michael A; Sobrin, Lucia; Palmer, Colin (Lead / Corresponding author).

In: Acta Ophthalmologica, Vol. 96, No. 7, 01.11.2018, p. e811-e819.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes

AU - Meng, Weihua

AU - Shah, Kaanan P.

AU - Pollack, Samuella

AU - Toppila, Liro

AU - Hebert, Harry

AU - McCarthy, Mark I

AU - Groop, Leif C.

AU - Ahlqvist, Emma

AU - Lyssenko, Valeriya

AU - Argardh, Elisabet

AU - Daniell, Mark

AU - Kaidonis, Georgia

AU - Craig, Jamie E

AU - Mitchell, Paul

AU - Liew, Gerald

AU - Kifley, Annette

AU - Wang, Jie Jin

AU - Jensen, Richard A.

AU - Penman, Alan

AU - Hancock, Heather

AU - Chen, Ching J.

AU - Correa, Adolfo

AU - Kuo, Jane Z

AU - Li, Xiaohui

AU - Chen, Yii-Der Ida

AU - Rotter, Jerome I.

AU - Klein, Ronald

AU - Klein, Barbara E.

AU - Wong, Tien Y

AU - Morris, Andrew D.

AU - Doney, Alexander S. F.

AU - Colhoun, Helen M.

AU - Price, Alkes L

AU - Burdon, Kathryn P.

AU - Groop, Per-Henrik

AU - Sandholm, Nina

AU - Grassi, Michael A

AU - Sobrin, Lucia

AU - Palmer, Colin

N1 - Funding: Wellcome Trust (90532; 98381)

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant SNPs were taken forward for meta-analysis using multiple Caucasian cohorts.Results: 560 cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a P value of 4.05 x 10-9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising P values (P values = 7.41 x 10-8 and 1.23 x 10-8, respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (P=0.003 and 0.007, respectively) while the P value of rs3913535 was not significant (P=0.429).Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

AB - Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant SNPs were taken forward for meta-analysis using multiple Caucasian cohorts.Results: 560 cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a P value of 4.05 x 10-9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising P values (P values = 7.41 x 10-8 and 1.23 x 10-8, respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (P=0.003 and 0.007, respectively) while the P value of rs3913535 was not significant (P=0.429).Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

KW - diabetes

KW - diabetic complications

KW - diabetic retinopathy

KW - genome-wide association study

KW - NOX4

U2 - 10.1111/aos.13769

DO - 10.1111/aos.13769

M3 - Article

VL - 96

SP - e811-e819

JO - Acta Ophthalmologica

JF - Acta Ophthalmologica

SN - 1755-375X

IS - 7

ER -