Serum Cystatin C and Risk of Diabetic Nephropathy: A Mendelian Randomization Study

Background: Cystatin C, an inhibitor of cysteine protease, has been used as a biomarker for estimating glomerular filtration rate. However, the causal relation between cystatin C and diabetic nephropathy remain uncertain.Method: Utilizing summary-level data from a genome-wide association study (GWAS), we assessed the causal association between cystatin C and diabetic nephropathy by employing Mendelian randomization (MR) analysis. We selected 234 genetic variants as instrumental variables to estimate the causal effects of cystatin C(NGWAS=361194) on diabetic nephropathy (Ncase/Ncontrol up to 3283/210463). Causal estimates were also performed among other five serum biomarkers including KIM-1, GDF-15, TBIL, uric acid, and Scr.Findings: Among the six serum biomarkers, only Cystatin C causally associated with diabetic nephropathy (IVW OR: 1.36, 95%CI [1.15, 1.61]). After adjusting with the potential confounders BMI and SBP, Cystatin C maintained its causal effect on the DN (OR: 1.17, 95%CI [1.02, 1.33]), which means that the incidence of DN increased 17% by an approximate 1 standard deviation (SD) increment of serum Cystatin C level. Two-step MR results also indicated that Cystatin C might mediate the causal effect of BMI on diabetic nephropathy.Interpretation: Our findings discovered that cystatin C was a risk factor for diabetic nephropathy independent of BMI and SBP in diabetes mellitus patients. Future research is required to illustrate the underlying mechanism and prove targeting cystatin C could be a potential therapy method.Funding: AC is supported by grants from the National Natural Science Foundation for Excellent Young Scholars (NO. 82222013) and Natural Science Foundation for Distinguished Young Scholars of Hunan province (2021JJ10075).Declaration of Interest: None to declare.