TCF7L2 variation and proliferative diabetic retinopathy

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes, leading to vision loss.
• Genetic factors play a role in PDR development, but specific associations require further investigation.

Purpose of the Study:

• To investigate the genetic association between the TCF7L2 gene variant rs7903146 and PDR in Caucasian type 2 diabetes mellitus (T2DM) patients.
• To explore the functional consequences of this genetic association, including its role in endoplasmic reticulum (ER) stress and VEGFA expression.

Main Methods:

• Genotyping of TCF7L2 rs7903146 in 383 T2DM patients with PDR and 756 T2DM patients without retinopathy.
• In vitro studies using lymphoblastoid cells to assess TCF7L2 and VEGFA mRNA levels under ER stress conditions.
• In vivo studies using a mouse model of oxygen-induced retinopathy to evaluate TCF7L2 and VEGFA expression in retinal tissue.

Main Results:

• The risk allele (T) frequency of TCF7L2 rs7903146 was significantly higher in T2DM patients with PDR compared to those without retinopathy (allelic P = 2.52E-04).
• ER stress induced higher TCF7L2 and VEGFA mRNA levels in cells with the rs7903146-TT genotype.
• Silencing TCF7L2 reduced TCF7L2 and VEGFA mRNA levels, and retinas in a PDR mouse model showed elevated TCF7L2 and VEGFA mRNA.

Conclusions:

• The TCF7L2 rs7903146 variant is associated with PDR in Caucasian T2DM patients.
• TCF7L2 may promote pathological retinal neovascularization in PDR through ER stress-dependent upregulation of VEGFA.