Genetic risk factors in mitochondrial DNA associated with diabetic kidney disease – GWAS discovery and meta-analysis

Diabetic kidney disease (DKD) affects ~40% of persons with diabetes and is the leading cause of chronic kidney disease and end-stage renal disease (ESRD) globally. Mitochondrial dysfunction is implicated in the pathophysiology of DKD. Previous research reported SNPs in nuclear genes, which influence mitochondrial function, are significantly associated with DKD. Furthermore, these genetic and functional data prompted further investigation of SNPs affecting mitochondrial function for association with DKD.

Initial analyses were performed using DNA samples from the All Ireland / Warren 3 Genetics of Kidneys in Diabetes UK Collection (UK-ROI) which comprised 1,804 white individuals with T1D, diagnosed before 31 years of age, whose parents and grandparents were born in the British Isles. Genotyping was performed using HumanOmni1-Quad array (n=1,051,295 SNPs directly typed), with data imputed to the Haplotype Reference Consortium for SNPs in mitochondrial DNA (mtDNA, n=225 total SNPs) and 2,526 nuclear-encoded mitochondria genes (NEMGs) (n=2,880,249 total SNPs).

PLINK was used to investigate association with DKD, ESRD and estimated glomerular filtration rate (eGFR) in the UK-ROI with follow-up in up to 19,406 individuals from up to 17 independent collections. The SNP that showed most evidence for association with decreased eGFR after adjusting for covariates was MitoG11915A (P =0.0003) which is a synonymous variant found in the mitochondrial gene MT-ND4. In NEMGs there were 8 SNPs in 4 genes associated with DKD related phenotypes.

In conclusion, mtDNA variants and SNPs in NEMGs are associated with DKD in T1D. Further research is needed to explore the functional impact of these variants.