Novel Genetic Variants identified by Next Generation Sequencing (NGS) in patients “Protected” from Diabetic Retinopathy despite the long duration of diabetes: The DRGen Study

Abstract

Purpose : Glycemic control and diabetes duration are the strongest predictors of the progression of diabetic retinopathy (DR). However, some individuals, despite the long duration of diabetes, do not develop DR or show only mild nonproliferative DR (NPDR). These “extreme” phenotype patients are unlikely to experience further worsening of DR. In this study, using a well-defined phenotypic strategy, we seek to understand better the role of genetic variants that may protect people from developing advanced DR.

Methods : We explored two distinct patient cohorts: Group 1, the "No DR/Very Mild NPDR" cohort despite the long duration of diabetes (>20 years; n =104), and Group 2, the "Proliferative Diabetic Retinopathy" cohort group(n = 170). Ultrawide field retinal images were graded for DR severity at a masked central reading center by ETDRS standard grading protocol. We leveraged the whole genome and exome to define the "protective" genetic factors from the cohort. To test for association between rare or common variants and No DR phenotype, we performed multimarker SNP-set Kernel Association Test (SKAT) analysis. A combined functional prediction (CFP) algorithm was used to evaluate the impact of coding variants in the cohort.

Results : SKAT analysis of “No DR/V.Mild NPDR” (cases) and PDR (control) patients for a total of 15,693 gene sets, including sex and three ancestry principal components as covariates, revealed a statistically significant association between the MTCH2 gene and the extreme phenotype (15,693 gene sets Bonferroni adjusted p = 3.5 x 10^-04). MTCH2 is a mitochondrial protein that regulates cellular metabolism and apoptosis, and its expression has been previously found to be associated with diabetic retinopathy. Analysis based on rare and low-frequency variants highlighted the differential burden of genetic variants between the two groups. Iterative CFP analysis highlighted the enrichment of loss of rare functional variants with likely impact on VEGF and inflammatory pathway activation in the “No DR/V.Mild NPDR” cohort.

Conclusions : Our results suggest several common and rare variants yield novel insights into the genetic architecture of protection against advanced DR. If validated in future studies, protective genetic factors could represent new biomarkers and therapeutics for DR.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.