O69
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 investigate genetic 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’s HumanMethylation 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 ten CpG 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.