Validation of association signals identified from genome-wide association studies of diabetic retinopathy in Chinese patients with type 2 diabetes

Abstract

Objectives Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes mellitus (T2DM). Individuals with a family history of DR show an increased risk of DR development, suggesting that genetic factors play an important role in the pathogenesis of this disease. Some novel genetic susceptibility variants have been identified from several genome-wide association studies (GWAS) conducted in various populations. However, it is unclear whether these DR susceptibility variants would also show an impact in our population. This study aimed to examine the associations of these previously identified single nucleotide polymorphisms (SNPs) with sight-threatening DR (STDR) in Chinese patients with T2DM. Methods Seventy SNPs that showed top association signals (r2<0.9, P<5x10-4) in previous GWAS of DR were examined for their associations with STDR in the current study. These SNPs were genotyped in 3 groups of subjects: 1161 T2DM patients with STDR (STDR cases), 2088 T2DM patients without retinopathy (Non-DR controls), and 1021 healthy controls. The associations between the SNPs and STDR were examined by multiple logistic regression analyses with adjustment for traditional risk factors, e.g. sex, age, body mass index (BMI), duration of diabetes, the presence of hypertension and dyslipidemia, under an additive genetic model. Results: COL5A1 rs59126004 (odds ratio [OR] [95%CI] = 0.82 [0.70-0.95], P=0.009), IGSF21-KLHDC7A rs3007729 (OR [95%CI] = 0.88 [0.78-0.99], P=0.033), LOC728275-LOC728316 rs227455 (OR [95%CI] = 0.89 [0.80-1], P=0.041) and C6orf170 rs17083119 (OR [95%CI] = 0.83 [0.70-0.99], P=0.043) were significantly associated with STDR after adjustment for age, sex, BMI, duration of diabetes, the presence of hypertension and dyslipidemia. These SNPs remained significantly associated with STDR after further adjustment for HbA1c. None of these STDR-associated SNPs showed significant association with T2DM. Conclusions We have successfully confirmed the independent associations of several SNPs reported from previous GWAS of DR in Southern Chinese patients with T2DM. These genetic data may potentially contribute to risk profiling of chronic microangiopathic complications in diabetes management. Acknowledgement This study was supported by the Health and Medical Research Fund of the Food and Health Bureau, HKSAR (Project No. 03144016).