Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy

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Abstract

Background

Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes.

Methods

Caucasian Australians with type 2 diabetes were evaluated in a genome-wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non-retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates.

Results

The top ranked SNP for DME was rs1990145 ( p = 4.10 × 10 ^− 6, OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 ( p = 3.87 × 10 ^− 6, OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 ( p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK2 ( p = 0.007) in the PDR cohort.

Conclusion

This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology.

Electronic supplementary material

The online version of this article (10.1186/s12881-018-0587-8) contains supplementary material, which is available to authorized users.

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Most cited references 17

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Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study.

R. Heine, Marjolein Visser, Jacob Seidell … (2003)

The higher risk of type 2 diabetes in persons with a high waist-to-hip ratio (WHR) or waist-to-thigh ratio (WTR) has mostly been attributed to increased visceral fat accumulation. However, smaller hip or thigh circumference may also explain the predictive value of the WHR or WTR for type 2 diabetes. This study considered prospectively the association of hip and thigh circumferences, independent of waist circumference, with the incidence of type 2 diabetes. The Hoorn Study is a population-based cohort study of diabetes. A total of 1357 men and women aged 50-75 y and nondiabetic at baseline participated in the 6-y follow-up examination. Glucose tolerance was assessed by use of a 75-g oral-glucose-tolerance test. Baseline anthropometric measurements included body mass index (BMI) and waist, hip, and thigh circumferences. Logistic regression analyses showed that a 1-SD larger hip circumference gave an odds ratio (OR) for developing diabetes of 0.55 (95% CI: 0.36, 0.85) in men and 0.63 (0.42, 0.94) in women, after adjustment for age, BMI, and waist circumference. The adjusted ORs for a 1-SD larger thigh circumference were 0.79 (0.53, 1.19) in men and 0.64 (0.46, 0.93) in women. In contrast with hip and thigh circumferences, waist circumference was positively associated with the incidence of type 2 diabetes in these models (ORs ranging from 1.60 to 2.66). Large hip and thigh circumferences are associated with a lower risk of type 2 diabetes, independently of BMI, age, and waist circumference, whereas a larger waist circumference is associated with a higher risk.

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Blood pressure, lipids, and obesity are associated with retinopathy: the hoorn study.

H van Leiden, J. M. Dekker, A. Moll … (2002)

To study potential risk factors for retinopathy in diabetic and nondiabetic individuals. The Hoorn Study is a population-based study including 2,484 50- to 74-year-old Caucasians. A subsample of 626 individuals stratified by age, sex, and glucose tolerance underwent extensive measurements during 1989-1992, including ophthalmologic examination and two-field 45-degree fundus photography. The prevalence of (diabetic) retinopathy was assessed among individuals with normal glucose metabolism (NGM) and impaired glucose metabolism (IGM) and individuals with newly diagnosed diabetes mellitus (NDM) and known diabetes mellitus (KDM) (new World Health Organization 1999 criteria). The prevalence of retinopathy was 9% in NGM, 11% in IGM, 13% in NDM, and 34% in KDM. Retinopathy worse than minimal nonproliferative diabetic retinopathy was present in 8% in KDM and 0-2% in other glucose categories. The prevalence of retinopathy was positively associated with elevated blood pressure, BMI, cholesterol, and triglyceride serum levels in all glucose categories. The age-, sex-, and glucose metabolism category-adjusted odds ratios were 1.5 (95% CI 1.2-1.9), 1.3 (1.0-1.7), and 1.3 (1.0-1.6) per SD increase of systolic blood pressure, BMI, and total cholesterol concentration, respectively, and 1.2 (1.0-1.5) per 50% increase of triglyceride level. Elevated blood pressure and plasma total and LDL cholesterol levels showed associations with retinal hard exudates. Retinopathy is a multifactorial microvascular complication, which, apart from hyperglycemia, is associated with blood pressure, lipid concentrations, and BMI.

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A Systematic Meta-Analysis of Genetic Association Studies for Diabetic Retinopathy

Sotoodeh Abhary, Alex Hewitt, Kathryn Burdon … (2009)

OBJECTIVE Diabetic retinopathy is a sight-threatening microvascular complication of diabetes with a complex multifactorial pathogenesis. A systematic meta-analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy. RESEARCH DESIGN AND METHODS All studies investigating the association of genetic variants with the development of diabetic retinopathy were identified in PubMed and ISI Web of Knowledge. Crude odds ratios (ORs) and 95% CIs were calculated for single nucleotide polymorphisms and microsatellite markers previously investigated in at least two published studies. RESULTS Twenty genes and 34 variants have previously been studied in multiple cohorts. The aldose reductase (AKR1B1) gene was found to have the largest number of polymorphisms significantly associated with diabetic retinopathy. The z−2 micro satellite was found to confer risk (OR 2.33 [95% CI 1.49–3.64], P = 2 × 10−4) in type 1 and type 2 diabetes and z+2 to confer protection (0.58 [0.36–0.93], P = 0.02) against diabetic retinopathy in type 2 diabetes regardless of ethnicity. The T allele of the AKR1B1 promoter rs759853 variant is also significantly protective against diabetic retinopathy in type 1 diabetes (0.5 [0.35–0.71], P = 1.00 × 10−4), regardless of ethnicity. These associations were also found in the white population alone (P < 0.05). Polymorphisms in NOS3, VEGF, ITGA2, and ICAM1 are also associated with diabetic retinopathy after meta-analysis. CONCLUSIONS Variations within the AKR1B1 gene are highly significantly associated with diabetic retinopathy development irrespective of ethnicity. Identification of genetic risk factors in diabetic retinopathy will assist in further understanding of this complex and debilitating diabetes complication.

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Author and article information

Contributors

Patricia S. Graham: p.graham@utas.edu.au

Georgia Kaidonis: georgia.kaidonis@gmail.com

Sotoodeh Abhary: sue.abhary@yahoo.com.au

Mark C. Gillies: mark.gillies@sydney.edu.au

Mark Daniell: daniellm@unimelb.edu.au

Rohan W. Essex: Rohan.Essex@act.gov.au

John H. Chang: john.chm@gmail.com

Stewart R. Lake: srlake@gmail.com

Bishwanath Pal: Bishwanath.Pal@moorfields.nhs.uk

Alicia J. Jenkins: alicia.jenkins@ctc.usyd.edu.au

Alex W. Hewitt: hewitt.alex@gmail.com

Ecosse L. Lamoureux: ecosse@unimelb.edu.au

Philip G. Hykin: philhykin@aol.com

Nikolai Petrovsky: nikolai.petrovsky@flinders.edu.au

Matthew A. Brown: matt.brown@qut.edu.au

Jamie E. Craig: jamie.craig@flinders.edu.au

Kathryn P. Burdon:

ORCID: http://orcid.org/0000-0001-8217-1249

Kathryn.Burdon@utas.edu.au

Journal

Journal ID (nlm-ta): BMC Med Genet

Journal ID (iso-abbrev): BMC Med. Genet

Title: BMC Medical Genetics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2350

Publication date (Electronic): 8 May 2018

Publication date PMC-release: 8 May 2018

Publication date Collection: 2018

Volume: 19

Electronic Location Identifier: 71

Affiliations

[1 ]ISNI 0000 0004 1936 826X, GRID grid.1009.8, Menzies Institute for Medical Research, , University of Tasmania, ; Hobart, Tasmania Australia

[2 ]ISNI 0000 0004 0367 2697, GRID grid.1014.4, Department of Ophthalmology, , Flinders University, Flinders Medical Centre, ; Adelaide, South Australia Australia

[3 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Save Sight Institute, Clinical Ophthalmology and Eye Health, , University of Sydney, ; Sydney, New South Wales Australia

[4 ]ISNI 0000 0004 0624 1200, GRID grid.416153.4, Department of Ophthalmology, , Royal Melbourne Hospital, ; Parkville, Victoria Australia

[5 ]ISNI 0000 0001 2180 7477, GRID grid.1001.0, Academic Unit of Ophthalmology, , Australian National University, ; Canberra, Australia

[6 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, School of Medical Sciences, , University of NSW, ; Sydney, New South Wales Australia

[7 ]ISNI 0000 0000 8726 5837, GRID grid.439257.e, Medical Retina Service, , Moorfields Eye Hospital, ; London, UK

[8 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, NHMRC Clinical Trials Centre, , University of Sydney, ; Camperdown, New South Wales Australia

[9 ]ISNI 0000 0000 8606 2560, GRID grid.413105.2, St Vincent’s Hospital, ; Fitzroy, Victoria Australia

[10 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Centre for Eye Research Australia, , University of Melbourne, ; East Melbourne, Victoria Australia

[11 ]ISNI 0000 0001 0706 4670, GRID grid.272555.2, Singapore Eye Research Institute, ; Singapore, Singapore

[12 ]ISNI 0000 0004 0367 2697, GRID grid.1014.4, Department of Endocrinology, , Flinders University, Flinders Medical Centre, ; Adelaide, South Australia Australia

[13 ]ISNI 0000000089150953, GRID grid.1024.7, Institute of Health and Biomedical Innovation, , Queensland University of Technology, ; Brisbane, Australia

Author information

Kathryn P. Burdon http://orcid.org/0000-0001-8217-1249

Article

Publisher ID: 587

DOI: 10.1186/s12881-018-0587-8

PMC ID: 5941644

PubMed ID: 29739359

SO-VID: 1df4f533-678c-4e08-a8a8-5e0391d9d300

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 August 2017

Date accepted : 19 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: 595918

Award ID: 1059954

Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;

Funded by: FundRef http://dx.doi.org/10.13039/501100000923, Australian Research Council;

Award ID: LP0884108

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ScienceOpen disciplines: Genetics

Keywords: genome-wide association study,diabetic retinopathy,macular edema,genetics,diabetes complications

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ScienceOpen disciplines: Genetics

Keywords: genome-wide association study, diabetic retinopathy, macular edema, genetics, diabetes complications

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy

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Genome Engineering using CRISPR

Most cited references 17

Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study.

Blood pressure, lipids, and obesity are associated with retinopathy: the hoorn study.

A Systematic Meta-Analysis of Genetic Association Studies for Diabetic Retinopathy

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