Integrating evidence on the genetic architecture of diabetic retinopathy among Mexican Americans with type 2 diabetes in Starr County, Texas
Diabetic retinopathy is a leading cause of blindness in adults. Several genetic studies have found consistent evidence on familial aggregation of severe diabetic retinopathy. However, genetic factors that explain the heritability are still unknown.^ To elucidate genetic architecture of diabetic retinopathy, this research utilized vast empirical genetic data of Mexican Americans with type 2 diabetes in Starr County Health Studies (1981-2009) with the following aims; 1) to identify common variants associated with severe diabetic retinopathy in 1000 Genomes imputed data on 780 subjects, 2) to identify all variants or genes associated with severe diabetic retinopathy using whole exom sequencing data on 706 subjects, and 3) to identify variants or genes associated with progression of diabetic retinopathy in time-to-event analyses with 1000 Genome imputed data for 526 subjects and whole exom sequencing data for 481 subjects. In analysis, single-variant test and gene-based rare-variant tests were used with logistic (for the first and second aims) and cox regressions (for the third aim).^ We identified 58 genetic loci suggestively associated with severe diabetic retinopathy or progression of diabetic retinopathy. One of the 58 loci (16p13.3) was identified with a novel SNP (rs76148227 on FLYWCH2) passing genome-wide significance (P-value = 1.1 × 10-08) in time-to-event analysis for proliferative diabetic retinopathy. Other than that, 18 out of the 58 loci were previously implicated with diabetic retinopathy susceptibility. And confirmative evidence of genetic susceptibility was found at 4 loci (1p36.12, 2q37.1, 17p11.2, and 18q21.31). ARL4C (2q37.1) and TNFRSF13B (17p11.2) are very likely to be susceptibility genes as these were consistently mapped in current and previous genome-wide association studies of diabetic retinopathy.^ The present findings provide diverse genetic evidence that helps better understanding genetic architecture of diabetic retinopathy. Replication or meta-analysis will be necessary to confirm the findings. Further exploration such as transcriptome or gene expression analysis will be useful to uncover biological mechanisms that are important for treatment and prevention of diabetic retinopathy.^
Kim, Jihye, "Integrating evidence on the genetic architecture of diabetic retinopathy among Mexican Americans with type 2 diabetes in Starr County, Texas" (2016). Texas Medical Center Dissertations (via ProQuest). AAI10182181.