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Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.
Burdon, Kathryn P; Fogarty, Rhys D; Shen, Weiyong; Abhary, Sotoodeh; Kaidonis, Georgia; Appukuttan, Binoy; Hewitt, Alex W; Sharma, Shiwani; Daniell, Mark; Essex, Rohan W; Chang, John H; Klebe, Sonja; Lake, Stewart R; Pal, Bishwanath; Jenkins, Alicia; Govindarjan, Gowthaman; Sundaresan, Periasamy; Lamoureux, Ecosse L; Ramasamy, Kim; Pefkianaki, Maria; Hykin, Philip G; Petrovsky, Nikolai; Brown, Matthew A; Gillies, Mark C; Craig, Jamie E.
Affiliation
  • Burdon KP; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia. Kathryn.burdon@utas.edu.au.
  • Fogarty RD; Menzies Institute for Medical Research, University of Tasmania, Private bag 23, Hobart, TAS, 7000, Australia. Kathryn.burdon@utas.edu.au.
  • Shen W; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
  • Abhary S; Save Sight Institute, Clinical Ophthalmology and Eye Health, The University of Sydney, Sydney, NSW, Australia.
  • Kaidonis G; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
  • Appukuttan B; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
  • Hewitt AW; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
  • Sharma S; Centre for Eye Research Australia, University of Melbourne, East Melbourne, VIC, Australia.
  • Daniell M; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
  • Essex RW; Department of Ophthalmology, Royal Melbourne Hospital, Parkville, VIC, Australia.
  • Chang JH; Academic Unit of Ophthalmology, Australian National University, Canberra, ACT, Australia.
  • Klebe S; School of Medical Sciences, University of NSW, Sydney, NSW, Australia.
  • Lake SR; Medical Retina Service, Moorfields Eye Hospital, London, UK.
  • Pal B; Department of Anatomical Pathology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia.
  • Jenkins A; Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
  • Govindarjan G; Medical Retina Service, Moorfields Eye Hospital, London, UK.
  • Sundaresan P; St Vincent's Hospital, Fitzroy, VIC, Australia.
  • Lamoureux EL; Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India.
  • Ramasamy K; Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India.
  • Pefkianaki M; Centre for Eye Research Australia, University of Melbourne, East Melbourne, VIC, Australia.
  • Hykin PG; Department of Population Health, Singapore Eye Research Institute, Singapore, Singapore.
  • Petrovsky N; Retina Clinic, Aravind Eye Hospital, Madurai, Tamil Nadu, India.
  • Brown MA; Medical Retina Service, Moorfields Eye Hospital, London, UK.
  • Gillies MC; Medical Retina Service, Moorfields Eye Hospital, London, UK.
  • Craig JE; Department of Endocrinology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia.
Diabetologia ; 58(10): 2288-97, 2015 Oct.
Article in En | MEDLINE | ID: mdl-26188370
ABSTRACT
AIMS/

HYPOTHESIS:

Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.

METHODS:

Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot.

RESULTS:

The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. CONCLUSIONS/

INTERPRETATION:

Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
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Full text: 1 Database: MEDLINE Main subject: Genetic Predisposition to Disease / Polymorphism, Single Nucleotide / Diabetes Mellitus, Type 2 / Diabetic Retinopathy / GRB2 Adaptor Protein Type of study: Prognostic_studies Limits: Animals / Humans Country/Region as subject: Oceania Language: En Journal: Diabetologia Year: 2015 Type: Article Affiliation country: Australia
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Full text: 1 Database: MEDLINE Main subject: Genetic Predisposition to Disease / Polymorphism, Single Nucleotide / Diabetes Mellitus, Type 2 / Diabetic Retinopathy / GRB2 Adaptor Protein Type of study: Prognostic_studies Limits: Animals / Humans Country/Region as subject: Oceania Language: En Journal: Diabetologia Year: 2015 Type: Article Affiliation country: Australia