Identifying gene variants underlying the pathogenesis of diabetic retinopathy based on integrated genomic and transcriptomic analysis of clinical extreme phenotypes

Abstract

Diabetic retinopathy (DR) is a common complication and the leading cause of blindness in patients with type 2 diabetes. DR has been shown to be closely correlated with blood glucose levels and the duration of diabetes. However, the onset and progression of DR also display clinical heterogeneity. We applied whole-exome sequencing and RNA-seq approaches to study the gene mutation and transcription profiles in three groups of diabetic patients with extreme clinical phenotypes in DR onset, timing, and disease progression, aiming to identify genetic variants that may play roles in the pathogenesis of DR. We identified 23 putatively pathogenic genes, and ingenuity pathway analysis of these mutated genes reveals their functional association with glucose metabolism, diabetic complications, neural system activity, and dysregulated immune responses. In addition, ten potentially protective genes were also proposed. These findings shed light on the mechanisms underlying the pathogenesis of DR and may provide potential targets for developing new strategies to combat DR.

Identification of Genetic Variants for Diabetic Retinopathy Risk Applying Exome Sequencing in Extreme Phenotypes

“…After filtering for genes with null alleles in greater than two cases, 44 candidate genes were identified, including rare nonsynonymous variants in FAM132A, SLC5A9, ZNF600, and TMEM217. More recently, Song et al [20] studied 15 subjects covering three extreme phenotypes of T2DM: the early-onset (DR) group (n = 6) included patients who developed DR within a median time of 1 year after the onset of T2DM, the non-DR group (DM; n = 5) included subjects who had no DR at least 10 years after the onset of T2DM, and the lateonset DR group (DM-DR; n = 4) included patients who had the first diagnosis of DR at least 10 years after the onset of T2DM. Through strict filtering (mutation rate difference ≥ 60% among comparison groups), a total of 54 genes were identified to exhibit significant differences.…”

“…To our knowledge, only three studies using exome sequencing for the identification of DR-associated variants have been previously published [18][19][20]. In 2016, Shtir et al [18] analyzed a cohort of 43 diabetics who did not develop DR a decade or more after diagnosis (cases) and 64 diabetics with DR (controls) of Saudi origin; three genes (NME3, LOC728699, and FASTK) reached gene-based genome-wide significance and were considered as candidate DR-protective genes.…”

“…The frequency of variants occurring in at least two individuals in either group, with significant differences between cases and controls, and occurring in a group of 169 genes previously associated with diabetic retinopathy 3 BioMed Research International [18][19][20]24] was compared. Thus, from the 50 candidate genes identified by Song et al [20], we identified 5 variants, located in 5 of such genes (KMT2C, AHNAK2, DNAH10, KIR2DS4, and PAPSS2). From the 43 DR-candidate genes identified by Ung et al [19], 2 variants located in 2 different genes (VPS13B and CFAP74) were identified.…”

“…5). Interestingly, one of the identified variants, c.381 +2_381+3insAAAA in the PAPSS2 gene, has been recently associated with DR in a Chinese cohort [20].…”

“…Recently, exome sequencing (ES) has emerged as a cost-effective strategy for extending these studies to include rare coding variants, which could have more significant functional consequences. To date, a few studies have been performed using ES for the identification of DR-associated variants [18][19][20].…”