Background: Diabetic kidney disease (DKD) is a microvascular complication of type 2 diabetes (T2D) with significant variability in disease onset and progression. The objective of this study is to evaluate the role of genetic propensity to insulin resistance with kidney disease (KD) in individuals with and without T2D.

Methods: A total of 373,487 unrelated European subjects (5.7% T2D) were selected from the UK Biobank. An insulin resistance polygenic risk score (IR-PRS) was constructed using 18 genome-wide significant SNPs from the latest GWAS for insulin resistance. A T2D-PRS was derived using 277 SNPs. Each PRS was categorized into high (>90thpercentile), mid (10th-90th), and low (< 10th) genetic risk groups. Ten KD phenotypes were constructed using eGFR and/or urine albumin cutoffs. T2D-stratified logistic regression models were run for IR-PRS and KD outcomes, adjusting for principal components, age, sex, education, Townsend Deprivation Index, BMI, hypertension, and statin use; similar models were run for T2D-PRS.

Results: Among T2D, higher IR-PRS was associated with higher odds of DKD (Mid PRS: OR=5.20, 95% CI: 1.28-21.09; High PRS: OR = 4.17, 95% CI: 0.94-18.52; overall p=0.007) and macroalbuminuria (Mid PRS: OR = 2.05, 95% CI:1.12-3.77; High PRS: OR = 1.62, 95% CI: 0.80-3.27; overall p=0.02). Among nondiabetics, higher IR-PRS was associated with higher odds of microalbuminuria (Mid PRS: OR = 1.08, 95% CI: 1.02-1.15; High Risk: OR = 1.15, 95% CI: 1.06-1.25; overall p=0.006) and albuminuria groups (Mid Risk, OR=1.08, 95% CI: 1.01-1.14; High Risk, OR = 1.15, 95% CI: 1.06-1.24; overall p=0.004). No associations were observed with T2D-PRS.

Conclusion: Genetic propensity for insulin resistance is associated with KD or its predisposition among subjects with and without T2D. In contrast, genetic risk of T2D is not associated with KD. Future work will focus on the replication of these results in independent cohorts.

Disclosure

A. C. Garduno: None. E. L. Richard: None. S. Cao: None. V. Thaker: None. R. Salem: None.

Funding

National Heart, Lung, and Blood Institute (1R00HL122515)

© 2021 by the American Diabetes Association
2021
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