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, Kaanan P. Shah, Samuela Pollack, Iiro Toppila, Harry L. Hebert, Mark I. McCarthy, Leif Groop, Emma Ahlqvist, Valeriya Lyssenko, Elisabet Agardh, Mark Daniell, Georgia Kaidonis, Jamie E. Craig, Paul Mitchell, Gerald Liew, Annette Kifley, Jie Jin Wang, Mark W. Christiansen, Richard A. Jensen, Alan PenmanHeather A. Hancock, Ching J. Chen, Adolfo Correa, Jane Z. Kuo, Xiaohui Li, Yii der I. Chen, Jerome I. Rotter, Ronald Klein, Barbara Klein, Tien Y. Wong, Andrew D. Morris, Alexander S.F. Doney, Helen M. Colhoun, Alkes L. Price, Kathryn P. Burdon, Per Henrik Groop, Niina Sandholm, Michael A. Grassi, Lucia Sobrin, Colin N.A. Palmer, Wellcome Trust Case Control Consortium 2 (WTCCC2), Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group

Research output: Contribution to journalArticlepeer-review


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 Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. Results: Five hundred and sixty 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 × 10−9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10−8 and 1.23 × 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
JournalActa Ophthalmologica
Issue number7
Early online date2018
Publication statusPublished - 2018

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Free keywords

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


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