Impact of genetic variants identified in genome-wide association studies of diabetic retinopathy in Chinese patients with type 2 diabetes

Abstract

Background: Diabetic retinopathy (DR) is the most common microvascular complication of type 2 diabetes (T2DM). Novel DR-susceptibility loci have been identified from recent genome-wide association studies (GWAS) in various populations. If validated, these genetic markers may be used for risk profiling of DR in diabetic patients. This study aimed to examine the associations of these DR-associated single nucleotide polymorphisms (SNPs) with sight-threatening DR (STDR) in Chinese patients with T2DM. Methods: A total of 68 SNPs showing top association signals with DR (P<5x10-4, r2<0.9) in previous GWAS were genotyped in 3 groups of subjects: 1000 T2DM patients with STDR (STDR-cases), 2000 T2DM patients without retinopathy (non-STDR controls), and 1000 non-diabetic subjects recruited from the general population of Hong Kong (healthy-controls). STDR cases were defined as patients with either proliferative DR (PDR) or pre-PDR, or with clinically significant macular oedema. Multiple logistic regression models with adjustment for confounding factors were employed to examine for the independent association between the SNPs with STDR (STDR cases versus non-STDR controls; and STDR cases versus healthy controls). Results: When the STDR cases were compared with non-STDR controls, significant associations were observed at IGSF21-KLHDC7A rs3007729 (P=0.020; OR[95%CI]:0.86[0.76-0.98]), SLC25A32 rs3098241 (P=0.046; OR[95%CI]:0.88[0.78-1.00]), and COL5A1 rs7861012 (P=0.046; OR[95%CI]:0.88[0.78-1.00]), after adjustment for age, gender, duration of diabetes, hemoglobin A1c (HbA1c) and presence of hypertension. When the STDR cases were compared with healthy controls, significant association between IGSF21-KLHDC7A rs3007729 (P=0.021; OR[95%CI]:0.84[0.73-0.97]) was also detected. BFSP2 rs1197310 (P=3.71x10-3; OR[95%CI]: 1.23[1.07-1.41]), CNTN5 rs10501943 (P=0.022; OR[95%CI]:1.66[1.08-2.57]), FMN1 rs10519765 (P=0.037; OR[95%CI]:0.80[0.64-0.99]), and MAP3K7IP2 rs7772697 (P=0.044; OR[95%CI]:0.84[0.70-0.99]) also demonstrated significant associations with STDR after adjustment for age, sex, HbA1c and presence of hypertension. None of these SNPs were associated with T2DM. Conclusion: We have successfully validated the significant and independent associations of several SNPs identified in previous GWAS with STDR in Chinese patients with T2DM. Acknowledgement: This study was supported by the Health and Medical Research Fund of the Food and Health Bureau, HKSAR (Project No. 03144016). and these genetic data may contribute to risk profiling in future diabetes management.