Genetic variants affecting mitochondrial function provide further insights for kidney disease

Marisa Cañadas-Garre; Blanca Baños-Jaime; Joaquin Maqueda; Laura J. Smyth; Ruaidhri Cappa; Ryan Skelly; Claire Hill; Eoin P. Brennan; Ross Doyle; Catherine Godson; Alexander P.  Maxwell; Amy Jayne McKnight

doi:10.1186/s12864-024-10449-1

Genetic variants affecting mitochondrial function provide further insights for kidney disease

Marisa Cañadas-Garre^*, Blanca Baños-Jaime, Joaquin Maqueda, Laura J. Smyth, Ruaidhri Cappa, Ryan Skelly, Claire Hill, Eoin P. Brennan, Ross Doyle, Catherine Godson, Alexander P. Maxwell, Amy Jayne McKnight

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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Abstract

Background
Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.

Methods
We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.

Results
Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI_95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.

Conclusions
We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

Original language	English
Article number	576
Number of pages	20
Journal	BMC Genomics
Volume	25
DOIs	https://doi.org/10.1186/s12864-024-10449-1
Publication status	Published - 10 Jun 2024

Keywords

Adult
Aged
Association
Chronic kidney disease
DNA, Mitochondrial - genetics
Diabetes Mellitus, Type 1 - genetics - complications
Diabetic kidney disease
Female
Genetic Predisposition to Disease
Genetic Variation
Glomerular Filtration Rate
Haplotypes
Humans
Male
Middle Aged
Mitochondria - genetics
Mitochondrial DNA
Mitochondrial haplogroups
Polymorphism, Single Nucleotide
Renal Insufficiency, Chronic - genetics
Single nucleotide polymorphisms
UK Biobank

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10.1186/s12864-024-10449-1Licence: CC BY

Genetic variants affecting mitochondrial function provide further insights for kidney disease
Copyright 2024 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited
Final published version, 1.8 MBLicence: CC BY

Cite this

@article{1eb216b3ead54ddc8c07e9039bfde2e6,

title = "Genetic variants affecting mitochondrial function provide further insights for kidney disease",

abstract = "BackgroundChronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.MethodsWe used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.ResultsFourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.ConclusionsWe identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.",

keywords = "Adult, Aged, Association, Chronic kidney disease, DNA, Mitochondrial - genetics, Diabetes Mellitus, Type 1 - genetics - complications, Diabetic kidney disease, Female, Genetic Predisposition to Disease, Genetic Variation, Glomerular Filtration Rate, Haplotypes, Humans, Male, Middle Aged, Mitochondria - genetics, Mitochondrial DNA, Mitochondrial haplogroups, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic - genetics, Single nucleotide polymorphisms, UK Biobank",

author = "Marisa Ca{\~n}adas-Garre and Blanca Ba{\~n}os-Jaime and Joaquin Maqueda and Smyth, {Laura J.} and Ruaidhri Cappa and Ryan Skelly and Claire Hill and Brennan, {Eoin P.} and Ross Doyle and Catherine Godson and Maxwell, {Alexander P.} and McKnight, {Amy Jayne}",

year = "2024",

month = jun,

day = "10",

doi = "10.1186/s12864-024-10449-1",

language = "English",

volume = "25",

journal = "BMC Genomics",

issn = "1471-2164",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Genetic variants affecting mitochondrial function provide further insights for kidney disease

AU - Cañadas-Garre, Marisa

AU - Baños-Jaime, Blanca

AU - Maqueda, Joaquin

AU - Smyth, Laura J.

AU - Cappa, Ruaidhri

AU - Skelly, Ryan

AU - Hill, Claire

AU - Brennan, Eoin P.

AU - Doyle, Ross

AU - Godson, Catherine

AU - Maxwell, Alexander P.

AU - McKnight, Amy Jayne

PY - 2024/6/10

Y1 - 2024/6/10

N2 - BackgroundChronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.MethodsWe used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.ResultsFourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.ConclusionsWe identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

AB - BackgroundChronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.MethodsWe used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.ResultsFourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.ConclusionsWe identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

KW - Adult

KW - Aged

KW - Association

KW - Chronic kidney disease

KW - DNA, Mitochondrial - genetics

KW - Diabetes Mellitus, Type 1 - genetics - complications

KW - Diabetic kidney disease

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Glomerular Filtration Rate

KW - Haplotypes

KW - Humans

KW - Male

KW - Middle Aged

KW - Mitochondria - genetics

KW - Mitochondrial DNA

KW - Mitochondrial haplogroups

KW - Polymorphism, Single Nucleotide

KW - Renal Insufficiency, Chronic - genetics

KW - Single nucleotide polymorphisms

KW - UK Biobank

U2 - 10.1186/s12864-024-10449-1

DO - 10.1186/s12864-024-10449-1

M3 - Article

SN - 1471-2164

VL - 25

JO - BMC Genomics

JF - BMC Genomics

M1 - 576

ER -

Genetic variants affecting mitochondrial function provide further insights for kidney disease

Abstract

Keywords

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