7-OR: Causal Associations between Glyoxalase 1 Expression and Kidney Disease in Type 1 Diabetes

Introduction & Objective: Glyoxalase 1 (GLO1) is a crucial enzyme detoxifying methylglyoxal, linked to diabetes and kidney disease. This study aims to unravel link between GLO1 expression and diabetic kidney disease (DKD) in type 1 diabetes using Mendelian randomization (MR).

Methods: The potential causality between GLO1 and DKD was analyzed by two-sample MR. As instrumental variables (IV) we selected cis-expression quantitative trait loci (eQTL) independently associated with GLO1 expression (r²<0.01) in blood, kidney, and other tissues from publicly available datasets (blood: eQTLGen, kidney tissue: Human Kidney eQTL atlas, other tissues: GTEx v8). Serum protein expression data were retrieved from genome-wide association study (GWAS) Catalogue (Study accession: GCST90090884). DKD outcome data were retrieved from JDRF-DNCRI GWAS on DKD, including 19406 individuals with type 1 diabetes, with spectrum of ten DKD definitions based on albuminuria and kidney function.

Results: MR suggested that higher GLO1 mRNA expression (eQTL threshold p<5.0x10^-8) in skin (OR 0.86, [95%CI 0.77 - 0.97], p=0.01, three SNPs) and salivary gland (OR 0.83, [95%CI 0.72 - 0.97], p=0.02, one SNP) were associated with lower risk of chronic kidney disease (CKD). Interestingly, higher GLO1 protein expression (pQTL threshold p<0.05) in blood was associated with CKD (OR 1.43, [95%CI 1.11 - 1.84], p=0.005, 12 SNPs) and two other similar CKD/DKD definitions. No causal associations were observed in kidney-specific tissues or whole blood.

Conclusion: This study supports causality between GLO1 expression and DKD particularly in skin and salivary glands. On contrary, higher GLO1 protein expression was associated with CKD. These data suggest that altered GLO1 expression is involved in altered DKD susceptibility in type 1 diabetes.