Possible Modifying Effect of Hemoglobin A1c on Genetic Susceptibility to Severe Diabetic Retinopathy in Patients With Type 2 Diabetes

PURPOSE: Glycemic control has been recognized as an important modifiable risk factor for diabetic retinopathy (DR). Whether hemoglobin A1c (HbA1c), as an indicator of glycemic control, could modify the genetic susceptibility to severe DR remains to be investigated. This study aimed to investigate whether HbA1c could modulate the genetic susceptibility to severe DR in Chinese patients with type 2 diabetes. METHODS: A total of 3,093 Chinese individuals with type 2 diabetes were included in the cross-sectional case-control study: 1,051 with sight-threatening DR (STDR) and 2,042 without STDR. Sixty-nine top-ranked single nucleotide polymorphisms (SNPs) identified from previous genome-wide association studies were examined for their associations with STDR and proliferative DR as a subgroup analysis. SNPs showing suggestive associations with DR were examined in the stratified analysis by dichotomized HbA1c (<7% vs. ≥7%). An interaction analysis was performed by including an interaction term of SNP × HbA1c in the regression model. RESULTS: Four SNPs showed suggestive associations with STDR. In the stratified analysis, patients with adequate glycemic control (HbA1c <7%) had a 42% lower risk of STDR for carrying each additional protective C allele of COL5A1 rs59126004 (P = 1.76 × 10(−4); odds ratio, 0.58; 95% confidence interval, 0.44–0.77). rs59126004 demonstrated a significant interaction with dichotomized HbA1c on the risk of STDR (P(interaction) = 1.733 × 10(−3)). In the subgroup analysis for proliferative DR, the protective effect of rs59126004 was even more pronouncedly demonstrated (P = 8.35 × 10(−5); odds ratio, 0.37; 95% confidence interval, 0.22–0.60) and it showed similar interactions with dichotomized HbA1c (P(interaction) = 1.729 × 10(−3)). CONCLUSIONS: Our data provided evidence for possible interactions between HbA1c and COL5A1 rs59126004 on the risk of severe DR. These findings may provide new insight into the pathophysiologic mechanism of DR.