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

被引：69

作者：

Burdon, Kathryn P. ^{[1
,2
]}

Fogarty, Rhys D. ^{[1
]}

Shen, Weiyong ^{[3
]}

Abhary, Sotoodeh ^{[1
]}

Kaidonis, Georgia ^{[1
]}

Appukuttan, Binoy ^{[1
]}

Hewitt, Alex W. ^{[4
]}

Sharma, Shiwani ^{[1
]}

Daniell, Mark ^{[5
]}

Essex, Rohan W. ^{[6
]}

Chang, John H. ^{[7
,8
]}

Klebe, Sonja ^{[9
]}

Lake, Stewart R. ^{[1
]}

Pal, Bishwanath ^{[8
]}

Jenkins, Alicia ^{[10
]}

Govindarjan, Gowthaman ^{[11
]}

Sundaresan, Periasamy ^{[11
]}

Lamoureux, Ecosse L. ^{[12
]}

Ramasamy, Kim ^{[13
]}

Pefkianaki, Maria ^{[8
]}

Hykin, Philip G. ^{[8
]}

Petrovsky, Nikolai ^{[14
]}

Brown, Matthew A. ^{[15
]}

Gillies, Mark C. ^{[3
]}

Craig, Jamie E. ^{[1
]}

机构：

[1] Flinders Univ S Australia, Flinders Med Ctr, Dept Ophthalmol, Adelaide, SA 5001, Australia

[2] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas 7000, Australia

[3] Univ Sydney, Save Sight Inst, Clin Ophthalmol & Eye Hlth, Sydney, NSW 2006, Australia

[4] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia

[5] Royal Melbourne Hosp, Dept Ophthalmol, Parkville, Vic 3050, Australia

[6] Australian Natl Univ, Acad Unit Ophthalmol, Canberra, ACT, Australia

[7] Univ NSW, Sch Med Sci, Sydney, NSW, Australia

[8] Moorfields Eye Hosp, Med Retina Serv, London, England

[9] Flinders Univ S Australia, Flinders Med Ctr, Dept Anat Pathol, Adelaide, SA 5001, Australia

[10] St Vincents Hosp, Fitzroy, Vic 3065, Australia

[11] Aravind Med Res Fdn, Dept Genet, Madurai, Tamil Nadu, India

[12] Singapore Eye Res Inst, Dept Populat Hlth, Singapore, Singapore

[13] Aravind Eye Hosp, Retina Clin, Madurai, Tamil Nadu, India

[14] Flinders Univ S Australia, Flinders Med Ctr, Dept Endocrinol, Adelaide, SA 5001, Australia

[15] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia

来源：

DIABETOLOGIA | 2015年 / 58卷 / 10期

基金：

英国医学研究理事会; 澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

Blinding retinopathy; Diabetic complications; Genetic risk factors; Genome-wide association study; Muller cell; Proliferative retinopathy; METAANALYSIS; HERITABILITY; POPULATION; PREVALENCE; SEVERITY;

D O I：

10.1007/s00125-015-3697-2

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. Mothods 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 x 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 x 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 x 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.

引用

页码：2288 / 2297

页数：10

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