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

BACKGROUND: Type 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 METHODS: We 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<90ml/min/1.73m(2) and increased uACR as uACR≥30mg/g. We used the T2D_GRS as the instrumental variable (IV) to quantify the causal effect of T2D on decreased eGFR and increased uACR. RESULTS: Each 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). CONCLUSION: Our results provide novel evidence for a causal association between T2D and decreased eGFR by using MR approach in a Chinese population.