Common variants in or near ZNRF1, COLEC12, SCYL1BP1 and API5 are associated with diabetic retinopathy in Chinese patients with type 2 diabetes

Abstract

Aims/hypothesis Three recent genome-wide association studies (GWAS) identified several single-nucleotide polymorphisms (SNPs) with modest effects on diabetic retinopathy in Mexican-American and white patients with diabetes. This study aimed to evaluate the effects of these variants on diabetic retinopathy in Chinese patients with type 2 diabetes. Methods A total of 1,972 patients with type 2 diabetes were recruited to this study, including 819 patients with diabetic retinopathy and 1,153 patients with diabetes of ≥5 years duration but without retinopathy. Forty SNPs associated with diabetic retinopathy in three GWAS were genotyped. Fundus photography was performed to diagnose and classify diabetic retinopathy. Results rs17684886 in ZNRF1 and rs599019 near COLEC12 were associated with diabetic retinopathy (OR 0.812, p=0.0039 and OR 0.835, p=0.0116, respectively) and with the severity of diabetic retinopathy (p=0.0365 and p=0.0252, respectively, for trend analysis). Sub-analysis in patients with diabetic retinopathy revealed that rs6427247 near SCYL1BP1 (also known as GORAB) and rs899036 near API5 were associated with severe diabetic retinopathy (OR 1.368, p=0.0333 and OR 0.340, p=0.0005, respectively). The associations between rs6427247 and rs899036 and severe diabetic retinopathy became more evident after a meta-analysis of published GWAS data (OR 1.577, p=2.01×10 −4 for rs6427247; OR 0.330, p=5.84×10 −7 for rs899036). Conclusions/interpretation We determined that rs17684886 and rs599019 are associated with diabetic retinopathy and that rs6427247 and rs899036 are associated with severe diabetic retinopathy in Chinese patients with type 2 diabetes.

Associations between diabetic retinopathy and systemic risk factors

“…[4][5][6][7][8]10,19,21,22,24,28,30,34,[38][39][40][42][43][44][47][48][49][50][51][52][53] 69 This is consistent with other genome-wide association studies in Caucasian and Mexican-American patients. 70,71 As the relationship between genetic polymorphisms and diabetic retinopathy is still a new and emerging field, some studies have demonstrated new associations between single nucleotide polymorphisms, but these studies have not yet been replicable.…”

“…Investigating the polymorphisms associated with diabetic retinopathy may help us better understand the developmental pathway of diabetic retinopathy and lead to new targeted therapy in treating diabetes and preventing diabetic retinopathy. [69][70][71] rs6427247 near SCYL1BP1 Unmodifiable Positive rs6427247 near SCYL1BP1 positively associated with increased risk of severe diabetic retinopathy [69][70][71] rs899036 near API5 Unmodifiable Positive rs899036 near API5 positively associated with increased risk of severe diabetic retinopathy [69][70][71] …”

Identifying suitable reference genes for gene expression analysis in developing skeletal muscle in pigs

“…The API5 protein suppresses apoptosis induced by the transcription factor E2F1, and interacts with and negatively regulates Acinus, a nuclear factor involved in apoptotic DNA fragmentation. The API5 gene is involved in many human diseases including diabetes and cancers (Cho et al, 2014; Noh et al, 2014; Peng et al, 2015; Ramdas et al, 2011). However, API5 has not been reported to be involved in skeletal muscle development.…”

Unraveling the role of genetics in the pathogenesis of diabetic retinopathy

“…ZNRF1 (Zinc and ring finger 1, E3 ubiquitin protein ligase) is an E3 ubiquitin-protein ligase that mediates the ubiquitination of AKT1 and glutamate-ammonia ligase (GLUL), playing a role in neuronal cell differentiation. ZNRF1 regulates neurodegeneration, maintenance of neuronal transmission, plasticity, and Schwann cell differentiation in DR [62].…”