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

Abstract

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.

Keywords: Albuminuria; Causal modeling; Genetic epidemiology; Renal function; Type 2 diabetes.

Fig. 1

Observed versus the IV estimated association of T2D with decreased eGFR and increased uACR. In the MR framework, T2D_GRS-T2D association is assumed to be independent of confounders. All the analyses were adjusted for age (years), sex, BMI (kg/m²), current smoking (yes or no), current drinking (yes or no), physical activity (mild, moderate or vigorous), hypertension (yes or no), total cholesterol (mmol/l), HDL-cholesterol (mmol/l), LDL-cholesterol (mmol/l) and triglycerides (mmol/l).

Fig. 2

Associations of IS_GRS and IR_GRS with decreased eGFR and increased uACR IS_GRS: insulin secretion associated genetic risk score; IR_GRS: insulin resistance associated genetic risk score. Data were presented as odds ratios (ORs) and 95% confidence intervals (CIs). P values were calculated from a multivariable logistic regression models after adjustment for age (years), sex, BMI (kg/m²), current smoking (yes or no), current drinking (yes or no), physical activity (mild, moderate or vigorous), hypertension (yes or no), total cholesterol (mmol/l), HDL-cholesterol (mmol/l), LDL-cholesterol (mmol/l) and triglycerides (mmol/l).

Fig. 3

The associations of different GRSs with log-eGFR and log-uACR. Data are presented as regression coefficient (β) and 95% confidence interval (CI). P values were calculated from multivariable linear regression models, after adjustment for age (years), sex, BMI (kg/m²), current smoking (yes or no), current drinking (yes or no), physical activity (mild, moderate or vigorous), hypertension (yes or no), total cholesterol (mmol/l), HDL-cholesterol (mmol/l), LDL-cholesterol (mmol/l) and triglycerides (mmol/l). T2D_GRS: type 2 diabetes genetic risk score; IR_GRS: insulin resistance associated genetic risk score; IS_GRS: insulin secretion associated genetic risks score; eGFR: estimated glomerular filtration rate; uACR: urinary albumin-to-creatinine ratio.

Fig. 4

Sensitivity analysis of the associations of genetically determined T2D with decreased eGFR and increased uACR. Data were presented as odds ratios (ORs) and 95% confidence intervals (CIs). P values were adjusted for age (years), sex, BMI (kg/m²), current smoking (yes or no), current drinking (yes or no), physical activity (mild, moderate or vigorous), hypertension (yes or no), total cholesterol (mmol/l), HDL-cholesterol (mmol/l), LDL-cholesterol (mmol/l) and triglycerides (mmol/l). T2D_GRS: type 2 diabetes genetic risk score; SD: standard deviation. T2D_GRS_{/25 SNP} was calculated from the SNPs after excluding those were out of Hardy–Weinberg equilibrium (rs1801282, rs831571, rs6467136, rs864745, rs13266634, rs89654, rs17584499, rs111187 and rs1552224). T2D_GRS_{/18 SNP} was calculated using the SNPs after excluding those may have potential pleiotropic effects (rs5215, rs4402960, rs1111875, rs243021, rs231362, rs10906115, rs3786897, rs9356744, rs17817449, rs6017317, rs17584499, rs2191349, rs1552224, rs7612463, rs13266634 and rs780094).