Dataset Information

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.

SUBMITTER: Xu M

PROVIDER: S-EPMC4856750 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundType 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities.ObjectivesThis study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study.MethodsA 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger.ResultsINS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene.ConclusionsThis study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.