Genetic variants affecting mitochondrial function provide further insights for kidney disease

Area of Science:

• Genetics and Genomics
• Nephrology
• Mitochondrial Biology

Background:

• Chronic kidney disease (CKD) is a prevalent global health issue, often driven by diabetes.
• While autosomal genetic variations explain some CKD predisposition, mitochondrial DNA (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) roles remain underexplored.

Purpose of the Study:

• To investigate the association of variations in both mtDNA and NEMG with CKD and related traits.
• To specifically focus on the role of these genetic variations in the context of diabetes.

Main Methods:

• Utilized data from the UK Biobank (UKB) and UK-ROI, an independent cohort of type 1 diabetes mellitus (T1DM) patients.
• Analyzed associations between mitochondrial variants, haplogroups, NEMG, and kidney function markers like estimated glomerular filtration rate (eGFR), serum variables, and end-stage kidney disease (ESKD).

Main Results:

• Identified 14 mitochondrial variants associated with eGFR in UKB.
• Mitochondrial haplogroups U, H, and J showed associations with eGFR and serum variables; haplogroup H was linked to all serum variables irrespective of diabetes status.
• Novel associations were found for NEMG (e.g., SLC39A13, CFL1, ACP2, ATP5G1) with kidney damage and serum variables, and for SLC4A1, NUP210, and MYH14 with ESKD. The TBC1D32-rs113987180 variant increased ESKD risk in diabetic patients.
• In UK-ROI, AGXT2-rs71615838, SURF1-rs183853102, and TFB1M-rs869120 were associated with diabetic nephropathies and eGFR.

Conclusions:

• Discovered novel mtDNA and NEMG variants that may account for unexplained heritability in CKD and kidney phenotypes.
• Confirmed the role of MT-ND5 and mitochondrial haplogroup H in renal disease and identified MT-ND5-rs41535848G and mitochondrial haplogroup X as risk factors for ESKD.
• While most associations were diabetes-independent, NEMG showed potential roles in type 1 diabetes mellitus (T1DM).