T2DM/CKD genetic risk scores and the progression of diabetic kidney disease in T2DM subjects

• Published in: Gene Vol. 927; p. 148724
• Main Authors: Galuška, David, Pácal, Lukáš, Chalásová, Katarína, Divácká, Petra, Řehořová, Jitka, Svojanovský, Jan, Hubáček, Jaroslav A., Lánská, Věra, Kaňková, Kateřina
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.11.2024
• Subjects: Aged; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetic kidney disease; Diabetic Nephropathies - genetics; Disease Progression; Female; Genetic predisposition; Genetic Predisposition to Disease; Genetic Risk Score; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Risk Factors; Single nucleotide polymorphism; Sphingosine N-Acyltransferase - genetics; eGFR; ESRD; MCVE; T2DM; GWAS; Diabetes mellitus; ACM; Genetic risk score; uACR; Genetic predisposition; CVD; PRS; TG; w/uGRS; UAE; Single nucleotide polymorphism; DKD; CKD; Diabetic kidney disease
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148724

•30 SNPs were determined in a Czech Republic population to create genetic risk score.•WSF1 polymorphism were associated with MCVE and CANCAS1, CERS2 and C9 gene with ACM.•Predictive ability of observed endpoints of genetic and clinical model were compared.•Clinical model lightly improves predictive ability but not statistically significant. This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE − WSF1 (P = 0.029), several variants were associated with ACM − specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487–0.676) and 0.645 (95 % CI 0.556–0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.