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Genetic variation near GRB2 and KCNB2 identified by a genome-wide association
study is reproducibly associated with Diabetic Retinopathy
Kathryn P Burdon, Rhys Fogarty, Nikolai Petrovsky, Mark Gillies, Mark Daniell, Sotoodeh Abhary, Gowthaman Govindarjan, Periasamy Sundaresan, Georgia
Kaidonis, Alicia Jenkins, John Chang, Rohan Essex, Bishwanath Pal, Jamie E Craig
The Eye and Retina
Diabetic Retinopathy Non-Proliferative Retinopathy Proliferative Retinopathy
Normal Macula Macular Edema
Prevalence of Diabetic Retinopathy
* Kempen, J.H., B.J. O'Colmain, M.C. Leske, et al., The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol, 2004. 122:552-63
Study Any DR Sight Threatening DR
BMES 29% 6.4%
MVIP 27.5% 4.3%
AusDiab 22% -
ANNDIAB 30% 7%
Meta-analysis* 40% 8%
Risk Factors Diabetes
duration
Diabetic Retinopathy
High blood
pressure
High cholesterol Smoking Nephropathy
Poor Blood
Sugar Control
Genetics
Genome Wide Association Study for Diabetic Retinopathy
Controls: No DR Cases: DR
Caucasians with medically treated type 2 diabetes for at least 5 years
Cohorts
Discovery and Replication samples
Replication samples
Australia India
United Kingdom
Discovery Cohort
Phenotype N
Controls No DR 654
Any DR
Non-proliferative DR 408
Proliferative DR 224
Macular Edema 330
Sight Threatening 427
Total Participants 1150
Discovery Cohort Characteristics
Cases Controls P-value
Age (yrs) 66.2 ± 10.7 67.0 ± 12.4 0.255
Duration of diabetes (yrs) 18.3 ± 9.1 12.6 ± 7.6 <0.001
% Female 41.1% 47.4% 0.061
BMI (kg/m2) 32.4 ± 7.0 32.2 ± 6.9 0.525
HbA1c (%) 8.4 ±1.7 7.5 ± 1.4 <0.001
Hypertension 86.5 % 77.2% <0.001
Nephropathy 24.2% 11.6% <0.001
Typing and Analysis
• Illumina OmniExpress SNP array
– 617130 SNPs QC
• Data Cleaning
– Removed SNPs with low MAF, poor genotyping or not in HWE
– Remove related individuals (pi-hat>0.3)
– Principal components (Eigenstrat) with removal of ethnic outliers (>6SD from mean)
• Association analysis (PLINK)
– Lambda = 1.02
Any DR
Chr: 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22
-lo
g 10P
-val
ue
2.0x10-8
Sight Threatening DR
4.7x10-8
Chr: 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22
-lo
g 10P
-val
ue
Adjusted for duration of diabetes, HbA1c, nephropathy, hypertension and sex
Replication
rs7839922 Any DR
Chr 17 - rs9896052 Blinding DR
Cohort N
Case/Con Odds Ratio P-value
N Case/Con
Odds Ratio
P-value
GWAS 616/474 1.7 2.01x10-8 335/511 1.94 4.71x10-8
T2 525/300 1.33 0.010 122/226 1.50 0.035
T1 242/126 1.01 0.940 242/126 1.47 0.022
Indian 334/327 0.99 0.905 334/327 1.37 0.005
Cohort
Discovery
T2DM Caucasian
T1DM Caucasian
T2DM Indian
Chr 8 - rs7839922 Any DR
N Case/Con
Odds Ratio
P-value
616/474 1.70 2.01x10-8
525/300 1.33 0.010
242/126 1.01 0.940
334/327 0.99 0.905
GRB2 Function
• Insulin receptor • VEGF receptor • EGF receptor • EPO receptor
Adaptor molecule for receptor tyrosine kinases
GRB2 Function
• Insulin receptor • VEGF receptor • EGF receptor • EPO receptor
Adaptor molecule for receptor tyrosine kinases
Conclusion
• Chr8 (KCNB2) region associated with DR in Caucasian type 2 diabetes
• Chr17 (GRB2) region associated with sight threatening DR in type 1 and type 2 diabetes and multiple ethnicities, independently of other clinical risk factors
• First report of replicated, genome-wide significant loci for DR
Acknowledgements • Flinders University/Flinders
Medical Centre
– Jamie Craig, Rhys Fogarty, Sue Abhary, Emmanuelle Souzeau, Stacey Thorpe, John Chang, Georgia Kaidonis, Kathleen Dowell
• Sydney Eye Hospital
– Mark Gillies, Mila Kolmogorova
• Royal Melbourne Hospital
– Mark Daniell, Fiona Richter
• Canberra Hospital
– Rohan Essex, Jennifer Saarikko
• St Vincents Hospital Melbourne
– Alicia Jenkins
• Centre for Eye Research Australia
– Alex Hewitt
• Moorefields Eye Hospital
– Bishwanath Pal
• Aravind Medical Research Institute, India
– Periasamy Sundaresan, Gowthaman Govindarjan
• Diamantina Institute
– Matthew Brown, Patrick Danoy, Paul Leo
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