Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

Kathryn P. Burdon, Rhys D. Fogarty, Weiyong Shen, Sotoodeh Abhary, Georgia Kaidonis, Binoy Appukuttan, Alex W. Hewitt, Shiwani Sharma, Mark Daniell, Rohan W. Essex, John H. Chang, Sonja Klebe, Stewart R. Lake, Bishwanath Pal, Alicia Jenkins, Gowthaman Govindarjan, Periasamy Sundaresan, Ecosse L. Lamoureux, Kim Ramasamy, Maria Pefkianaki & 5 others Philip G. Hykin, Nikolai Petrovsky, Matthew A. Brown, Mark C. Gillies, Jamie E. Craig

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

LanguageEnglish
Pages2288-2297
Number of pages10
JournalDiabetologia
Volume58
Issue number10
DOIs
Publication statusPublished - 24 Oct 2015

Keywords

  • Blinding retinopathy
  • Diabetic complications
  • Genetic risk factors
  • Genome-wide association study
  • Müller cell
  • Proliferative retinopathy

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene. In: Diabetologia. 2015 ; Vol. 58, No. 10. pp. 2288-2297.
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title = "Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene",
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.",
keywords = "Blinding retinopathy, Diabetic complications, Genetic risk factors, Genome-wide association study, M{\"u}ller cell, Proliferative retinopathy",
author = "Burdon, {Kathryn P.} and Fogarty, {Rhys D.} and Weiyong Shen and Sotoodeh Abhary and Georgia Kaidonis and Binoy Appukuttan and Hewitt, {Alex W.} and Shiwani Sharma and Mark Daniell and Essex, {Rohan W.} and Chang, {John H.} and Sonja Klebe and Lake, {Stewart R.} and Bishwanath Pal and Alicia Jenkins and Gowthaman Govindarjan and Periasamy Sundaresan and Lamoureux, {Ecosse L.} and Kim Ramasamy and Maria Pefkianaki and Hykin, {Philip G.} and Nikolai Petrovsky and Brown, {Matthew A.} and Gillies, {Mark C.} and Craig, {Jamie E.}",
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Burdon, KP, Fogarty, RD, Shen, W, Abhary, S, Kaidonis, G, Appukuttan, B, Hewitt, AW, Sharma, S, Daniell, M, Essex, RW, Chang, JH, Klebe, S, Lake, SR, Pal, B, Jenkins, A, Govindarjan, G, Sundaresan, P, Lamoureux, EL, Ramasamy, K, Pefkianaki, M, Hykin, PG, Petrovsky, N, Brown, MA, Gillies, MC & Craig, JE 2015, 'Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene', Diabetologia, vol. 58, no. 10, pp. 2288-2297. https://doi.org/10.1007/s00125-015-3697-2

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.

In: Diabetologia, Vol. 58, No. 10, 24.10.2015, p. 2288-2297.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

AU - Burdon, Kathryn P.

AU - Fogarty, Rhys D.

AU - Shen, Weiyong

AU - Abhary, Sotoodeh

AU - Kaidonis, Georgia

AU - Appukuttan, Binoy

AU - Hewitt, Alex W.

AU - Sharma, Shiwani

AU - Daniell, Mark

AU - Essex, Rohan W.

AU - Chang, John H.

AU - Klebe, Sonja

AU - Lake, Stewart R.

AU - Pal, Bishwanath

AU - Jenkins, Alicia

AU - Govindarjan, Gowthaman

AU - Sundaresan, Periasamy

AU - Lamoureux, Ecosse L.

AU - Ramasamy, Kim

AU - Pefkianaki, Maria

AU - Hykin, Philip G.

AU - Petrovsky, Nikolai

AU - Brown, Matthew A.

AU - Gillies, Mark C.

AU - Craig, Jamie E.

PY - 2015/10/24

Y1 - 2015/10/24

N2 - 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.

AB - 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.

KW - Blinding retinopathy

KW - Diabetic complications

KW - Genetic risk factors

KW - Genome-wide association study

KW - Müller cell

KW - Proliferative retinopathy

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