TY - JOUR
T1 - Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene
AU - Burdon, Kathryn
AU - Fogarty, Rhys
AU - Shen, Weiyong
AU - Abhary, Sotoodeh
AU - Kaidonis, Georgia
AU - Appukuttan, Binoy
AU - Hewitt, Alex
AU - Sharma, Shiwani
AU - Daniell, Mark
AU - Essex, Rohan
AU - Chang, John
AU - Klebe, Sonja
AU - Lake, Stewart
AU - Pal, Bishwanath
AU - Jenkins, Alicia
AU - Govindarjan, Gowthaman
AU - Sundaresan, Periasamy
AU - Lamoureux, Ecosse
AU - Ramasamy, Kim
AU - Pefkianaki, Maria
AU - Hykin, Philip
AU - Petrovsky, Nikolai
AU - Brown, Matthew
AU - Gillies, Mark
AU - Craig, Jamie
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
UR - http://www.scopus.com/inward/record.url?scp=84942197116&partnerID=8YFLogxK
U2 - 10.1007/s00125-015-3697-2
DO - 10.1007/s00125-015-3697-2
M3 - Article
SN - 0012-186X
VL - 58
SP - 2288
EP - 2297
JO - Diabetologia
JF - Diabetologia
IS - 10
ER -
