Type 2 Diabetes, Diabetes Genetic Score and Risk of Decreased Renal Function and Albuminuria: A Mendelian Randomization Study

• A MR study was conducted to explore the causal association between T2D and decreased renal function.
• Weighted T2D genetic risk score (GRS) was used as the instrumental variable (IV).
• A higher T2D_GRS was associated with higher risk of decreased glomerular filtration rate (GFR).
• T2D estimated by the IV may causally associate with risk of decreased renal function in the MR analysis.Epidemiological and clinical studies show that type 2 diabetes (T2D) is a risk factor for dysregulation of kidney function and albuminuria, intensive diabetes treatment was associated with better renal outcomes, suggesting a possible causal link between T2D and renal outcomes. Recently, the Mendelian Randomization (MR) approach using genetic variants as the instrumental variable has been widely used for assessing causality in population studies, because the genetic alleles are allocated randomly during gamete formation and are inherited independent of potential confounding factors and represented as a life-long exposure, which could oppose the bias such as confounding or reverse causation, or short-term intervention. We found that in 11,502 community dwelling Chinese adults, a genetic risk score representing the susceptibility to T2D but not other metabolic traits was significantly associated with decreased renal function, in dependent of obesity, lipids and high blood pressure. These findings for the first time provided novel evidence for a causal relationship between genetically determined T2D and decreased kidney function by using MR.

BackgroundType 2 diabetes (T2D) is a risk factor for dysregulation of glomerular filtration rate (GFR) and albuminuria. However, whether the association is causal remains unestablished.Research Design and MethodsWe performed a Mendelian Randomization (MR) analysis in 11,502 participants aged 40 and above, from a well-defined community in Shanghai during 2011–2013, to explore the causal association between T2D and decreased estimated GFR (eGFR) and increased urinary albumin-to-creatinine ratio (uACR). We genotyped 34 established T2D common variants in East Asians, and created a T2D-genetic risk score (GRS). We defined decreased eGFR as eGFR < 90 ml/min/1.73 m2 and increased uACR as uACR ≥ 30 mg/g. We used the T2D_GRS as the instrumental variable (IV) to quantify the causal effect of T2D on decreased eGFR and increased uACR.ResultsEach 1-standard deviation (SD, 3.90 points) increment in T2D_GRS was associated with decreased eGFR: odds ratio (OR) = 1.18 (95% confidence interval [CI]: 1.01, 1.30). In the MR analysis, we demonstrated a causal relationship between genetically determined T2D and decreased eGFR (OR = 1.47, 95% CI: 1.15, 1.88, P = 0.0003). When grouping the genetic loci according to their relations with either insulin secretion (IS) or insulin resistance (IR), we found both IS_GRS and IR_GRS were significantly related to decreased eGFR (both P < 0.02). In addition, T2D_GRS and IS_GRS were significantly associated with Log-uACR (both P = 0.04).ConclusionOur results provide novel evidence for a causal association between T2D and decreased eGFR by using MR approach in a Chinese population.