Genetic Susceptibility to Chronic Kidney Disease - Some More Pieces for the Heritability Puzzle

Abstract

Chronic kidney disease (CKD) is a major global health problem with an increasing prevalence partly driven by aging population structure. Both genomic and environmental factors contribute to this complex heterogeneous disease. CKD heritability is estimated to be high (30-75%). Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci associated with CKD, including variants in UMOD, SHROOM3, solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and the causal pathways remain incompletely understood; other factors must be contributing to the missing heritability. Less investigated biological factors such as telomere length; mitochondrial proteins, encoded by nuclear genes or specific mitochondrial DNA (mtDNA) encoded genes; structural variants, such as copy number variants (CNVs), insertions, deletions, inversions and translocations are poorly covered and may explain some of the missing heritability. The sex chromosomes, often excluded from GWAS studies, may also help explain gender imbalances in CKD. In this review, we outline recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, sex chromosomes) that typically have received less attention than gene polymorphisms. Shorter telomere length has been associated with renal dysfunction and CKD progression, however, most publications report small numbers of subjects with conflicting findings. CNVs have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis and immunoglobulin A nephropathy. Information on mtDNA biomarkers for CKD comes primarily from case reports, therefore the data are scarce and diverse. The most consistent finding is the A3243G mutation in the MT-TL1 gene, mainly associated with focal segmental glomerulosclerosis. Only one GWAS has found associations between X-chromosome and renal function (rs12845465 and rs5987107). No loci in the Y-chromosome have reached genome-wide significance. In conclusion, despite the efforts to find the genetic basis of CKD, it remains challenging to explain all of the heritability with currently available methods and datasets. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mtDNA and sex chromosomes, hidden heritability in CKD remains elusive, and more comprehensive approaches, particularly through the integration of multiple -"omics" data, are needed.

Keywords: chronic kidney disease; copy number variants; mitochondria; single nucleotide polymorphisms; telomeres; whole exome sequencing.

FIGURE 1

Telomeres and kidney disease. Copyright disclosure: mouse: https://commons.wikimedia.org/wiki/File:Vector_diagram_of_laboratory_mouse_%28black_and_white%29.svg; https://creativecommons.org/licenses/by-sa/4.0/deed.en; attribution, “By Gwilz [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons. Kidney: https://commons.wikimedia.org/wiki/File:Kidney_Cross_Section.png; By Artwork by Holly Fischer [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons.

FIGURE 2

Increased mutation rate in mtDNA have previously been associated with several diseases including various forms of kidney disease. These mutations include point mutations, deletions and single nucleotide polymorphisms. Some of these mutations may result in several pathological phenotypes and these have been highlighted by a solid line between such genes.

FIGURE 3

Genetic variation or altered expression of nuclear genes which encode mitochondrial proteins may impair respiratory chain complex activities leading to an increase in production of reactive oxygen species (ROS). This initiates a negative feedback loop, further reducing mitochondrial function, and ATP production along with an increase in OXPHOS defects and ROS generation leading to increased oxidative stress which may lead to uncontrolled autophagy, mitophagy and further ROS production. Mitochondrial dysfunction, ROS generation and the resulting dysregulation of autophagic mechanisms may also activate intrinsic apoptotic mechanisms resulting in inflammation and fibrosis in the renal tubules, glomerulus and podocytes eventually leading to kidney disease. Red arrows indicate underexpression and green arrows overexpression.