2077
Biological Aging and Chronic Kidney Disease: Telomere and Mitochondrial Interaction as a Novel Risk Factor
S Duffy1, EJ Swan1, D Vance1, A Douglas1, AP Maxwell1, AJ McKnight1
1: Nephrology Research Group, Centre for Public Health, Queen’s University of Belfast
INTRODUCTION: As the population ages chronic kidney disease (CKD)becomes more prevalent and represents a major burden on the National Health Service. CKD promotes renal senescence, highlighting cellular processes of accelerated ageing as a potential target for disease markers and therapeutic intervention.
Telomere attrition and mitochondrial degradation are both considered key processes in natural ageing. Traditionally studied separately, recent work has revealed a strong inter-relationship between these two pathways. While CKD has previously been associated with shorter telomere length and oxidative damage due to mitochondrial dysfunction, the connection between these two features has not been determined. This study sought to investigategenetic and epigenetic factors influencing telomere and mitochondrial function with CKD.
METHODS: This project had full ethical approval. Associations were investigated for individuals with CKD using a case-control approach. Genotype data for polymorphisms in the nuclear genome that influence mitochondrial or telomere biology was extracted from existing genome-wide association data (n=1829; 2.4 million SNPs). Next generation sequencing of the mitochondrial genome was established using Illumina (n=96 individuals, Illumina Inc, San Diego, USA) or Ion Torrent technologies (n=96, Life Technologies, Warrington, UK). Differences in methylation status for CpG sites in mitochondrial and telomere pathways was extracted from Illumina’sHumanMethylation 27K or 450K Array. Telomere length was established by SYBR green assays on a 7900HT (n=2653 individuals, Life Technologies). Stringent quality control, adjustment for relevant covariates and correction for multiple testing was employed.
RESULTS:Within the mitochondrial genome, there is an excess burden of variants in individuals with CKD. Genetic and epigenetic variations in 1039 nuclear genes known to influence mitochondrial function were examined revealing eight SNPs with significant association across two independent replication cohorts demonstrating consistent direction of effects. Differential methylation at CpG sites in seven genes also reached statistical significance (P<10-8).
SNPs within 376 nuclear genes failed to reach genome-wide significance (P<10-8), however differential methylation at CpG sites in 154 genes were significantly associated with CKD. Of particular interest among top-ranked markers were tenCpG sites in the TERT gene (P<10-12), the enzymatic subunit of telomerase that maintains telomere ends and 72 CpG sites in the MAD1L1 gene (P<10-17), which binds to the TERT promoter and represses telomerase expression. TERT is of particular interest as it is not only crucial in telomere length maintenance but also has a role in biogenesis and protection of mitochondria. Our data suggests that studies evaluating telomere length for association with disease should also consider the influence of genetic and epigenetic contributions on observed, age-related telomere length.
There is an intrinsic relationship between mitochondrial and telomere pathways; this data facilitates determination of a synergistic/cumulative risk between telomeric and mitochondrial profiles associated with CKD.
CONCLUSION: Several biologically relevant markers affecting both mitochondrial and telomere function have been identified that may represent important risk factors for renal senescence, as well as improving our understanding of biological mechanisms that contribute to CKD.