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 Penman; Heather 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

doi: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

Acta Ophthalmol. 2018 Nov;96(7):e811-e819. doi: 10.1111/aos.13769. Epub 2018 Sep 4.

Authors

Weihua Meng¹, Kaanan P Shah², Samuela Pollack³, Iiro Toppila^{4

5

6}, Harry L Hebert¹, Mark I McCarthy^{7

8

9}, Leif Groop¹⁰, Emma Ahlqvist¹⁰, Valeriya Lyssenko¹⁰, Elisabet Agardh¹⁰, Mark Daniell¹¹, Georgia Kaidonis¹², Jamie E Craig¹², Paul Mitchell¹³, Gerald Liew¹³, Annette Kifley¹³, Jie Jin Wang¹³, Mark W Christiansen¹⁴, Richard A Jensen¹⁴, Alan Penman¹⁵, Heather A Hancock¹⁵, Ching J Chen¹⁵, Adolfo Correa¹⁵, Jane Z Kuo^{16

17}, Xiaohui Li^{17

18}, Yii-der I Chen^{17

18}, Jerome I Rotter^{17

18}, Ronald Klein¹⁹, Barbara Klein¹⁹, Tien Y Wong²⁰, Andrew D Morris²¹, Alexander S F Doney²², Helen M Colhoun²³, Alkes L Price³, Kathryn P Burdon^{12

24}, Per-Henrik Groop^{4

5

6

25}, Niina Sandholm^{4

5

6}, Michael A Grassi²⁶, Lucia Sobrin²⁷, Colin N A Palmer²⁸; Wellcome Trust Case Control Consortium 2 (WTCCC2), Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group¹

Affiliations

¹ Division of Population Health Sciences, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, UK.
² Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
³ Department of Epidemiology, Harvard T.H., Chan School of Public Health, Boston, Massachusetts, USA.
⁴ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
⁵ Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶ Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
⁷ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, UK.
⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁹ Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.
¹⁰ Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmo, Sweden.
¹¹ Department of Ophthalmology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹² Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
¹³ Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney C24, Sydney, Australia.
¹⁴ Cardiovascular Health Research Unit, School of Medicine, University of Washington, Seattle, Washington, USA.
¹⁵ Department of Ophthalmology, University of Mississippi Medical Center, School of Medicine, University of Mississippi, Jackson, Mississippi, USA.
¹⁶ Clinical and Medical Affairs, CardioDx Inc., Redwood City, California, USA.
¹⁷ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
¹⁸ Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
¹⁹ Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
²⁰ Singapore Eye Research Institute, Singapore National Eye Centre, Yong Loo Lin School of Medicine, National University of Singapore, Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore.
²¹ The Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
²² Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, UK.
²³ Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK.
²⁴ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
²⁵ Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
²⁶ Department of Ophthalmology, University of Illinois at Chicago, Chicago, Illinois, USA.
²⁷ Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
²⁸ Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, UK.

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 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.

Keywords: NOX4; diabetes; diabetic complications; diabetic retinopathy; genome-wide association study.

MeSH terms

Adult
Diabetes Mellitus, Type 2 / complications*
Diabetic Retinopathy / etiology
Diabetic Retinopathy / genetics*
Diabetic Retinopathy / surgery
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotyping Techniques
Humans
Laser Coagulation
Male
Middle Aged
NADPH Oxidase 4 / genetics*
Polymorphism, Single Nucleotide*
Scotland
White People / genetics

Substances

NADPH Oxidase 4
NOX4 protein, human

Abstract

MeSH terms

Substances

Grants and funding