Investigators Link an SNP to Diabetic Retinopathy Protection

August 14, 2020

A single nucleotide polymorphism is associated with severe and proliferative retinopathy risk reduction by 42% and 63%, respectively.

Results from a new study led by investigators at the University of Hong Kong revealed a possible interaction between glycemic control and a single nucleotide polymorphism (SNP) in relation to risk of severe diabetic retinopathy, a global leading cause of blindness.

Recent studies have uncovered a number of risk factors associated with diabetic retinopathy, such as inadequate glycemic control (as per HbA1c), as well as genetic susceptibility. However, there remains a severe shortcoming in robust evidence on associations between risk factors and susceptibility variants. Thus, these findings provide potential novel insight into the pathophysiologic mechanism of severe diabetic retinopathy.

The research team aimed to determine whether HbA1c could have a modulating effect on genetic susceptibility to severe diabetic retinopathy in exclusively Chinese patients with type 2 diabetes. They included 3093 individuals in their cross-sectional case-control study—about half (1051) of the population had sight-threatening diabetic retinopathy.

To assess genetic association with sight-threatening diabetic retinopathy and proliferative diabetic retinopathy as a subgroup analysis, the investigators examined a total of 69 top-ranked SNPs gathered from previous genome-wide association studies. Any SNPS that showed suggestive associations with diabetic retinopathy were further examined in the stratified analysis by dichotomized HbA1C (<7% vs ≥7%).

The investigators found a 42% lower risk of sight-threatening diabetic retinopathy in patients with adequate glycemic control (HbA1c < 7%) and for each protective C allele of the SNP COL5A1 rs59126004 that they carried (OR, 0.58; 95% CI, 0.44–0.77, P = 1.76 × 10−4).

They also noted that SNP showed a significant interaction with dichotomized HbA1c on the risk of sight-threatening diabetic retinopathy (P = 1.733 × 10−3).

Results showed that this protective effect of rs59126004 was even more noticeable for proliferative diabetic retinopathy, the most severe case of the disease—resulting in a 63% risk decrease (OR, 0.37; 95% CI, 0.22–0.60; P = 8.35 × 10−5 ). The effect showed similar interactions with dichotomized HbA1c (P = 1.729 × 10−3).

The team observed that the protective effect was clearly demonstrated in patients with adequate glycemic control; this was not the case in patients with inadequate glycemic control (HbA1c ≥7%).

This lack of observed protection in patients with inadequate glycemic control was observed in both sight-threatening diabetic retinopathy (OR, 1.01; 95% CI, 0.83-1.23; P = 0.893) and proliferative diabetic retinopathy cases (OR, 0.94; 95% CI 0.72-1.25; P = 0.729).

Several limitations of the study included the use of a cross-sectional as opposed to a prospective study design, hence causality could not be established; the lack of including recently reported SNPs; as well as the small sample size. Nonetheless, they acknowledged that a strength of the study to be the well-characterized phenotypes of their participants.

“In conclusion, our data provided supportive evidence for possible interactions between HbA1c and genetic variants on the risk of severe DR in Chinese patients with T2DM,” they wrote. “Our findings may provide novel insight into the pathophysiologic mechanism of DR, which may in turn lead to the design of more effective prevention and treatment strategies.”

The study, “Possible Modifying Effect of Hemoglobin A1c on Genetic Susceptibility to Severe Diabetic Retinopathy in Patients With Type 2 Diabetes,” was published online in IOVS.