Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy
sotoodeh Abhary 1*,
Kathryn P Burdon 2,
Aanchal Gupta 3,
Stewart Lake 2,
Dinesh Selva 3,
Nikolai Petrovsky 4,
and
Jamie E Craig 2
1 Ophthalmology, Flinders University and Flinders Medical Centre, Flinders Drive, BEDFORD PARK, Adelaide, South Australia, 5042, Australia
2 Ophthalmology, Flinders University and Flinders Medical Centre, Adelaide, South Australia, Australia
3 Ophthalmology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
4 Endocrinology, Flinders University and Flinders Medical Centre, Adelaide, South Australia, Australia
* To whom correspondence should be addressed. E-mail: sotoodeh.abhary{at}health.sa.gov.au.
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Abstract |
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Purpose: Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a role in angiogenesis and microvascular permeability. Our aims were to determine if common sequence variation in the VEGFA gene plays a role in the development of diabetic retinopathy (DR).
Method: 554 subjects with diabetes mellitus including 190 type 1 (T1DM) and 364 type 2 diabetes (T2DM) were recruited. The study group consisted of 235 participants without DR, 158 with non-proliferative DR (NPDR), 132 with proliferative DR (PDR) and 93 with clinically significant macular edema (CSME). Blinding DR was defined as severe NPDR, PDR or CSME. Fifteen VEGFA tag single nucleotide polymorphisms (SNPs) were genotyped in all subjects and tested for association with blinding DR.
Results: Multiple tag SNPs in the VEGFA gene were associated with blinding DR. After controlling for sex, HbA1c and duration of disease, in T1DM the AA genotype of rs699946 (p=0.006, OR 4.1, 95% CI 1.5-11.4) and the GG genotype of rs833068 (p=0.009, OR 3.1, 95% CI 1.3-7.2) were most significantly associated. In T2DM, the C allele of rs3025021 (p=0.006, OR 3.8, 95% CI 1.5-10.0) and the G allele of rs833068 (p=0.008 OR 2.6, 95% CI 1.3-5.3) were most significantly associated with blinding DR. Haplotype analyses suggested an important role for the haplotype TCCGCG in blinding DR (p=0.0004).
Conclusion: Sequence variation in the VEGFA gene is associated with risk of developing blinding DR in T1DM and T2DM. Identifying specific genetic markers will allow for refined screening algorithms and earlier intervention in patients at highest risk.
Key Words:
diabetic retinopathy, diabetes mellitus, VEGF, genetic, polymorphism
