A genome-wide association study for sight-threatening diabetic retinopathy in Chinese patients with type 2 diabetes - an Asian Screening Array analysis

Abstract

Background and aims: Diabetic retinopathy (DR) is the most common microvascular complication of type 2 diabetes (T2DM), which if left unchecked, can lead to blindness. Previous genome-wide association studies (GWAS) have identified a number of susceptibility variants showing significant associations with DR in different ethnic groups. However, many of these associations could not be replicated. It has been suggested that the variation in allele frequencies among different populations due to diverse genetic composition may affect the detectability of the risk variants. Therefore, it is important to perform populationspecific association analysis to detect novel population-specific loci for DR. This study aimed to identify the sight-threatening DR (STDR) susceptibility variants in Chinese subjects with T2DM, using an Asian-focused genotyping array. Materials and methods: A GWAS on STDR was conducted by genotyping 750 STDR cases and 750 non-STDR controls of Southern Chinese ancestry, using the newly developed Illumina Infinium Asian Screening Array (ASA). Single variant association analysis was performed on 503,039 single nucleotide polymorphisms (SNPs). Stringent quality control was applied on both sample- and SNP-levels to ensure high quality genotype data. Associations between SNPs and STDR were examined using the multiple logistic regression analysis with adjustment for age, gender, duration of diabetes, haemoglobin A1c (HbA1c), presence of hypertension and the first 5 principal components. Results: The strongest association was detected at ANXA2 rs4775262 (Padjusted=2.28x10-7; OR[95%CI]: 0.56[0.45-0.70]). ANXA2 encodes the cytosolic Ca2+-dependent and phospholipid-binding protein, annexin A2, which has been shown to play a key role in promoting angiogenesis. An Asian-specific variant, rs75545041, of WNT4 (Wnt Family Member 4) also showed a suggestive association with STDR (Padjusted=1.62x10-6; OR[95%CI]: 0.35[0.23-0.54]). This variant is monomorphic in European and African populations but is polymorphic in Asian populations. Dysregulated canonical Wnt signalling has been shown to play a causative role in many human ocular diseases, including DR. Furthermore, we also identified a marginal association at an intronic variant (rs3773643) of TGFBR2 (Padjusted=2.50x10-5; OR[95%CI]: 1.62[1.29-2.02]). TGFBR2 encodes the receptor for the transforming growth factor-beta (TGF-beta). TGF-beta signalling has been implicated in the pathogenesis of DR. Conclusion: We identified a number of novel genetic variants showing suggestive associations with STDR, some of which having potential functional relevance. Our findings have provided novel insights into the genetic architecture of STDR in Chinese patients with T2DM. Further replication studies in independent cohorts to validate our findings are warranted.